Virtual Library

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    ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      ES06.01 - Recent Advances in Second Line Treatment (Now Available) (ID 3181)

      13:30 - 15:00  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite advances in the treatment of cancer and reductions in smoking rates, lung cancer continues to be one of the leading causes of cancer death worldwide. Over the past decade, a handful of immune-checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) have been shown to improve survival and changes have been made to the standard of care for first-line treatment of patients with non-small cell lung cancer (NSCLC). However, only a minority of patients respond to these treatments and even these patients acquire resistance to the therapy. Continued investigation and research for second-line therapy options are vital to provide treatment options to patients who progress. Master protocols, like LUNGMAP, are efficient trial designs used to quickly and safely investigate new therapies or combinations. LUNGMAP is the first major trial, supported by the National Cancer Institute (U.S.) to simultaneously test multiple treatments under an umbrella design. LUNGMAP was launched in 2014 to investigate new therapies for squamous cell lung cancer, enrolling over 2000 patients. In 2018, the trial underwent a major expansion to include all non-small cell lung cancer patients. Treatments being tested include immunotherapy combinations and targeted therapies that are associated with specific genomic alterations. This allows for the identification of potential biomarkers which can help identify the treatments that would most likely benefit a patient. LUNGMAP is an unprecedented public-private partnership that is more flexible and efficient and will help to speed-up the development process for new lung cancer drugs.

      References:

      RS Herbst et al. Clin Cancer Res. 2015 Apr 1;21(7):1514-24 doi: 10.1158/1078-0432.CCR-13-3473. Epub 2015 Feb 13.

      lung map schema.jpg

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      ES06.02 - What Is the Best Strategy in Progressive Disease After Consolidation with Durvalumanb, or Rapid Progressors to First Line? (Now Available) (ID 3182)

      13:30 - 15:00  |  Presenting Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
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      Abstract

      Immune Check Points Inhibitors (ICIs) have dramatically changed the management of locally advanced and advanced NSCLC patients. While the survival improvement compared to previous standard of care is undoubtable, several patients still progress on or relapse after ICIs. How should these patients be managed?

      To better understand how to manage these patients, we should probably try to better understand the underlying mechanism(s) of resistance to ICIs. Schematically, we can propose three main categories, with primary resistances, occurring early after ICIs initiation, secondary resistances, occurring after a previous response or disease stabilization on ICIs, and follow-up resistances, occurring after stopping ICIs, either per protocol or severe adverse event(s).

      Management of primary resistances to ICIs. Although no validated definition is available, primary resistances might include hyperprogressors and progressors within the first 12- (to 18) weeks of treatment with ICIs. It represents approximately 20 to 30% of stage III NSCLC patients receiving durvalumab after concomitant chemo-radiation, 30% of stage IV patients PD-L1 50% or more NSCLC patients treated with pembrolizumab and 20 to 30% of stage IV patients NSCLC patients treated with a combination of chemotherapy and ICIs.

      Few data are available on the underlying biological mechanisms to explain these primary resistances.

      Considering clinical data of the PACIFIC trial, 41% of patients in the durvalumab arm (without precise characterization of the time or progression) received a subsequent therapy. For the patients who already received durvalumab as a consolidation treatment, 20 patients received a subsequent ICI. The response rate in this case was 0%. With a longer follow, different patients’ profiles will certainly be reported in this setting, with possibly responses to ICIs alone or in combination for patients relapsing a long time after stopping Durvalumab.

      Considering clinical data for stage IV NSCLC patients treated in the first line setting in monotherapy, a recent long term analysis of the Keynote 024 trial. The management of patients with an early progression on Pembrolizumab was not specifically detailed. Globally, 56 out of 154 patients received a subsequent oncologic treatment, mainly chemotherapy.

      Considering clinical data for stage IV NSCLC patients treated in the first line setting with combination of chemotherapy and ICIs, few results are available to date on the management of early progressors.

      Finally, all trials assessing the efficacy of new IO agents or new ICI-based combinations as a rescue treatment after failure of a previous line of ICIs are globally disappointing. A summary of ongoing trials will be presented at the meeting.

      In summary, the best strategy to date for early progressors on ICIs, alone or in combination, unfortunately remains a standard chemotherapy; a participation in a clinical trials should be also discussed giving the efficacy of rescue treatments in this situation.

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      ES06.03 - Future Strategies in Second Line Treatment (Now Available) (ID 3183)

      13:30 - 15:00  |  Presenting Author(s): Gregory J Riely

      • Abstract
      • Presentation
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      Abstract

      With the continued refinement of molecularly targeted therapy and the dramatic changes in initial therapy for patients with newly diagnosed NSCLC without a molecular target, the concept of "second line" therapy has largely become outdated. For the more than one-third of patients who have a targetable oncogenic driver (with aberrations in genes such as EGFR [exon 19 deletion, exon 21 point mutation, or exon 20 insertion], ALK, ROS1, BRAF, RET, MET exon 14, or TRK), multiple lines of targeted therapy are possible prior to receiving a platinum-based combination chemotherapy combination (sometimes with the addition of an anti-PD-1/PD-L1 antibody). In such patients, "second line treatment" could actually be the fifth treatment regimen. Similarly, for patients with PD-L1 that is 50% or greater, the second-line treatment is typically platinum-based doublet chemotherapy. Practically, "second line treatment" is that given after a regimen that contains platinum-based chemotherapy. Despite the difficulties in defining second line treatment, it is an area with critical need for development of new treatments.

      Some new approaches to development of second line therapies are dependent upon a molecular evaluation of the patient’s tumor, typically selecting for targets that are not oncogenic drivers but rather other, non-driver, vulnerabilities found in a patient's tumor. This approach is best exemplified by the Lung MAP (Lung Cancer Master Protocol). This NCI-sponsored trial that began by enrolling only patients with squamous cell lung cancer but now enrolls patients with any NSCLC, uses the results of a comprehensive genomic profiling platform that looks at over 200 cancer-related genes for genomic alterations to assign patients to a genetically matched sub-study or randomize patients to an immunotherapy treatment. Cohorts have included patients with PI3KCA mutations receiving GDC-0032, patients with FGFR amplifications receiving AZD4547, patients with homologous repair deficiency receiving PARP inhibitors, and patients with STK11 alterations receiving talazoparib + avelumab. Critically, this trial uses staged evaluation of an arm to minimize the number of patients treated with relatively ineffective therapies.

      There is a great deal of interest in identifying new immunologic approaches for patients with NSCLC who have progressed after initial treatment with anti-PD-1/PD-L1 therapy. These approaches include the exploration of antibodies against such targets as the T-cell inhibitory receptor Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) or small molecule inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in tryptophan catabolism alone or in combination with anti-PD-1 or PD-L1 antibodies. Beyond this, there are attempts to improve the efficacy of single-agent anti-PD-1 antibodies by adding MEK inhibitors. Building off great successes in hematologic malignancies, there are new effort that seek to use cell-based therapies in patients with solid tumors. These include clinical trials of autologous T-cells that have been transduced with vectors expressing T-cell receptors against such targets as NY-ESO-1 and LAGE-1a for patients with NSCLC as well as trials exploring ex vivo expansion of tumor infiltrating lymphocytes.

      Treatment of patients who have progressed on available targeted therapies as well as platinum-based chemotherapies remains a notable challenge, with current treatments having limited activity. While none have yet proven effective, there are a broad array of treatments under study, whether using targeted therapies, chemotherapy combinations, or immunologic approaches.

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      ES06.04 - The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt (Now Available) (ID 3184)

      13:30 - 15:00  |  Presenting Author(s): Juergen Wolf

      • Abstract
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      Abstract

      The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt

      Jürgen Wolf

      Most current guidelines recommend molecular testing of activating alterations in EGFR, ALK, ROS1 and BRAF before first line treatment decision in advanced NSCLC. These recommendations mostly are based on the approval status of the respective targeted therapies. For the remaining patients combinations of immunecheckpoint inhibitor (ICI) therapy and platinum-based chemotherapy (CT) has become standard for patients with a PD-L1 tumor proportion score (TPS) of below 50% and may also be used for patients with a higher score in case of aggressive tumor growth and good performance score (PS). Patients with a TPS of 50% and more may be treated with ICI alone. Tumor mutational burden (TMB) is currently evaluated as new predictive marker for either ICI mono- or combination therapy, the definitive value of this approach in first or second line so far, however, is still unclear.

      If these (EGFR-, ALK-, ROS1-, BRAF wildtype) patients relapse after ICI monotherapy, platinum-based CT, eventually with the addition of bevacizumab, widely is considered standard treatment. By comparison, for patients with relapse after ICI/CT combination systemic treatment options are quite unsatisfying. Docetaxel monotherapy has only marginal efficacy which may be modestly increased by the addition of antiangiogenic agents. Numerous immunotherapeutic approaches are evaluated In this situation (next generation ICIs and other immunomodulatory drugs), preferably in combinations. However, so far, no convincing results have been reported from these clinical trials.

      It is therefore particularly important to identify from these patients the subgroup with a possible benefit from driver-mutation directed treatments – either within a clinical trial or a compassionate use program or as off-label treatment. Numerous such approaches are in clinical evaluation. Examples are kinase inhibitors against RET-fusions, TRK-fusions, MET exon 14 skipping mutations, MET amplification, HER2 mutations, EGFR-/HER2 exon 20 mutations, NRG-1 fusions. High response rates and clinical significant duration of responses have already been reported for many of these personalized treatment options, some of them are already in accelerated approval procedures. Many of them will forge ahead towards first line treatment in particulary, since ICI therapy partly seems not to work well here.

      Until the approval of these new treatment options it is of particular importance to test patients at the latest upon failure of ICI with or without chemotherapy on the presence of driver mutations in their tumors and to try hard to bring them into a clinical trial or to enable off-label treatment.

      Given the dynamics in the field, this treatment algorithm will change in the near future not only by the approval of several of these new driver-mutation directed treatments, but also by the development of more effective and more tailored immunotherapies as well as by the availability of potent KRAS inhibitors.

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    ES13 - Global Political, Legal, and Financial Strategies For Tobacco Control (ID 16)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Prevention and Tobacco Control
    • Presentations: 5
    • Now Available
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      ES13.01 - Tobacco Cessation and Cancer Patients (Now Available) (ID 3224)

      15:15 - 16:45  |  Presenting Author(s): Esteve Fernandez  |  Author(s): Cristina Martínez

      • Abstract
      • Presentation
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      Abstract

      Smoking among cancer patients reduces the effectiveness of treatment, increases the risk of recurrence, and reduces survival time. One third of cancer patients continue smoking after diagnosis or during their treatment. Smoking is also common in patients with a cancer for which there is limited evidence for carcinogenicity of tobacco smoking. Cancer patients who smoke have greater risks, not only of the well known tobacco-related health problems, such as cardiovascular and respiratory diseases and further cancers, but also unfavourable cancer treatment outcomes. There is sufficient evidence to infer a causal relationship between cigarette smoking and adverse health outcomes, including all-cause mortality, cancer-specific mortality and further primary tobacco-related cancers among cancer patients. Poorer cancer treatment outcomes linked to tobacco use by cancer patients re related to altered cancer biology, altered drug metabolism, increased treatment-related complications, and increased tobacco-related comorbidity.

      Although smoking cessation is associated with better outcomes, this key and cost-effective preventive strategy is rarely addressed in health care services. Barriers to incorporating tobacco cessation interventions into hospitals include lack of knowledge, expertise, time, and organizational constraints. In addition, many cancer patients show higher rates of nicotine dependence, low self-efficacy, and higher levels of depression.

      The existing data support the conclusion that continued smoking negatively affects cancer treatment outcomes including survival, recurrence and quality of life and that, by quitting smoking, patients with cancer have the potential to improve their cancer treatment outcomes. At the population-level, there is a need to establish a basic infrastructure to provide tobacco cessation services to cancer patients who smoke, sustainable funding should be identified and allocated to dedicated tobacco cessation services (e.g. quitlines, available treatment for tobacco cessation) as well as tobacco treatment training programmes for health-care providers. At the individual-level, motivational interventions addressed to recognize the cancer-specific risks of smoking do increase patients’ self-efficacy in quitting. Morover, cessation using the "5 A’s model" provides good abstinence rates, and about 80% of smokers could be reached using this approach.

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      ES13.02 - Pursuing Criminal Charges Against Big Tobacco (Now Available) (ID 3225)

      15:15 - 16:45  |  Presenting Author(s): Wanda De Kanter

      • Abstract
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      Abstract

      Abstract 1

      Court of appeal rejects charges made against tobacco industry-

      The Court of Appeal in The Hague has declined to instruct the Netherlands Public Prosecution Service to bring criminal charges against cigarette manufacturers. The court concluded that it is up to the government, not the judiciary, to tackle the rigging of cigarettes. In other words, it’s the government’s move.

      On December 6th, 2018 the Court of Appeal in The Hague delivered its verdict in the proceedings brought by criminal lawyer Bénédicte Ficq on behalf of various individual complainants and a large number of legal entities who previously lodged complaints against cigarette manufacturers. Last February the Public Prosecution Service (OM) decided not to instigate legal proceedings, prompting the complainants to instigate an Article 12 procedure in an effort to force the OM to prosecute.

      In its verdict, the court writes that “the products of cigarette manufacturers are made and tested in accordance with stringent Dutch and European legislation and regulations. As long as the cigarette manufacturers respect these European and national rules, the member states must respect these rules and cannot prohibit the sale of cigarettes. Radical measures against cigarette manufacturers can only be taken by the European regulator.”

      In her reaction, lawyer Bénédicte Ficq draw attention to the significance of the court’s comment, in its detailed motivation, that cigarette manufacturers deliberately market a deadly and harmful product with the sole objective of making money.

      The court writes: “The fact that smoking is harmful to your health, is a serious health risk, can cause serious illness and even death, and is moreover highly addictive, can in the opinion of the court be considered general knowledge and is not disputed by the defendants. The defendants supply cigarettes that they know are or can be addictive and harmful to the health of active and passive smokers. The court assumes that the defendants act with the aim of making a profit
      Here the lawyers note the similarities with verdicts reached against cocaine and heroin dealers. Ficq: “The court could have avoided making these remarks, but has instead chosen to make clear that there is a social evil that the court is powerless to address. In other words, the ball is in the government’s court.”

      Legislator must intervene

      In its conclusion the court expresses it very clearly once again: “Complainants have chosen to address a social problem concerning public health within a criminal framework. However, the court agrees with the Public Prosecution Service that criminal law offers no solution. Radical measures such as banning the production and sale of tobacco, which is produced in accordance with the legal directives, can only be taken by the legislator. The ultimate goal of the complainants, to ban cigarettes cannot be achieved through criminal law. It will instead have to involve an appeal to the European legislator.”

      Conclusion: . “The court recognizes the scale of the social problem and the fact that cigarettes are extremely addictive and deadly, and should actually be banned, but it’s up to the government to take action. That strengthens us in our demand that the Netherlands Food and Consumer Product Safety Authority and the government must take measures to tackle the phenomenon of ‘rigged cigarettes’

      We feel as if we have ended up in a Kafkaesque situation in which it is patently obvious that cigarettes with holes in their filters release more toxic substances than legally allowed. But the legally prescribed smoking machines measure different levels, so cigarettes in their present form are permitted. Those responsible for passing legislation must now change this situation, especially since we’ve know that ‘rigged cigarettes’ cause more lung cancer. Time for government action!”

      ABSTRACT 2

      Tobacco Industry: first we fix the law, then we abide by it

      A little-known issue is the way that the tobacco industry has succeeded, over the years, in bending the implementation of anti-smoking laws to its own will. After all, in violation of all international laws, it exerts a strong influence on how the State determines emission values for cigarette smoke. As a result of that interference, the margins for enforcing the law are far too wide.

      According to Dutch law, every three years cigarette manufacturers must show the government how much tar, nicotine and carbon monoxide (TNCO) their cigarettes contain. These levels are controlled by the National Institute for Public Health and the Environment (RIVM). The RIVM then sends the results to the Dutch Food and Consumer Product Safety Authority (NVWA). If the legally set limits are exceeded, the NVWA must act. It must enforce the law.
      Those legal norms are unequivocally determined in the Law on Tobacco and Smoking Products. A cigarette may emit a maximum of 10 mg tar, 1 mg nicotine and 10 mg carbon monoxide. A smoker may not inhale more poison than that. The law also determines how levels are measured and the margins within which the legal norms must be met.

      However, the margins determined by law are very wide: 20% for tar and nicotine and 25% for carbon monoxide. This means that a cigarette with 12 mg tar (instead of 10), 1.2 mg nicotine (instead of 1) and 12.5 mg carbon monoxide (instead of 10) is still permissible. The NVWA will only intervene above those levels. The literature tells us that maximum margins of 10% are more than enough to conceal variations in measured levels.

      In developing and determining the measurements, the government has — following the example of the European lawmaker — used the services of two private organizations: the Netherlands Normalization Institute (NEN) and the International Organization for Standardization (ISO). These organizations consist entirely of representatives from the cigarette industry. The chairperson himself comes from Philip Morris.

      If you examine the explanation that accompanies the legal article, it turns out that the legal emission margins are statistically baseless. “The conclusions within the report are based on practical experience of verifying these measurements in a number of different marketplaces underpinned by a theoretical consideration of the sources of statistical variation.” (NEN-ISO 8243.2013, IDT)

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      ES13.03 - Foundation for a Smoke Free Future: Funding Opportunities or Smoke Screen for the Tobacco Industry? (Now Available) (ID 3226)

      15:15 - 16:45  |  Presenting Author(s): Emily Stone

      • Abstract
      • Presentation
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      Abstract

      The tobacco industry has long sought interactions with the health and medical communities that will enhance its legitimacy and augment profits. In the early 20thcentury, advertising involved the medical community emphasizing doctors who recommended cigarette smoking. From the mid 20thcentury, as scientific evidence developed, the tobacco industry contested restrictions vigorously as tobacco regulation intensified. The advent of ENDS products opened a new phase in marketing which stretched the limits of conventional tobacco control. The PMI Foundation, launched in 2017, targets the health and medical communities, promising research funding, the “Smoke-Free” aim and its interactions with high profile researchers. In the first few decades of the 20thcentury, tobacco companies involved physicians in advertising campaigns to promote health benefits and minimisation strategies for particular brands. Analysis of 1930s and 40s tobacco advertising in medical journals identified a number of strategies employed to involve doctors in promoting cigarettes including flattery, tobacco ‘science’, the advisory role to patients, less “irritating” brands and promotion of specific brands1. Analysis of tobacco advertising from the 1920s to the 1950s identified a focus on throat irritation, strategies to protect from harmful symptoms and portrayal of otorhinolaryngologists as promoters of cigarette-related benefits2. The “More Doctors smoke Camels” campaign3launched in the late 1940s by RJ Reynolds made a number of zealous health benefit claims, although landmark publications linking tobacco cigarettes to lung cancer led to scepticism from the health community and eventual banning of cigarette advertising and promotion in medical journals and at medical conventions3.

      From the mid-1960s, the paradigm for tobacco regulation shifted as evidence accumulated for the harmful effects. Additional key papers include a 1912 monograph, one of the first publications to link lung cancer with tobacco, early writings on lung cancer surgery and the 1964 US Surgeon General Report on Smoking and Health. Legislative efforts to control tobacco accelerated with, in the United States, the pivotal 1998 Master Settlement Agreement by which tobacco companies were obliged to pay compensation to 46 states to offset costs of smoking-induced illnesses4. In the early 21stcentury the WHO FCTC came in to force in 2005 with the launch of the MPOWER measures in 2008, setting up the tobacco framework that has characterised the last decade and a half and to which 181 countries are signatories. The emergence of e-cigarettes and other ENDS products has shifted tobacco control outside the current purview of the FCTC and opened up new areas of controversy as these products evade conventional regulation. E-cigarettes first appeared in the 20thcentury including designs from the 1960s from BAT and from the 1990s from PMI with the contemporary model attributed to an individual inventor5. The early designs were abandoned at least in part due to concerns about commercial viability­6­,7and it was not until the last decade or so that e-cigarettes have reached prominence. The emergence of highly appealing and commercially successful ENDS products such as the Juul device has stimulated concern at the level of the FDA and review of e-cigarette regulation. Companies such as Juul Labs (now owned by a tobacco corporation) and PMI advocate harm-minimization through their ENDS products while parent companies continue to sell conventional tobacco cigarettes in less tightly regulated markets.

      The Phillip Morris Foundation for a Smoke-Free World8was launched in 2017 and immediately prompted controversy. The stated aims of the Foundation include the funding of research, a focus on smoking cessation and harm reduction and the search for solutions to “unique challenges”8. Its launch prompted immediate debate and discussion, including a Lancet Viewpoint by the Foundation’s director, advocating the benefits of reduced-harm products and expressing concern that full implementation of the FCTC would take many years. An editorial in the same Lancet issue raised strong concerns about involving the tobacco industry in tobacco control while acknowledging that (at the time of writing) the Foundation had yet to begin work9. An accompanying commentary piece questions the credibility of the Foundation and points out that the funding of research is used by the tobacco industry as a deliberate strategy that in fact acts as a “public relations” exercise while PMI, in this instance, continues to sell cigarettes as its core product10. More recently, a review of the published tax returns from the Foundation suggest that it is having trouble both raising and spending funds, perhaps indicating some trouble engaging with the research community and multiple publications raise questions about its ethical robustness, the risks of long-term nicotine dependence and its commercial integrity. While the stated aims of the Foundation may appeal, concerns remain about engaging with the tobacco industry, about persistent global cigarette sales, about the use of the Foundation to divert attention from PMI’s efforts to build its market for ENDs products and about the prioritisation of harm-minimisation (with accompanying profits) over genuine efforts to make the world free from tobacco.

      References

      1. Jackler RK, Ayoub NF. “Addressed to you not as a smoker… but as a doctor”: doctor-targeted cigarette advertisements in JAMA. Addict Abingdon Engl. 2018 Jul;113(7):1345–63.

      2. Samji HA, Jackler RK. “Not one single case of throat irritation”: misuse of the image of the otolaryngologist in cigarette advertising. The Laryngoscope. 2008 Mar;118(3):415–27.

      3. Gardner MN, Brandt AM. “The doctors’’ choice is America’s choice": the physician in US cigarette advertisements, 1930-1953.” Am J Public Health. 2006 Feb;96(2):222–32.

      4. Schroeder SA. Tobacco control in the wake of the 1998 master settlement agreement. N Engl J Med. 2004 Jan 15;350(3):293–301.

      5. Grana R, Benowitz N, Glantz SA. E-cigarettes: a scientific review. Circulation. 2014 May 13;129(19):1972–86.

      6. Risi S. On the Origins of the Electronic Cigarette: British American Tobacco’s Project Ariel (1962-1967). Am J Public Health. 2017;107(7):1060–7.

      7. Dutra LM, Grana R, Glantz SA. Philip Morris research on precursors to the modern e-cigarette since 1990. Tob Control. 2017;26(e2):e97–105.

      8. Foundation for a Smoke-Free World [Internet]. [cited 2019 Mar 2]. Available from: https://www.smokefreeworld.org/

      9. Lancet T. Tobacco control: a Foundation too far? The Lancet. 2017 Oct 14;390(10104):1715.

      10. Daube M, Moodie R, McKee M. Towards a smoke-free world? Philip Morris International’s new Foundation is not credible. The Lancet. 2017 Oct 14;390(10104):1722–4.

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      ES13.04 - Comparing ENDS to NRT for Smoking Cessation (Now Available) (ID 3227)

      15:15 - 16:45  |  Presenting Author(s): Hayden McRobbie

      • Abstract
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      Abstract

      Comparing ENDS to NRT for smoking cessation

      For people who smoke, quitting completely is associated with numerous benefits for current and future health. There are a range of effective stop smoking medicines that can increase long-term abstinence rates, compared with unassisted quitting. However, these rates remain low (eg. < 25%), with most people relapsing within 3-6 months. Over the past decade electronic nicotine delivery systems (ENDS), more commonly known as e-cigarettes or vaporisers, have become increasing popular among smokers, and in some countries are now the most commonly used tool to aid smoking cessation.

      Until recently the evidence for the effectiveness of ENDS in helping people stop smoking has been limited, with only two published randomised controlled trials (RCTs). There are now four RCTs; three show the superiority of nicotine containing ENDS, compared to those without nicotine, in helping smokers quit for at least six months and one found vaping to be associated with higher 12-month quit rates than nicotine replacement therapy (NRT; 18% vs. 10%; RR=1.83; 95% CI: 1.30-2.58). The difference in quit rates may have been due to ENDS providing greater withdrawal relief, providing better subjective effects, and smokers being able to self-titrate their nicotine intake. Among 12-month ex-smokers, rates of ongoing ENDS use were significantly higher than ongoing NRT use. This could raise concern if long-term ENDS use is associated with health risk. Alternatively, this could be beneficial if it prevents relapse and so risk-benefit analysis is required.

      Health professionals are often asked by their patients if ENDS can help aid quitting smoking and if they are safe. There are data to show that ENDS are an effective smoking cessation aid, and some evidence to support their superiority over NRT. Current data suggest that health risks associated with ENDS use are substantially less, overall, than risks associated with smoking tobacco. However, the health risks associated with long-term ENDS use remain unknown, and long-term cohort studies, especially regarding lung health in vapers, are needed. To mitigate concern over unknown health risks associated with long-term vaping ex-smokers can be advices to stop vaping as soon as they feel they are safe from relapse to smoking.

      This presentation will summarise the evidence of effectiveness of ENDS for smoking cessation, and provide an overview of possible health risks, to enable health professionals to better advise their patients who ask about using ENDS.

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      ES13.05 - Stigma and Impact of Tobacco Control Policy (Now Available) (ID 3228)

      15:15 - 16:45  |  Presenting Author(s): Andrea Borondy Kitts

      • Abstract
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      Abstract

      figure1bcandlcpeople.jpg

      A simple quick google search on breast cancer people and lung cancer people is enough to show the impact of stigmatizing smoking on people with lung cancer (Figure 1). Breast cancer people are perceived as pink, young, healthy, cheerful, supportive and happy although that is not an accurate depiction of the breast cancer journey. In contrast, lung cancer people are seen as diseased and dying, sad, concerned, bleak, and alone with little support.

      The stigma associated with smoking stops people from going to the doctor because they are afraid the doctor will think they are stupid for continuing to smoke, it stops people from getting screened for lung cancer because they blame themselves for smoking and feel they deserve the disease or because they are afraid their loved ones will blame them for getting sick. The stigma reduces the funding available for lung cancer research. In the US, federal funding for lung cancer research per lung cancer death is only 15% of the funding amount for breast cancer per breast cancer death.

      People with lung cancer, regardless of their smoking status, encounter stigma on a regular basis.(1) Often after disclosing a lung cancer diagnosis for themselves or for a loved one the first comment is not, I’m so sorry you have this awful disease. The first comment is invariably “I didn’t know you smoked” or “Was he a smoker” or “He smoked a lot. It’s not surprising he got lung cancer” or “It’s to be expected since you are a smoker” In a Global Lung Cancer Coalition survey, one in five people (21%) agreed with the statement that they have less sympathy for people with lung cancer than for people with other types of cancer.

      Studies have shown that the stigma encountered by people with lung cancer reduces quality of life, increases depression and negatively impacts outcomes.(2)

      Probably most disturbing is that stigmatization of smokers has the greatest impact on the socioeconomically deprived, the disadvantaged populations.(3) These populations have the highest prevalence of smokers and encounter the stigma of their race or disadvantage (poverty, disability, sexual preference, behavioral health etc.) in addition to the stigma associated with smoking.(4)

      One could argue that tobacco control (tobacco denormalization efforts) may be tolerable if they resulted in short term stigma but increase tobacco cessation for these disadvantaged populations resulting in an overall public health benefit. Unfortunately, studies show that tobacco control efforts have the least impact on socioeconomically deprived populations thus actually increasing the health inequity (and stigma) for this already marginalized population. Smoking related stigma may actually help reinforce smoking in this population by being perceived as resistance to the norms of society. In other words, tobacco control efforts may not work and may actually have the opposite effect.(5,6,7)

      This stigmatization leads people who smoke to be less likely to seek medical care when they have symptoms, more likely to lie about their smoking, more likely to be refused access to care including curative surgery for early stage lung cancer unless they quit smoking, less likely to be offered smoking cessation help if they are uncomfortable disclosing their smoking status due to stigma and bias from their healthcare professional.(5,6)

      Tobacco control and stigmatization of smokers has resulted in stigmatizing all people with lung cancer regardless of smoking history or socioeconomic status. It’s time to stop stigmatizing people who smoke and people with lung cancer but rather to promote and implement policies that have been shown to work in deterring tobacco use and helping people quit.(8) These include increased age limits for tobacco purchase and use, increased taxes on tobacco sales, free access to tobacco cessation counseling, nicotine replacement products and prescription smoking cessation medications.

      1. Hamann HA, Howell LA, McDonald JL. “You did this to yourself”: causal attributions and attitudes toward lung cancer patients. J Appl Soc Psychol. 2013;43:E37–E45. doi:10.1111/jasp12053.

      2. Cataldo, JK, & Brodsky, JL. Lung cancer stigma, anxiety, depression and symptom severity. Oncology (Switzerland). 2013;85(1):33-40. http://dx.doi.org/10.1159/000350834

      3. Bell K, Salmon A, Bowers M, Bell J, McCullough L. Smoking, stigma and tobacco ‘denormalization’: Further reflections on the use of stigma as a public health tool. A commentary on Social Science & Medicine's Stigma, Prejudice, Discrimination and Health Special Issue (67: 3). Social Science & Medicine. 2010;70(6):795-799. https://doi.org/10.1016/j.socscimed.2009.09.060

      4. Borondy Kitts AK. The patient perspective on lung cancer screening and health disparities. J Amer Coll Rad. 2019;16(4):601-606. https://doi.org/10.1016/j.jacr.2018.12.028.

      5. Evans-Polce RL, Castaldelli-Maia JM, Schomerus G, Evans-Lacko SE. The downside of tobacco control? Smoking and self-stigma: A systematic review. Social Science & Medicine. 2015;145:26-34. https://doi.org/10.1016/j.socscimed.2015.09.026

      6. Kirsten Bell K, Salmon A, Bowers M, Bell J, McCullough L. Smoking, stigma and tobacco ‘denormalization’: Further reflections on the use of stigma as a public health tool. A commentary on Social Science & Medicine's Stigma, Prejudice, Discrimination and Health Special Issue (67: 3). Social Science & Medicine. 2010; 70(6):795-799. https://doi.org/10.1016/j.socscimed.2009.09.060.

      7. Lozano P, Thrasher JF, Forthofer M, Hardin J, Reynales Shigematsu LM, Santillán EA, Fleischer NL. Smoking-related stigma: A public health tool or a damaging force?, Nicotine & Tobacco Research, , nty151, https://doi.org/10.1093/ntr/nty151

      8. Hill S, Amos A, Clifford D, et al. Impact of tobacco control interventions on socioeconomic inequalities in smoking: review of the evidence. Tobacco Control. 2014;23:e89-e97.

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    ES18 - Acquired Resistance to TKIs: The Rebiopsy Case and the Future Options (ID 21)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 4
    • Now Available
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      ES18.01 - Rebiopsy in Oncogene Addicted NSCLC at Progression (Now Available) (ID 3252)

      11:00 - 12:30  |  Presenting Author(s): D. Ross Camidge

      • Abstract
      • Presentation
      • Slides

      Abstract

      As we have defined piecharts of different oncogenes at diagnosis in NSCLC, each oncogene, under the selection pressure of an active targeted agent may develop acquired resistance after initial benefit in a number of different ways, allowing intra-oncogene piecharts of acquired resistance mechanisms to be described.

      Key features to consider when considering a rebiopsy - either of the tumor or of a surrogate of the tumor (cf-DNA) is the ease and risks of rebiopsy, its false positive and false negative rates and the potential 'actionability' of the data generated. These factors allow rebiopsies for research purposes to be differentiated from those that could inform changes in clinical care immediately.

      Rebiopsies of systemic disease, became standard when osimertinib was used post 1st- or 2nd-generation EGFR TKIs to look for T790M. With the move of osimertinib to the first line setting, the need to detect T790M has becoem less, but other mechanisms of resistance in the post 1/2nd generation EGFR TKI setting, separate from T790M, and in the post-osimertinib setting including small cell transition and MET amplification are also likely to change clinical management and maintain the role for biopsies in EGFR mutant disease.

      In ROS1 rearranged lung cancer - the lack of efficacy of lorlatinib and crizotinib to G2032R clinically, but the possible activity of repotrectinib in trials, can make the case for a rebiopsy and reanalysis post-crizotinib or lorlatinib in ROS1+ disease. Actionable second drivers remain under exploration.

      In ALK rearranged lung cancer, on target mutations are multiple - preclinical data suggesting specific drugs for specific mutations post-crizotinib can be identified remains partially determined, with multiple caveats about the preclinical-clinical transferability of data. The ALK master protocol will address some of these issues. However, perhaps the biggest issue relates to the potential for non-ALK related second drivers to be actionable, suggesting the methodology of testing in the acquired resistance setting, as in EGFR, should be broad.

      Rebiopsies performed in the setting of CNS progression, in the absence of prior overt CNS benefit, are of limited practicality or use at present, however, with the advent of CNS penetrant drugs for key oncogenes, true CNS acquired resistance may emerge and some form of CNS sampling may become relevant.

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      ES18.02 - When to Switch to a New TKI : Imaging Based Crtieria or Positive Liquid Biopsy? (Now Available) (ID 3253)

      11:00 - 12:30  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Abstract

      The discovery of specific mutations and associated addicted pathways in lung adenocarcinoma cells has led to the development of many targeted therapies useful for corresponding activating mutation. In addition, conventional chemotherapy and novel immunotherapy such as PD1/PDL1 antibodies are also very effective for lung cancer patients with or without specific driver mutation. Patients with metastatic lung cancer nowadays can be treated with multiple lines of effective treatment. Patients who receive more lines of therapy tend to live longer than those who had only receive limited number of treatment. In order to maximize the overall survival outcome of metastatic lung cancer patient who receives systemic treatment, it is important to find out the best first line choices and the best timing to change the treatment regimen to second line and so forth. Tumor reduction or stabilization by imaging criteria has been used widely for a long time in chemotherapy and targeted therapy era. RECIST (Response evaluation criteria in solid tumors) has been adopted as a uniform criteria for cancer clinical trial to classify the tumor response to certain treatment. However, in order to accommodate different cancer types and sites of metastasis, several variants of RECIST emerged to better evaluate the treatment response and necessity of maintain the present treatment. In daily practice, changes of tumor size in the image provide the best guidance for clinicians to continue or change regimen for the patients. In patients who has no reliable evaluable radiological image for follow up, such as patients who presented with effusion, bone metastasis, leptomeningeal metastasis or tumor with poor margin, patients’ clinical performance and alterations in tumor markers occasionally can provide clinicians information for judgement. The introduction of cell free plasma tumor DNA for the molecular diagnosis of cancer gave us a new change of how to manage the patients properly when changing regimen to prolong patients chance to survive or improving quality of life are attainable. There are a least 3 important applications for cell free tumor DNA detection. First is to provide information of specific mutation at the time of diagnosis or progression, so that a corresponding targeted therapy can be chosen as the best treatment of choice. Second is to use quantitative amount of specific mutation found in plasma cell free DNA to follow patient’s tumor. The presumption is the amount of specific mutation may represent the tumor load of the treated patients. The 3rd possible application is to use the novel mutations detected in the plasma at the time of diagnosis or during treatment follow up to select a theoretical best combination for patients. There are ample of analysis reported in the literature for the first and second possible applications of plasma cell free DNA. The evidence for the 3rd possible application is accumulating. However, there is no emphasis of using this vast information gathered in the plasma to guide the right timing to switch regimen. In addition, there has been a trend to continue original treatment in slow progressing patients beyond imaging progression, or to treat oligo-progressing sites with local irradiation or surgery in order to keep the original treatment. These approaches certainly will further complicate the rationale decision of right timing to change regimen. Thus, a few options exist for patients who are receiving targeted therapies. One is to use conventional ways of RECIST progression by imaging studies to change the treatment to further lines. The treatment outcome may be more predictable, because most of the clinical trials follow this dogma. A second choice is to treat patients beyond progression by RECIST and follow physicians judgment to switch the regimen. Several recent clinical trials use this criteria to change regimen and collect the treatment time as duration-of-treatment, or time-to-treatment-failure. The 3rd possible timing is to switch regimen according to plasma DNA alterations, for example, emergence of activating mutation when plasma tumor DNA was previously eradicated by current targeted therapy; add another targeted therapy when a new parallel pathways amplification is predicted from the plasma sample analysis. This strategy lack the support of prospective clinical trial data and was purely based on direct scientific deduction or instinct and a few case reports. Therefore, studies specifically designed to address the switch timing is very important. Unfortunately, the effort devoted to this area is lacking.

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      ES18.03 - New Strategies to Overcome Resistance in EGFR Mutated NSCLC (Now Available) (ID 3254)

      11:00 - 12:30  |  Presenting Author(s): Paul A Bunn, Jr

      • Abstract
      • Presentation
      • Slides

      Abstract

      New Strategies to Overcome Resistance in EGFR Mutated NSCLC

      Activating EGFR mutations occur in 15-50% of lung adenocarcinomas with a higher frequency in never or light smokers and individuals of East Asian origin. First and second generation EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, afatinib and dacomitinib are associated with high response rates (50-75% and median progression free survival rates of 9-14 months. Failure in the CNS is frequent because these agents have poor CNS penetration and the most frequent cause of systemic failure is the development of T790M resistance mutations. Other reported mechanisms of resistance to first and second generation EGFR TKIs include small cell transformation, AXL overexpression, HER2 mutation and overexpression, Wnt pathway overexpression and other less common alterations. Standard platinum doublet chemotherapy is generally used for those with small cell transformation and these cases usually have Rb loss and p53 mutation. The addition of cetuximab to first or second generation EGFR TKIs did not appear to improve outcomes.

      Osimertinib is a third generation EGFR TKI whose advantages include high sensitivity to both activating EGFR mutations and T790M mutations with lesser sensitivity to wild type EGFR. Osimertinib also crosses the blood brain barrier. A randomized phase III trial, AURA3, demonstrated that osimertinib was superior to chemotherapy and was associated with decreased CNS relapse in the second line setting after failure on a first generation EGFR TKI due to T790M.

      These data with second line osimertinib led to a first line phase III randomized trial, FLAURA, comparing osimertinib to either gefitinib or erlotinib. Osimertinib was associated with a significantly longer PFS, a significantly longer time to CNS progression, a significantly longer duration of response and a longer overall survival that had not reached significance at most recent analysis. Patterns of resistance to first line osimertinib are only emerging now but include alterations that have specific targeted therapy such as MET amplification (15%), BRAF mutations (3%), HER2 amplification (1%), ALK fusions (1%), PI3K mutations (3%), KRAS mutations (2%), C797s or other resistance mutations (2%), SCLC transformation (5%), CDK and cell cycle alterations (2-5%). Because these have specific non-chemotherapy treatment options, NGS testing should be done on blood ctDNA and if negative on tissue at the time of progression.

      For those without these actionable alterations, chemotherapy is the next standard therapy although combinations of chemotherapy with checkpoint inhibitors with or without anti-VEGF agents is under investigation due to a positive subset analysis of the IMPOWER 150 trial. The addition of checkpoint inhibitors to first line TKIs has proven to have increased toxicity with low activity.

      Another way to delay or prevent resistance is to use combinations in the first line therapy. Combinations of EGFR TKIs with anti-VEGF therapies, with anti-MET therapies, with anti-EGFR antibodies, and with chemotherapy are in progress. Initial trials combining erlotinib with bevacizumab demonstrated improved PFS but not OS. Current trials are combining newer EGFR TKIs such as osimertinib with anti-VEGF antibodies such as bevacizumab or ramicirumab are in progress. Trials using anti-VEGFR TKIs are also in progress. Preclinical studies indicated that combining anti-EGFR antibodies such as cetuximab or necitumumab with EGFR TKIs could overcome some resistance led to other ongoing clinical trials combining these agents. Amplification of MET is a common mechanism of resistance to EGFR TKIs, so the combination of MET TKIs with EGFR TKIs is rational and trials are ongoing. Understanding the mechanisms by which EGFR mutant cells can persist in the presence of initial EGFR TKIs remains a priority for future investigation.

      The adjuvant use of EGFR TKIs after surgical resection of early stage NSCLC patients with EGFR mutations has clearly established superiority in recurrence free survival but not in overall survival. It appears that there is insufficient cell kill to lead to an increase in the cure rate but additional survival based adjuvant trials such as ”ALCHEMIST” are ongoing.

      Neoadjuvant studies could provide downstaging because the response rates are high. It is not clear whether this would be more likely to provide an increase in cure rates compared to adjuvant use of these agents. These neoadjuvant trials are providing surgical samples to explore mechanisms by which cells persist after EGFR TKI therapy. This incredibly important information could lead to rational combinations that could increase pCR rates in early stage patients and improved outcomes in advanced stage patients.

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      ES18.04 - New Strategies to Overcome Resistance in ALK Rearranged NSCLC (Now Available) (ID 3255)

      11:00 - 12:30  |  Presenting Author(s): Sai-Hong Ignatius Ou

      • Abstract
      • Presentation
      • Slides

      Abstract

      Since the discovery of ALK+ NSCLC in 2007, there are now 6 ALK TKI have been approved or in clinical development. These 6 ALK TKI can be generally divided into 3 generations. First-generaion (Crizotinib). Second Generaion (Alectinib, Ceritinib, Brigatinib, Ensartinib). THrid-generation (Lorlatinib). The advantages of the second-generation ALK TKI or beyond is better potentcy an excellent improved CNS penetration. The mode of progression in ALK+ NSCLC are 4 fold and can be single or combination according to individaul patients: developed of acquired second site ALK mutations, CNS progression, bypass activation, and histological transformation.

      For second site ALK mutations, sequencing ALK TKIs that will overcome the particular second site mutation(s) or proceed to the most potent ALK TKI is likley be successful.

      For CNS progression, lorlatinib has demonstrated CNS activity in CNS progression from second generation ALK TKIs (ceritinib, alectinib). Additionally the use of stereotactic radiation (SRS) or whole brian radiation can contral CNS progression but clinicians should look out for radiation necrosis.

      For second bypass activation such as (i.e. RAS, SRC, EGFR, Kit) in vritro pre-clinical modles of combining specific bypass inhibitor and ALK TKI were albe to inhibit growth of these resistance cell lines or patient dervied PDX model, clinical trials are on-going but to date clinical data are lacking. Additional the use of chemotherapy especailyl pemetrexed-based chemotherapy in addition to ALK TKI has showen to be more efficacious than just switching to chemotherapy while discontinuing ALK TKI

      For histologic transformation most commonly small cell transformation, the switching to small cell regimen is only viable option at this point. The addition to immunotherapy to chemotherapy (e.g. IMpower133 regimen) or IO + IO combination (e.g. chckmate-032) should be explored in small cell tranformation as mode of progression in ALK+ NSCLC.

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    ES22 - Immunotherapy - Discovering New Areas (ID 25)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Immuno-oncology
    • Presentations: 5
    • Now Available
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      ES22.01 - Immunotherapy in Resectable NSCLC (Now Available) (ID 3275)

      15:45 - 17:15  |  Presenting Author(s): Patrick M. Forde

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint blockade with inhibitors of the PD-1/PD-L1 interaction have improved survival substantially for patients with advanced non-small cell lung cancer. Despite many clinical trials of different combination regimens, the benefit from perioperative platinum doublet chemotherapy in resectable lung cancer is modest with an approximate 5% improvement in 5 year survival over surgery alone.

      This session will review the background of systemic therapy for resectable lung cancer and data reported to date with single agent PD-1 blockade, PD-(L)1-based immunotherapy combinations, and chemotherapy combined with anti-PD-1. Ongoing phase 3 clinical trials of neoadjuvant and adjuvant immunotherapy will be discussed and future directions both in novel science and clinical trials explored.

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      ES22.02 - A Milestone in Locally Advanced NSCLC (Now Available) (ID 3276)

      15:45 - 17:15  |  Presenting Author(s): Solange Peters

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stage III NSCLC encompasses locally advanced tumours with infiltration of locoregional nodes and central thoracic structures and accounts for about a third of newly diagnosed NSCLC[1]. It represents the most advanced stage of NSCLC in which treatment is delivered with curative intent, but eventually more than 60% of patients die from their disease.

      Stage III NSCLC patients must strictly be discussed in a multidisciplinary tumor board, whereat the definition of resectability suffers from a certain heterogeneity across centers. Resectability is usually defined by the degree of invasion of lymph nodes, most often excluding multilevel or bulky N2 and N3 disease as well as invasion of the oesophagus, aorta and myocardium. Controversy exists on the role of surgery in stage III NSCLC since two large randomized trials investigated either induction chemoradiation therapy followed by resection versus radiotherapy[2], or induction chemotherapy followed by resection versus radiotherapy[3]. Both studies failed to demonstrate a difference in survival[2-5], however these treatment strategies are evidence-based and can be pursued in restectable NSCLC[6].

      In the surgical scenario, randomised trials and meta-analyses have consistently shown that either adjuvant or neoadjuvant chemotherapy added to surgery results, with a better survival than surgery alone[7,8]. Adding preoperative radiotherapy to chemotherapy in patients with stage IIIA/N2 NSCLC did not improve the clinical outcome in a phase 3 randomised trial[9]. The role of adjuvant radiotherapy in stage IIIA/N2 after neoadjuvant chemotherapy followed by surgery has been evaluated in a unique randomized trial with awaited results (Lung ART, NCT00410683).

      Early NSCLC stages offer a theoretical unique curative scenario for the development of immunotherapy startegies, with limited disease volumes, a relative immune system preservation as well as unique oportunities for the investigation and assessment of new biomarkers.

      Perspectives, rational, hopes and ongoing attempts to combine immunotherapy in the surgical setting or alterenatively complementary to chemoradiation will be discussed, with a focus on locally advanced disease.

      References

      1. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018;155:356-9.

      2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86.

      3. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50.

      4. O'Rourke N, Roque IFM, Farre Bernado N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140.

      5. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-90.

      6. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21.

      7. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71.

      8. Group NM-aC, Arriagada R, Auperin A, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267-77.

      9. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56.

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      ES22.03 - New Hope in SCLC? (Now Available) (ID 3277)

      15:45 - 17:15  |  Presenting Author(s): Leora Horn

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for approximately 15-20% of cases. This aggressive tumor is characterized by rapid growth, early development of disseminated disease and dramatic responses to first line chemotherapy. For decades, first line therapy has traditionally included four to six cycles of platinum-based chemotherapy. While up to 80% of patients respond to first-line chemotherapy, the majority eventually relapse with a median survival of 8 to 12 months for patients with extensive stage disease and 12 to 20 months for those with limited stage disease. Until recently, topotecan was the only FDA approved second line therapeutic option. The shortcomings of traditional chemotherapy, as well as the limited role of targeted therapy in SCLC, led to the investigation of novel mechanisms to target lung cancer and specifically the discovery of immune checkpoint inhibitors.

      Immune checkpoint inhibitors work by blocking interactions between T cells and antigen presenting cells (APCs) or tumor cells. By inhibiting this interaction, the immune system is effectively upregulated and T-cells become activated against tumor cells. There are three major classes of checkpoint inhibitors. Ipilimumab and tremelimumab inhibit T-lymphocyte antigen-4 (CTLA-4); nivolumab and pembrolizumab target the programmed cell death-1 receptor (PD-1); and atezolizumab, durvalumab, and avelumab block PD-L1, the ligand of PD-1. Prior studies have shown lack of PD-L1 expression on tumor cells in patients with pulmonary and extra pulmonary SCLC. While PD-1 and PD-L1 are expressed in the tumor stroma of small cell carcinomas.[1] In addition PD-L1 has been shown to be prognostic in patients with SCLC.[2] The aggressive nature of SCLC is underscored by its high mutational burden, including loss of the tumor suppressor genes p53 in 75%–90% and retinoblastoma in almost 100% of tumors.[3] Higher tumor mutation burden has been associated with outcome in patients with select tumors treated with checkpoint inhibitor therapy, including non-small cell lung cancer. [4]

      Recently singly agent nivolumab and combination nivolumab and ipilimumab were shown to have activity in the second and third line setting for patients with advanced SCLC with response rates of approximately 10% and 20% respectively. Combination nivolumab and ipilimumab appeared particularly promising in patients with tumors with high tumor mutation burden and in 2018 nivolumab received approval in the third line setting for patients with advanced SCLC. [5] However, disappointingly Chekckmate 331, a large phase III trial of patients who had progressed on first line platinum-based chemotherapy, found nivolumab was not superior to topotecan or amrubicin in the second line setting. Recently a combined analysis of patients treated on the Keynote 158[6] and 028 trial[7] with pembrolizumab in the second line setting demonstrated a response rate of approximately 20% in patients, with a greater benefit in patients with tumors that were PD-L1 positive.

      In the first line setting, a single arm phase II trial demonstrated no benefit to maintenance pembrolizumab following induction chemotherapy in patients with advanced SCLC with a progression free survival of less than 2 months. [8] Earlier this year, a phase III trial (Checkmate 451) also found maintenance nivolumab with or without ipilimumab following induction chemotherapy in patients with advanced small cell lung cancer was not superior to placebo, suggesting this is not the optimal strategy in patients with advanced stage disease.

      Importantly, he Impower 133 phase III trial demonstrated combination chemotherapy with carboplatin, etoposide and atezolizumab was superior to chemotherapy alone in patients with advanced SCLC with a significant improvement in progression free and overall survival leading to FDA approval and a new standard of care for patients with advanced disease. [9] Two large phase III trials Keynote 604 and Poseidon are comparing a similar strategy with pembrolizumab and durvalumab respectively, with data anticipated in the upcoming year.

      While progress has finally been made. Limited tissue specimens in patients with SCLC remain a challenge and many unanswered questions remain including the optimal patient population in which these agents will have benefit (PD-L1 positive or negative, tumor mutation high or low), the optimal duration of therapy, the appropriate combinations (can we improve upon chemotherapy with a different checkpoint inhibitor), and the safety of these agents long term, particularly in patients with comorbid disease.

      References:

      1. Schultheis, A.M., et al., PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer, 2015. 51(3): p. 421-6.

      2. Ishii, H., et al., Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol, 2015. 10(3): p. 426-30.

      3. Byers, L.A. and C.M. Rudin, Small cell lung cancer: where do we go from here? Cancer, 2015. 121(5): p. 664-72.

      4. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.

      5. Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol, 2016. 17(7): p. 883-895.

      6. Chung, H.C., et al., Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol, 2019. 37(17): p. 1470-1478.

      7. Ott, P.A., et al., Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol, 2017. 35(34): p. 3823-3829.

      8. Gadgeel, S.M., et al., Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol, 2018. 13(9): p. 1393-1399.

      9. Horn, L., et al., First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med, 2018. 379(23): p. 2220-2229.

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      ES22.04 - Any Chance in Mesothelioma (Now Available) (ID 3278)

      15:45 - 17:15  |  Presenting Author(s): Giorgio Vittorio Scagliotti

      • Abstract
      • Presentation
      • Slides

      Abstract

      Section not applicable

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      ES22.05 - Role in Thymic Epithelial Tumours (Now Available) (ID 3279)

      15:45 - 17:15  |  Presenting Author(s): Rina Hui

      • Abstract
      • Presentation
      • Slides

      Abstract

      Although thymic epithelial tumours (TETs) are rare, they are the commonest primary tumours of the anterior mediastinum. TETs are heterogenous with histological classification into thymoma and thymic carcinoma. Subtypes of thymomas include A, AB, B1, B2 and B3 depending on the presence of spindle cells, the relative proportion of lymphocytes and abnormal epithelial cells. The commonest histological subtype of thymic carcinoma is squamous cell, others include sarcomatoid, adenocarcinoma, basaloid etc. The traditional Masaoka-Koga staging system is widely used to stage TETs (I: no breaching of capsule; II: invasion through capsule to involve surrounding fatty tissue; III: invasion into nearby organs; IV: pleural/pericardial spread or distant metastases), while TNM staging (T1a: with or without invasion into mediastinal fat; T1b: mediastinal pleura; T2: pericardium; T3/T4: nearby organs; N1: peri-thymic anterior mediastinal nodes; N2: deep thoracic or cervical nodes; M1a: separate pleural or pericardial nodules; M1b: distant metastases) has been introduced more recently. The prognosis of TETs depends on both histology and disease extent. Thymomas are usually more indolent with 10- year overall survival rate of >80% for stage I and II, but thymic carcinoma confers poorer prognosis with 5-year survival of around 50% for stage III and 25% for stage IVa.

      The treatment of choice for early stage disease is surgical resection with curative intent. Concurrent chemoradiation can be considered for unresectable locally advanced TETs. 10-15% of resected TETs recur and radical radiation may be appropriate for local recurrence. In unresectable stage III and IV disease with spread to pleural and pericardial cavities or beyond, standard first-line systemic treatment is platinum-based chemotherapy, usually with cisplatin, doxorubicin and cyclophosphamide. Although TETs are reported to be chemo-sensitive with a response rate (ORR) of 50% for thymomas and around 20% for thymic carcinoma, they ultimately will progress and research into second-line treatments besides chemotherapy is important. Targeted therapies including sunitinib and everolimus with disease control rate (DCR) of >80% in previously treated TETs have been reported.

      Cancer treatment landscape has been rapidly evolving in recent years due to the successful development of PD1 blockade in many cancer types including melanoma, non-small cell lung cancer, bladder cancer, renal cell cancer, head and neck cancer, etc. The function of thymus during childhood in the production, differentiation and maturation of immunocompetent T cells together with the observation of high level of PD-L1 expression in normal thymus and TETs suggest a possible role of immunotherapy in TETs. Of 40 eligible patients with chemotherapy refractory thymic carcinoma in a phase 2 study, pembrolizumab provided an ORR of 22.5%, DCR of 75%, median progression-free survival (PFS) of 4.2 months, and median overall survival (OS) of 24.9 months with 1-year OS rate of 71%. Exploratory analysis in this study suggested an association of high-level PD-L1 with longer PFS and OS. A similar phase 2 study of pembrolizumab after at least 1 line of chemotherapy in Korea included 7 patients with thymoma and 26 patients with thymic carcinoma achieving an ORR of 27% with DCR of 100% in thymoma and ORR of 19% with DCR of 73% in thymic carcinoma. A phase 1 study with avelumab showed confirmed ORR of 29% with DCR of 86% in 7 thymoma patients and stable disease in the 1 thymic carcinoma patient.

      As thymus is involved in positive and negative T cell selection process for self-major histocompatibility complex molecules, thereby inducing self-tolerance avoiding auto-immunity, one third of thymoma is associated with autoimmune diseases, the commonest being myasthenia gravis. Other associated autoimmune conditions include systemic lupus erythematosus, pure red cell aplasia, syndrome of inappropriate anti-diuretic hormone secretion, bullous dermatoses autoimmune blistering diseases, polymyositis, dermatomyositis, pernicious anaemia, haemolytic anaemia, scleroderma, Sjogren’s syndrome, rheumatoid arthritis, ulcerative colitis, Takayasu syndrome, Grave’s disease etc. However, autoimmune disorders are much less likely to occur in thymic carcinoma. It is not surprising that a significant incidence of immune-related adverse events (irAE) is evident with immune-checkpoint inhibitors in the treatment of TETs with higher frequency of irAE in thymoma than in thymic carcinoma. 71% of patients with thymoma and 15% of patients with thymic carcinoma treated with pembrolizumab in the Korean study experienced grade 3-4 irAE including 12% hepatitis, 9% myocarditis, 6% myasthenia gravis, 3% thyroiditis, colitis, nephritis and myoclonus. The other phase 2 pembrolizumab study in patients with thymic carcinoma also reported similar incidence of 15% severe irAE with 5% myocarditis. IrAE was observed in 63% of patients in the phase 1 avelumab study with 38% myositis and 13% enteritis. PD-L1 status did not predict irAE.

      In conclusion, the main issue of PD1 blockade in TETs is common irAEs with higher frequency in thymomas. Therefore, immunotherapy is still not standard of care, needing further research to identify possible biomarkers to spare patients with less likelihood to benefit taking the risk of serious irAEs. There may be a role of immunotherapy in advanced TETs with aggressive pathology after failing chemotherapy, but thorough discussion with patients about the potential irAEs is warranted.

      References:

      Girard N, Ruffini E, Marx A, et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v40-v55.

      Miyamoto K and Acoba J. Thymomas and thymic carcinomas: a review on pathology, presentation, staging, treatment, and novel systemic therapies. EMJ Respir. 2017;5:100-107.

      Detterbeck F, Stratton K, Giroux D, et al. The IASLC/ITMIG thymic epithelial tumors staging project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol. 2014;9:S65-S72.

      Shelly S, Agmon-Levin N, Altman A, et al. Thymoma and autoimmunity. Cell Mol Immunol. 2011;8:199-202.

      Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19;347-355.

      Cho J, Kim K, Ku B, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol. 2018;36:1-8.

      Rajan A, Heery C, Mammen A, et al. Safety and clinical activity of avelumab in patients with advanced TETs. J Thorac Oncol. 2017;12:1S:OA18.03.

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    IBS21 - Combating Toxicity of IO-Chemotherapy Combinations (Ticketed Session) (ID 52)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 2
    • Now Available
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      IBS21.01 - Enhanced Toxicity of IO with Concurrent Chemotherapy (Now Available) (ID 3379)

      07:00 - 08:00  |  Presenting Author(s): Carlos H. Barrios  |  Author(s): Ana Zimmer Gelatti Gelatti

      • Abstract
      • Presentation
      • Slides

      Abstract

      Of the more than 18 million new cancer cases seen worldwide in 2018, approximately 2 million (11%) were lung cancer. More importantly, 1.7 million deaths were seen due to the disease, representing 18% of all cancer related deaths. Global age standardized incidence/mortality rates (22.5/18.6) clearly indicate that today, most patients diagnosed with lung cancer succumb to the disease. With the increasing incidence and mortality seen particularly in developing countries lung cancer is one of the most important global public health current challenges.

      With recent advances seen over the last couple of decades, therapeutic decisions for NSCLC are based not only on disease stage, comorbidities, performance status and histology, but also should consider the mutational and immunological profile of the tumor and obviously each patient’s preferences as well.

      Until recently, for tumors without any identifiable molecular driver, platinum doublets were the standard treatment for advanced disease. In these patients, despite extensive studies trying to improve current results, “old” targeted agents (bevacizumab, cetuximab) added to standard chemotherapy regimens suggested very modest if any benefit at all. Immune check-point inhibitors introduced over the last few years, have revolutionized our treatment approach and stand to change the natural history of the disease.

      As single agents, immune check-point inhibitors are effective in a proportion of patients, however a large majority either do not respond or develop resistance. On the basis of still very limited knowledge of primary and secondary mechanisms of resistance, combination approaches with other standard therapies and other immunotherapy strategies have been explored. Unfortunately, in most cases, lack of specific information on the molecular interactions between these therapies remains an important barrier. Albeit basically empirically designed, combinations of PD1/PDL1 inhibitors with standard platinum doublets have demonstrated benefits and are apparently increasing the proportion of patients benefiting from single agent immunotherapies.

      For many years, chemotherapy has been considered as an immunosuppressant. This is clearly the case in some situations depending on the specific agent and the dose being administered. However, in preclinical models, chemotherapy has shown the potential to increase the immunogenicity of cancer cells increasing the release of tumor antigens, attracting DCs, downregulating PDL1/PDL2 in DCs, enhancing tumor cell recognition and lysis and at the same decreasing microenvironment immunosuppressive factors. With the current need of designing rational combinations, it becomes extremely important to recognize that different chemotherapeutic agents have different interactions with the immune system and that addressing these differences is mandatory to achieve the best possible results.

      So, with these reasoning, it is fair to say that, among the multitude of specific cytotoxic effects of the different available chemotherapeutic agents and regimens it can be hypothesized that the combination of chemotherapy and IO may enhance immune effects.

      The combination of chemotherapy and immunotherapy (CIT) has attracted attention of clinicians and researchers and has been investigated in multiple clinical trials. Improved efficacy has been seen with these combinations but as expected, toxicity issues have also been observed. In this particular setting, we will address the intriguing question of how combining chemotherapy and immunotherapy may interfere in chemotherapy related adverse events.

      A recent metanalysis explored this particular issue and collected trial information from 6 randomized studies in the first line treatment of NSCLC patients. Compared with standard chemotherapy, the combination of PD-1/PD-L1 inhibitors with chemotherapy is statistically associated with a 38% reduction in the risk of disease progression, a 32% reduction in the risk of death and increases 1.6 times the probability of achieving an objective response. These results are achieved at the expense of increased treatment-related adverse events.

      In particular, the combination was associated with an increased risk of developing grade 3 or worse severity adverse events, an increase in treatment related drug discontinuations and an increase in serious adverse events. However, the number of treatment related deaths was similar with both treatments.

      Importantly, we need to consider that these data, as most of the information we have available form randomized phase III trials reflect the effects in the limited patient populations included in these trials and do not apply to special populations such as elderly patients, patients with autoimmune diseases, patients with worse ECOG PS (>2), patients with HIV or with hepatitis B/C and patients on chronic use of steroids. RWD and further trials specifically exploring these groups of patients will be essential to better inform the optimal management of these cases.

      Nevertheless, recent presented information on the long-term benefits of mainly single agent immunotherapy with a proportion of patients with advanced NSCLC surviving in excess of 3-5 years, raises the issue of a clear impact on the natural history of the disease. This has been previously shown in diseases that explored immunotherapy earlier such as melanoma for example. Further research should try to rationally approach combination regimens and to specifically select patient populations that could derive more benefit. At the same time this will help defining and improving the risk benefit relationship of these regimens.

      References:

      Galluzzi L, et. al. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 28, December 14, 2015.

      Hato SV, et al. Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics Clin Cancer Res; 20(11); 2831–7, 2014

      Zhou Y, et al. Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis. Journal for Immuno Therapy of Cancer (2018) 6:155.

      Kanwal B, et al. Immunotherapy in Advanced Non-small Cell Lung Cancer Patients: Ushering Chemotherapy Through the Checkpoint Inhibitors?Cureus. 2018 Sep; 10(9): e3254.

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      IBS21.02 - Real World Toxicities of Radiation Plus IO in NSCLC (Now Available) (ID 3380)

      07:00 - 08:00  |  Presenting Author(s): Ronan Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract

      As the indications for immune checkpoint inhibitors expand in stage III and stage IV non small cell lung cancer, medical and radiation oncologists will need to risk-stratify patients for the development of immune related toxicities most notably checkpoint-inhibitor pneumonitis (CIP) and to differentiate this from radiation induced pneumonitis. Real-world patient data is providing new insights into the epidemiological and clinical characteristics of CIP and emerging data which needs to be validated suggest a higher incidence of CIP approaching 19% in non- trial patients compared to 3-5% reported in clinical trials. A seasonal pattern of CIP with an increase in the number of cases in the Winter months when viral infections are at a high and in patients that may be more susceptible due to existing comorbidities than ECOG 0-1 trial patients need to be further evaluated. Additionally, it appears the risk of developing CIP is histology dependent with a lower risk being seen in nonsquamous lung cancer. A variety of radiographic patterns ranging from organizing pneumonia to ground glass or interstitial patterns are seen and time-to-onset analysis suggest that there may be two differing phenotypes most notably early onset CIP which is high grade and associated with higher mortality and late-onset CIP which is of lower grade and has less mortality. At the present time, no specific radiotherapy-related treatment parameter such as technique (stereotactic body RTor intensity-modulated RT), timing or number of courses have been associated with CIP, however, there is a trend associated with curative-intent radiotherapy compared with palliative intent radiation. Interestingly, the development of non-pulmonary immune related adverse events has been associated with an improved response and overall survival to checkpoint inhibitors. While these phenomena require further investigation it has been suggested that the poor outcomes associated with CIP relate to the fact that hypoxia from pneumonitis is poorly tolerated in patients who already have respiratory compromise as a result of lung cancer and may precipitate multiorgan failure due to decreased oxygenation. The creation of multi-disciplinary teams that have a specific interest in the management of immune related toxicities may help improve patient outcomes due to early identification but a more comprehensive understanding of the underlying biology is needed if we are to refine our existing diagnostic and treatment algorithms to appropriately manage life-threatening complications associated with changing paradigms of care.

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    IS08 - Symposium by Pfizer: EGFR+ and ALK+ NSCLC: More Options, Right Choices (Not IASLC CME Accredited) (ID 372)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS13 - Symposium by Illumina: Benefiting Lung Cancer Patients with Comprehensive Genomic Profiling (Not IASLC CME Accredited) (ID 377)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
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      MA21.01 - Generation and Characterization of Novel Preclinical Disease Models of NSCLC with NRG1 Rearrangements to Improve Therapy (Now Available) (ID 2811)

      14:30 - 16:00  |  Presenting Author(s): Eric Gladstone  |  Author(s): Morana Vojnic, Michael Offin, Lukas Delasos, Allan J. W. Lui, Evan Siau, Hirko Sato, Ryma Benayed, Renate Kurth, Marissa Mattar, Inna Khodos, Elisa De Stanchina, Robert Daly, Alison Schram, Alexander Drilon, Marc Ladanyi, Romel Somwar

      • Abstract
      • Presentation
      • Slides

      Background

      Chimeric proteins encoded by NRG1 rearrangements retain the EGF-like domain of NRG1, a HER3 ligand that triggers HER3-HER2 heterodimerization and drives tumor growth. Activating NRG1 fusions have been identified in a variety of cancers including lung, pancreatic, breast, head and neck, etc, and previous work by our group has shown that anti-HER3 antibody (GSK2849330) therapy was effective at inducing a durable response in a NSCLC patient with a CD74/NRG1-fusion. It is possible that targeting both HER2 and HER3 would be more effective than targeting HER3 alone given that HER3-HER2 dimerization is necessary for tumorigenesis induced by NRG1 rearrangements. However, this has not been explored extensively due to a paucity of well-characterized preclinical models of NRG1-driven NSCLC. We aimed to establish patient-derived xenograft (PDX) and cell line models with NRG1-rearrangements to evaluate signaling networks and the role of novel therapies for this recently identified oncogene.

      Method

      Approximately 30,000 tumor samples were evaluated for the presence of NRG1-fusions by targeted DNA and RNA sequencing (using the MSK-IMPACT and MSK-Fusion panels, respectively). Fresh tumor samples were collected and implanted into immune-compromised mice to generate PDX models and/or used to generate cell lines. Separately, NRG1-fusions were genomically engineered using CRISPR-Cas9 systems or by lentiviral transduction of cDNAs into immortalized human bronchiolar epithelial (HBEC) cells. RT-PCR and Sanger sequencing were used to verify NRG1-fusion mRNA expression, whereas western blot analysis examined fusion protein expression and phosphorylation. Subsequently, cell viability following inhibition of HER2, HER3 and downstream signaling pathways was assessed.

      Result

      NRG1 fusions were identified in 24 patients (9 NSCLC); and we successfully generated two PDX models with corresponding cell lines from two NSCLC surgical specimens (2/2). One model harbors a CD74/NRG1 fusion whereas the second harbors a SLC3A2/NRG1-fusion. Using CRISPR-Cas9 mediated gene editing, we are introducing NRG1 fusions that were identified in NCSLC (CD74/NRG1, SLC3A2/NRG1, VAMP2/NRG1) into HBEC cells, and have generated a stable cell line with VAMP2/NRG1 fusion to date. In addition, we established a CD74/NRG1-positive model in HBEC cells using lentiviral transduction. Treatment of NRG1-fusion positive cells with small molecule inhibitors of HER2 (afatinib, neratinib, sapitinib) or trastuzumab inhibited growth, induced caspase 3/7 activity and blocked activation of PI3K and ERK signaling. Neratinib was more potent than other small anti-HER2 molecules. The PI3K inhibitor pictilisib inhibited growth of NRG1 fusion-positive cells as a single agent with little effect on non-tumor control cells.

      Conclusion

      We generated novel NSCLC PDX and cell line models with verified NRG1 chromosomal rearrangements. In vitro studies show that targeting HER2 and PI3K effectively inhibits growth and induces apoptosis. Studies exploring the efficacy of additional agents targeting HER2, HER3 and PI3K alone or in combination using in vivo models are ongoing and results will be presented.

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      MA21.02 - Genomic Origin and EGFR-TKI Efficacy of Pulmonary Adenosquamous Carcinoma (Now Available) (ID 578)

      14:30 - 16:00  |  Presenting Author(s): Gen Lin  |  Author(s): Chao Li, Pansong Li, Wenzhang Fang, Haipeng Xu, Yuhua Gong, Zhengfei Zhu, Yi Hu, Wenhua Liang, Qian Chu, Wen-Zhao Zhong, Lin Wu, Huijuan Wang, Zhijie Wang, Ziming Li, Jie Lin, Yan-Fang Guan, Xuefeng Xia, Xin Yi, Qian Miao, Biao Wu, Kang Jiang, Xiaobin Zheng, Weifeng Zhu, Xinlong Zheng, Huang Peisha, Xiao Wenjin, Dan Hu, Longfeng Zhang, Xirong Fan, Tony Mok, Cheng Huang

      • Abstract
      • Presentation
      • Slides

      Background

      Lung adenosquamous carcinoma (ASC) is a heterogeneous disease that comprises of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Their genomic profile, evolutionary origin, and clinical management remain controversial. Objective of this study is to define the genomic origin of this heterogeneous tumor by independent genomic analyses of the AC and SCC components.

      Method

      Surgical ASCs were collected. AC component and SCC component were obtained separately by microdissection, and Lymph node (LN) metastases were gathered. Targeted sequence was performed for the two components using a 1021-gene panel, independently. Evolutionary relationship of the two components was analyzed. The independent cohorts of adenocarcinoma (n=170) and squamous cell carcinomas (n=62) were used for comparison. EGFR and concomitant mutations with response to EGFR-TKI were analyzed. Retrospective 517 ASCs underwent EGFR detections were collected from 11 centers. Objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed in EGFR-positive patients received EGFR-TKIs.

      Result

      28 ASCs were collected. NGS was performed on AC component and SCC component samples, respectively. The most frequent alterations in 28 ASCs were EGFR mutation (79%), TP53 mutation (68%), MAP3K1 mutation (14%), EGFR amplification (32%), and MDM2 amplification (18%). 27 patients had trunk variations in the both components suggesting the monoclonal origin of ASCs. The prevalence of trunk mutations was correlated to those of AC, indicating that ASC might originate from AC. Only one patient did not carry any trunk variations between AC and SCC components, which were clearly and geographically distinguishable under the microscope. 22 had AC component or/and SCC component specific variations suggesting the common event of branch evolution. The 23 LNs of 13 patients mainly contained AC and ASC components (AC, SCC, and ASC: 11, 1, and 11, respectively), and each of the LNs carried the trunk mutations of the primary ASC. Like pure AC, the alterations of L858R and Exon 19 Dels of EGFR were common in the 28 ASCs. Unfortunately, these patients have not been treated with TKIs. Further, of 517 retrospective ASCs from 11 centers, 51.8% were EGFR-positive. For the 129 EGFR-positive ASCs who had received TKIs, the ORR and DCR were 56.6% and 89.1%, respectively. The median PFS was 10.1 months (95% CI: 9.0-11.2).

      figure-1-wclc.jpg

      Conclusion

      The AC and SCC components share a monoclonal origin, and a majority have branching evolution. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR-TKIs.

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      MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)

      14:30 - 16:00  |  Presenting Author(s): Matthew P Smeltzer  |  Author(s): Murry W Wynes, Meghan Taylor, Kristin Richeimer, Kelsey Wood, Kristen Howell, Mercedes Liliana Dalurzo, Enriqueta Felip, Keith Kerr, Edward Kim, Sylvie Lantuejoul, Clarissa Mathias, Pieter E. Postmus, Charles Powell, Suresh S Ramalingam, Ross Soo, Masahiro Tsuboi, Ignacio Wistuba, Marileila Varella-Garcia, Giorgio Vittorio Scagliotti, Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.

      Method

      Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.

      Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.

      Result

      We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.

      1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.

      The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).

      The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.

      Conclusion

      These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.

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      MA21.04 - Discussant - MA21.01, MA21.02, MA21.03 (Now Available) (ID 3806)

      14:30 - 16:00  |  Presenting Author(s): Michael Duruisseaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.05 - Phase II Trial of the Combination of Alectinib with Bevacizumab in ALK-Positive Nonsquamous Non-Small Cell Lung Cancer (Now Available) (ID 1306)

      14:30 - 16:00  |  Presenting Author(s): Satoshi Watanabe  |  Author(s): Naoya Matsumoto, Jun Koshio, Akane Ishida, Tomohiro Tanaka, Tetsuya Abe, Daisuke Ishikawa, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Aya Otsubo, Ami Aoki, Tomosue Kajiwara, KENICHI Koyama, Satoru Miura, Hirohisa Yoshizawa, Toshiaki Kikuchi

      • Abstract
      • Presentation
      • Slides

      Background

      Alectinib is a 2nd generation highly selective anaplastic lymphoma kinase (ALK) inhibitor. Although alectinib has improved progression-free survival (PFS) in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC), there are limited treatment options after progression of alectinib. Recent evidences have described promising results of the combination of bevacizumab with EGFR-TKIs, cytotoxic chemotherapies and immune-checkpoint inhibitors. We report the results from a phase II study of the combination of alectinib with bevacizumab in ALK-positive Nonsquamous NSCLC patients who were treated with alectinib and showed disease progression (UMIN 000017828).

      Method

      Patients with ALK+ Nonsquamous NSCLC who had progressed after alectinib treatment were enrolled. Primary objective of this study was PFS and safety. Secondary endpoints included overall survival, objective response rate and disease control rate.

      Result

      Twelve patients received alectinib (600 mg/day) with bevacizumab (15 mg/kg, Q3W). Nine patients were treated with crizotinib and alectinib, and 2 patients were treated with crizotinib, alectinib and ceritinib before enrollment to this study. The median PFS was 3.1 months (95% CI 1.2-16.1) and the median survival time was 32 months (95% CI 8.3-NE). The median treatment cycle was 5 (range, 1-37) and 3 patients received alectinib with bevacizumab more than 20 cycles. The objective response rate and disease control rate were 8% and 67%, respectively. The most common treatment related adverse events were decreased appetite (42%), proteinuria (42%), hypertension (33%), anemia (33%) and fatigue (33%). Treatment related adverse events of grade > 3 were anemia (8%), proteinuria (8%), diarrhea (8%) and hypokalemia (8%). No severe adverse events were observed.

      Conclusion

      This is the first study to investigate the combination of alectinib and bevacizumab. This combination had clinical efficacy and was well tolerated.

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      MA21.06 - Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC   (Now Available) (ID 1720)

      14:30 - 16:00  |  Presenting Author(s): Helena A Yu  |  Author(s): Melissa Johnson, Conor E Steuer, Michele Vigliotti, Shuquan Chen, Yasuki Kamai, Channing Yu, Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (TKIs), in particular osimertinib. Overall, 57%–83% of NSCLC tumors express human epidermal growth factor receptor 3 (HER3). Because signaling through HER3 is not an established mechanism of resistance to EGFR TKIs, treatment with an anti-HER3 antibody–drug conjugate (ADC) presents an approach to targeting diverse resistance mechanisms in EGFR-mutant NSCLC. U3-1402 is a HER3-targeted ADC with a fully humanized antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Here, we present the safety/tolerability and antitumor activity data from the dose-escalation phase of an ongoing, multicenter, phase 1 study (NCT03260491).

      Method

      Patients had locally advanced or metastatic EGFR TKI-resistant, EGFR-mutant NSCLC. Patients with stable brain metastases were eligible. Dose escalation was based on dose-limiting toxicities (DLTs) guided by a Bayesian logistic regression model. U3-1402 was administered every 3 weeks via intravenous infusion. Pretreatment tumor tissue was required for retrospective HER3 immunohistochemistry analysis. Next-generation sequencing analysis was performed on available tumor tissue. Primary objectives included safety, tolerability, and identification of the recommended dose for expansion (RDE).

      Result

      As of May 2019, 30 patients were enrolled across 4 doses (3.2 [n=4], 4.8 [n=9], 5.6 [n=12], and 6.4 [n=5] mg/kg). Thirteen patients (43%) have discontinued (progressive disease [n=9], clinical progression [n=1], consent withdrawal [n=2], adverse event [AE; n=1]). All 30 patients received prior EGFR TKIs, of which 28 (93%) received prior osimertinib, and 15 (50%) prior chemotherapy. Activating EGFR mutations were reported in all patients (Ex19del: 57%; L858R: 40%; L861Q: 3%). All 25 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score, 183 [range, 56–290]). History of central nervous system (CNS) metastases was reported in 15 patients (50%). Treatment-emergent AEs were reported in 29 patients (97%; 13 patients [43%] reported grade 3/4). Two DLTs (grade 3 febrile neutropenia and grade 4 platelet count decrease) were reported in 1 patient (5.6 mg/kg) and 3 DLTs (all grade 4 platelet count decrease) in 3 patients (6.4 mg/kg). Of patients with a history of CNS metastases, 9 have progressed (2 with CNS progression; 3 with both CNS and non-CNS progression). One patient without a history of CNS metastasis progressed with new CNS disease. Of 26 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 6.4 mg/kg), including 2 patients with an EGFR C797S mutation. Median best percentage change in sum of diameters (SoD) was −25.7% (range, −82.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (–25.7% and –17.8%), HER2 amplification (–28.6%), and both CCNE1 amplification and PIK3CA mutation (–28.8%).

      Conclusion

      U3-1402 demonstrated tolerable safety and antitumor activity in this ongoing study. Antitumor activity of U3-1402 was seen in cancers with EGFR-mediated and other resistance mechanisms. These findings support the hypothesis that targeting HER3 with U3-1402 may provide clinical benefit to patients with EGFR-mutant NSCLC with diverse mechanisms of resistance. RDE evaluation is ongoing.

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      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.

      Method

      We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.

      Result

      At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.

      Conclusion

      ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.

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      MA21.08 - Discussant - MA21.05, MA21.06, MA21.07 (Now Available) (ID 3807)

      14:30 - 16:00  |  Presenting Author(s): Toyoaki Hida

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)

      14:30 - 16:00  |  Presenting Author(s): Arthur Geraud  |  Author(s): Laura Mezquita, Edouard Auclin, David Combarel, JULIA Delahousse, CHARLES Naltet, CECILE Jovelet, pernelle Lavaud, Anas Gazzah, LUDOVIC Lacroix, Jordi Remon, CAROLINE Caramella, David Planchard, OLIVIER Mir, ANGELO Paci, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).

      Method

      We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.

      Result

      Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.

      Conclusion

      TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.

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      MA21.10 - Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI (Now Available) (ID 1705)

      14:30 - 16:00  |  Presenting Author(s): Myung-Ju Ahn  |  Author(s): Sehhoon Park, Sunyoung Hong, JuYoun Park, MI RA Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (TKI) has successfully improved clinical outcome in non-small cell lung cancer (NSCLC) with activating EGFR mutation. However, up to 40% of TKI treated patients present with disease progression in the central nerve system (CNS) either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib is a 3rd generation EGFR TKI effective in T790M mutant NSCLC and characterized by high blood-brain barrier penetration. In this phase II, multicenter prospective single-arm two cohort study, the clinical efficacy of 160mg of osimertinib in T790M mutant BM or LM patients progressed on prior EGFR TKI was evaluated. (NCT0325712)

      Method

      BM only patients were included in the BM cohort (n=40). Patients with cerebrospinal cytology confirmed LM with or without BM were included in the LM cohort (n=40). 3rd generation TKI, including 80mg of osimertinib, was exposed to 18 patients in BM and 16 patients in LM cohort. T790M need to be identified from either tissue, plasma or cerebrospinal fluid. The primary endpoint was overall response rate (ORR) (H1=30%) for BM cohort and overall survival (OS) (H1=5months) for LM cohort, respectively.

      Result

      Median follow-up duration was 7.9 months for BM and 8.3 months for LM cohort. In BM cohort, median progression-free survival (PFS) was 7.3 months (95% confidential interval [CI] 3.6-13.7), and median OS was not reached (NR). Intracranial ORR and disease control rate (DCR) was 40.0% and 77.5%. Extracranial ORR and DCR was 30.0% and 67.5%. In LM cohort, median PFS was 8.9 months (95%CI 5.6-NR) and median OS was 13.2 months (95%CI 8.0-NR). When response of leptomeningeal lesion is separately evaluated, CR rate was 25.0% (n=10) and non-CR/non-PR rate was 65.0% (n=26). Extracranial ORR and DCR was 22.5% and 85.0%. Intracranial median PFS was not reached in both BM and LM cohort. Grade 3 adverse event (AE) was observed in 7 BM and 11 LM patients. Four patients required dose reduction due to AE. Among the patients who previously received 3rd generation TKI, 33.3% (6 out of 18) in BM cohort and 81.2% (13 out of 16) in LM cohort showed an intracranial DCR to 160mg of osimertinib. Extended survival analyses and exploratory outcomes will be presented at the conference.

      Conclusion

      In this study, 160mg of osimertinib demonstrated promising ORR and survival benefit with tolerable safety profile in EGFR T790M positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKI.

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      MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)

      14:30 - 16:00  |  Presenting Author(s): Sakiko Otani  |  Author(s): Kazuhiko Yamada, Shingo Miyamoto, Koichi Azuma, Hidenobu Ishii, Akihiro Bessho, Shinobu Hosokawa, Hideo Kunitoh, Kazuhito Miyazaki, Hiroshi Tanaka, Satoru Miura, Hiromi Aono, Yoshiro Nakahara, Kei Kusaka, Yukio Hosomi, Akinobu Hamada, Hiroaki Okamoto

      • Abstract
      • Presentation
      • Slides

      Background

      We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).

      Method

      Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.

      Result

      From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.

      Conclusion

      This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.

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      MA21.12 - Discussant - MA21.09, MA21.10, MA21.11 (Now Available) (ID 3808)

      14:30 - 16:00  |  Presenting Author(s): Hong-Xu Liu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS02 - What Molecular Screening for Which Patients? (ID 65)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 4
    • Now Available
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      MS02.01 - Platform Selection in an Era of Increasing Numbers and Types of Relevant Biomarkers (Now Available) (ID 3446)

      10:30 - 12:00  |  Presenting Author(s): David P Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract

      30 years ago, the selection of therapy for lung cancer patients was simple, with only a few choices available, and very little personalization beyond that which can be defined by standard light microscopy and physical exam. The treatment of lung cancer patients today has greatly improved with the discovery of features of tumors and patients that enable the selection of specific targeted and immunotherapy approaches resulting in substantially improved quality and quantity of life. Selection of the appropriate therapeutic based on these features makes huge differences in the lives of these patients, and many studies are now showing that starting with the matched therapy improves survival over switching to it after trying “one size fits all” therapy.

      Scientific advances are introducing more and more of these markers every year, and while this is undoubtedly a good thing for our patients, each of them has sensitivity, specificity, and platform issues that need to be defined, and adds a level of complexity to lung cancer management that is unprecedented. Individually, many of these features are rare so that the vast majority of individual assays performed are negative, further adding to clinical frustration. Technology has advanced to allow the testing of hundreds or thousands of gene sequences in a single analysis, but other markers are not simple gene sequence alterations, but rather gene rearrangements, protein expression alterations, and some RNA expression profiles that require testing on different platforms. As a result, optimal tumor profiling can involve several different analyses, can cost a significant amount of money, and take a significant amount of time to return a result in a disease where both time and resources available are scarce. Biopsy adequacy also becomes an issue with multi-platform testing, and the availability of blood-based testing lessens this issue for certain types of testing, but introduces issues of limited sensitivity and scope of analyses.

      Layered upon this are the different health care systems and availability of testing platforms found worldwide, each of which has to make hard decisions about doing the best thing for their patients within these local constraints. However, the impact on patient outcomes and the health care system of missing a key tumor feature and the selection of inappropriate and potentially toxic therapy, in a world where a single dose of a drug costs several times the cost of the testing makes cost of testing less of an issue than sample adequacy, speed of results availability, accuracy of results interpretation, and availability of matching drugs.

      In this section, the clinical and technical features of the currently available platforms in use and their advantages and disadvantages will be reviewed and compared.

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      MS02.02 - Liquid Biopsy: Who, When, What and How (Now Available) (ID 3445)

      10:30 - 12:00  |  Presenting Author(s): Christian Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Presentation Title: Liquid Biopsy: Who, When, What and How

      Prof. Dr. Christian Rolfo, MD, PhD, MBA, Dr.h.c., Director of Thoracic Medical Oncology and Early Clinical Trials at University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center, 22 S Greene Street Rm. N9E08, Baltimore, MD 21201.

      Liquid biopsy (LB) refers to a multitude of biomarkers that can be isolated with minimally invasive methods from human body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) that include cell free DNA (cfDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), long non coding RNAs (lncRNAs), and exosomes (Fig. 1). Plasma genotyping of cfDNA entered clinical practice in non-small cell lung cancer (NSCLC) for detection of EGFRmutations in both treatment-naïve and EGFR-mutated NSCLC after progression to EGFR tyrosine kinase inhibitors (TKIs) as an alternative source to tissue when histological samples are insufficient or when a biopsy is not feasible. Indeed according to the LB IASLC statement1, plasma cfDNA analysis should be offered to the same population candidate for molecular testing using DNA isolated from tissue (all non-squamous NSCLC subjects, or adenosquamous or in patients with clinical features suggestive of the presence of a molecular driver) in cases with insufficient tumor tissue specimens or where tissue specimens are not obtainable. Moreover, LB is indicated for the identification of acquired resistance mutations in EGFR-mutated NSCLCs progressing during treatment with first- or second-generation EGFR TKIs, reserving tissue re-biopsy in case of negative or inconclusive results.

      The PCR-based cobas EGFR Mutation Test v2 was the first FDA approved LB test for NSCLC, although several limitations on sensitivity of this technique. Fortunately, LB is a rapidly evolving field and several commercial and “in house”NGS platforms have been developed, allowing a more comprehensive plasma genotyping that include genetic rearrangements (such as ALK, ROS1, RET, and NTRK) as well as other relevant oncogene drivers, including mutations of BRAF, HER2, MET, and KRAS. Some of the vendors have a Medicare reimbursement in United States. Recently, the multicenter prospective Noninvasive versus Invasive Lung Evaluation (NILE) study demonstrated that a validated and highly sensitive plasma 73-gene NGS test (Guardant360) used at the time of diagnosis of NSCLC was non-inferior to standard-of-care tissue genotyping in identifying guideline-recommended genomic biomarkers, allowing a guideline-complete genotyping in a higher proportion of patients with a shorter median turnaround time2. These results support the rationale for a “blood-first” approach, reserving tissue for PD-L1 immunohistochemistry or in case of negative liquid biopsy testing. In addition to cfDNA, cfRNA is a novel approach to enhance the comprehensive analysis of circulating biormakers.

      Furthermore, the increasing use of more sensitive detection methods, such as NGS, poses novel technical and biological challenges in our clinical practice, including the identification of non tumor-related mutations due to clonal hematopoiesis (CH), increased risk of false positive in presence of low variation allelic fraction (VAF), need for standardization and validation of the analytical methods, definition of requirements for appropriate report and interpretation of the results. Novel technologies such as CH-filtering ultradeep NGS have been tested with promising results3. Moreover, the adoption of molecular tumor board is essential for helping oncologists in interpreting NGS testing results4, using evidence-based scales, such as OncoKB and ESCAT tiers5,6.

      Recently, LB use has been advocated in immunotherapy-treated patients as a minimally invasive method that can allow a real time monitoring of treatment response and interpretation of challenging radiographic situations, overcoming the limits of conventional radiological assessment methods7,8. Further prospective studies are needed to better clarify the role of cfDNA as a predictive biomarker for immune checkpoint blockage in NSCLC. LB can also allow the estimation of tumor mutational burden (TMB) in plasma, proving a valuable alternative to tissue. Exploratory analyses of two large randomized phase III studies explored the potential utility of blood TMB (bTMB) as predictive biomarker for immunotherapy, using two different platforms (Foundation Medicine and GuardantOMNI)9,10. The results of these studies support bTMB as potential biomarker for immunotherapy in NSCLC. Further prospective studies will clarify the role of bTMB in treatment selection of patient candidate for immunotherapy, as well as the optimal cut-off value, the minimum number of genes necessary for TMB estimation, and the specific mutations useful.

      References

      Rolfo C, et al. J Thorac Oncol 2018

      Leighl N, et al. Clin Cancer Res 2019

      Li BT, et al. Ann Oncol 2019

      Rolfo C, et al. ESMO Open 2018

      Chakravarty D, et al. JCO Precis Oncol 2017

      Mateo J, et al. Ann Oncol 2018

      Anagnostou V, et al. Cancer Res. 2019

      Guibert N, et al. ASCO-SITC 2019

      Peters S, et al. AACR Annual meeting 2019

      Gandara DR, et al. Nat Med 2018

      abstract lb wclc 2019 for christian 2.png

      Figure 1Liquid biopsy in NSCLC – Who, When, What and How? (Credit: created with BioRender)

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      MS02.03 - Achieving Effective Lung Cancer Genotyping While Balancing Constrained Resources (Now Available) (ID 3444)

      10:30 - 12:00  |  Presenting Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Abstract

      Modern oncologic practice for patients with non-small cell lung carcinoma (NSCLC) demands real time data for an increasing numbers of tumor biomarkers. As a result, laboratories are embracing panel-based approaches to tumor molecular profiling, a trend that is facilitated by the adoption of next generation sequencing (NGS) assays. NGS assays may be designed for highly sensitive and focused detection of hotspot mutations (typically by amplicon sequencing) or broader, more comprehensive profiling for detection of a wide variety of alterations in oncogenes and tumor suppressor genes (typically by hybrid capture technology). There are benefits and drawbacks to both approaches. In general, amplicon sequencing offers speed and sensitivity but limited scope and a propensity for PCR-related artifacts that may adversely affect detection of certain mutation types. In contrast, hybrid capture techniques offer tremendous breadth, enabling capture of 100s of genes to whole genomes, but are limited by sensitivity and longer turnaround time.1 Preanalytic steps including sample acquisition, pathologist review to confirm sample adequacy, and nucleic acid extraction often comprise the majority of the turnaround time required to complete focused tumor tissue molecular profiling. Some assays have been optimized for turnaround times of just a few hours- these assays bypass the separate nucleic acid extraction step,2 but are limited by the few number of mutational targets detected, ultimately requiring the use of multiple simultaneous or sequential focused panels.3 This practice, while perhaps the optimal current model from the standpoint of patient care, may be financially prohibitive for many laboratories. This approach additionally requires careful stewardship of patient tissues, as the use of multiple competing assays and may lead to exhaustion of tumor tissue and incomplete tumor molecular profiling. For patients with limited tissue, a considered plan incorporating input from the treating physician, surgical pathologist, and molecular laboratorian should developed early in order to guide assay priority and ensure adequate tissue is available to confirm any unexpected or contradictory results. When the turnaround time for comprehensive large panel testing is clinically acceptable, this approach may be theoretically more cost effective and in most cases will deliver information for essential and emerging biomarkers.4 It is important to keep in mind, however, that even comprehensive DNA-based assays may lack optimal sensitivity for certain structural variants (fusions, large insertion-deletion events), and it may be necessary to couple these tests with focused RNA-based panels optimized for transcript fusion detection.5

      1. Rizzo JM, Buck MJ. Key principles and clinical applications of "next-generation" DNA sequencing. Cancer Prev Res (Phila). 2012;5(7):887-900.

      2. Ilie M, Butori C, Lassalle S, et al. Optimization of EGFR mutation detection by the fully-automated qPCR-based Idylla system on tumor tissue from patients with non-small cell lung cancer. Oncotarget. 2017;8(61):103055-103062.

      3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018;20(2):129-159.

      4. Sireci AN. Single Genes, Panels, and Next-Generation Sequencing Platforms: A Financial Perspective. Arch Pathol Lab Med. 2018;142(7):790-791.

      5. Benayed R, Offin M, Mullaney K, et al. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019.

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      MS02.04 - The Role of Molecular Board (Now Available) (ID 3447)

      10:30 - 12:00  |  Presenting Author(s): Lara Pijuan

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Role of Molecular Board

      Lung Tumor Board is a multidisciplinary group of specialists who are responsible for diagnosing and deciding the best treatment for a patient with lung cancer. In cancers with little to no metastatic evidence, the case is handed over to surgeons or sometimes to radiotherapists for local and curative treatment. But in cases of locally advanced or metastatic stages, the patient visits the oncologist alone or in conjunction with the radiotherapists for a more systemic approach. A few years ago, the patient was presented to tumor board immediately, but now because we are in the age of precision medicine, the oncologist can gather more information about the tumour itself to initiate the best personalized treatment for each patient’s cancer. In fact, the oncologist requires 3 types of information: accurate histological diagnosis, molecular characteristics of the tumor, and PD-L1 expression.

      Prior to the creation of this molecular tumor board, this information could be given by mail, mobile phone messaging, phone call or in person, since all the information usually arrives a few days after the patient is presented at Lung Tumor Board. If all this information is presented in a room with all the specialists involved in obtaining it, the data can be better analysed and the therapeutic decision making will be much more precise. Hence the idea of creating a MTB with oncologists, pathologists, biologists, bioinformatics, technicians, palliative care, and residents to review the different results for a lung cancer patient.

      The type of patients to present in this type of Molecular Tumour Board is widely variable, but usually fall into one of these 6 categories:

      1) Newly diagnosed patients with metastatic disease.

      The MTB would reaffirm that there is sufficient material and that all the molecular or immunohistochemical techniques are underway (EGFR, BRAF, ALK, ROS1, and PD-L1). Oncologists re-assign the patient for the next MTB to review final results. The pathologist also comments on the percentage of tumour cellularity, so that technicians and biologists can make optimized calculations of the cuts and the type of sample that the biologist has to work with (biopsy and/or cell block and/or cytological smears).

      2) Patients with progressive disease with a known molecular marker.

      They can be patients where the oncologist repeats sampling. Usually the patient is more familiar to the biologist because he receives liquid biopsies to monitor the disease and the pathologist only knows the patient if he has a re-biopsy.

      3) Patients with possible disease progression, pseudoprogression or hyperprogression after immunotherapy.

      4) Patients with molecular results received from outside (FM, FOne, clinical trials)

      The patient is more familiar to the oncologist who treats him and who has decided to send a sample for a clinical trial or external platform. They are presented in the MTB in order to reaffirm the mutation or translocation found with technology available in the center or maybe it can be consulted outside.

      5) Surgical patients with multiple adenocarcinomas that require definitive staging.

      The patient is most familiar to the pathologist who diagnosed the surgical tumor. They are presented in order to know molecular details of multiple synchronous tumours.

      6) Patients that wish to utilize stored material for new diagnostic studies/techniques

      For reasons of disease progression, the patient may enter a clinical trial or has the option of systemic treatment, so some studies that were not previously performed in are required.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 8
    • Now Available
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      OA14.01 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (ID 1465)

      11:30 - 13:00  |  Presenting Author(s): Martin Reck  |  Author(s): Delvys Rodríguez-Abreu, Andrew G. Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Tara Garay, Erin Jensen, Victoria Ebiana, Julie R. Brahmer

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-024 trial (NCT02142738), first-line pembrolizumab significantly improved PFS (hazard ratio [HR] 0.50, P<0.001) and OS (HR 0.60, P=0.005) vs platinum-based chemotherapy in patients with advanced NSCLC, PD-L1 tumor proportion score (TPS) ≥50%, and no targetable EGFR/ALK alterations (median follow-up, 11.2 months). We present data with 3-years minimum follow-up.

      Method

      Patients were randomized to pembrolizumab 200 mg Q3W for 2 years or platinum doublet (investigator’s choice) for 4‒6 cycles plus optional maintenance (nonsquamous), with stratification by ECOG PS (0/1), tumor histology (squamous/nonsquamous), and region (East Asia/non‒East Asia). Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression if they met eligibility criteria. The primary endpoint was PFS; OS was a key secondary endpoint. Response per investigator by RECIST version 1.1 is reported.

      Result

      305 patients were randomized (pembrolizumab, n=154; chemotherapy, n=151). At data cutoff (February 15, 2019), median (range) follow-up was 44.4 (39.6‒52.9) months. 210 patients had died (pembrolizumab, n=97; chemotherapy, n=113). 98 (64.9%) patients crossed over from chemotherapy to anti‒PD-(L)1 therapy during/outside of the study. Median (95% CI) OS in the pembrolizumab arm was 26.3 (18.3‒40.4) months vs 14.2 (9.8‒18.3) months in the chemotherapy arm (HR, 0.65; 95% CI, 0.50‒0.86). 36-month OS rate was 43.7% in the pembrolizumab arm vs 24.9% in the chemotherapy arm. Despite longer mean treatment duration in the pembrolizumab arm (11.1 vs 4.4 months), grade 3‒5 treatment-related adverse events (AEs) were less frequent with pembrolizumab vs chemotherapy: 31.2% vs 53.3%. 38 patients in the pembrolizumab arm completed 2 years (35 cycles) of therapy. Among these, 34 were alive, 31 (81.6%) had an objective response (including 3 with complete response), and median duration of response was not reached (range, 4.2‒46.7+ months). OS rate 12 months after completing pembrolizumab treatment (ie, ~36 months after initiating treatment) was 97.4% (95% CI, 82.8‒99.6). Among the 38 patients who completed 2 years, 5 (13.2%) had treatment-related grade 3-4 AEs; no fatal treatment-related AEs occurred. 10 patients who completed 2 years (1 completed 34 cycles) and subsequently progressed received second-course pembrolizumab; 7 had an objective response, 8 remain alive.

      Conclusion

      With >3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide durable long-term OS benefit vs chemotherapy despite a majority of patients assigned to chemotherapy crossing over to pembrolizumab. Pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had durable clinical benefit and most were alive at data cutoff.

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      OA14.02 - IMpower131: Final OS Results of Carboplatin + Nab-Paclitaxel ± Atezolizumab in Advanced Squamous NSCLC (ID 1915)

      11:30 - 13:00  |  Presenting Author(s): Federico Cappuzzo  |  Author(s): Robert Jotte, Ihor Vynnychenko, Daniil Stroyakovskiy, Delvys Rodriguez Abreu, Maen Hussein, Ross Soo, Henry J Conter, Toshiyuki Kozuki, KC Huang, Vilma Graupner, Shawn Sun, Tien Hoang, Helen Jessop, Mark McCleland, Marcus Ballinger, Alan Sandler, Mark A Socinski

      • Abstract
      • Slides

      Background

      IMpower131 (NCT02367794) is a randomised Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC. Here we report the final OS results (Arm B vs Arm C).

      Method

      Enrolled patients were randomised 1:1:1 to Arm A (atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w), Arm B (atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw) or Arm C (carboplatin + nab-paclitaxel) for 4 or 6 cycles followed by atezolizumab maintenance therapy (Arms A and B) until loss of clinical benefit or progressive disease. Coprimary endpoints were investigator-assessed PFS and OS in the ITT population. Data cutoff: October 3, 2018.

      Result

      1021 patients were enrolled, with 343 in Arm B and 340 in Arm C. Median age was 65 years (range, 23-83 [Arm B] and 38-86 [Arm C]) and ≈80% of patients were male. The proportion of patients with high (14% vs 13%), positive (39% vs 37%) or negative (47% vs 50%) PD-L1 expression was similar between arms. Median OS in the ITT population was 14.2 months in Arm B vs 13.5 months in Arm C (HR, 0.88 [95% CI: 0.73, 1.05]; P = 0.158; Table), not crossing the boundary for statistical significance. In the PD-L1–high subgroup, median OS was 23.4 vs 10.2 months, respectively (HR, 0.48 [95% CI: 0.29, 0.81]; not formally tested). Treatment-related Grade 3-4 AEs and treatment-related SAEs occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses.

      Conclusion

      Final OS in Arm B vs C did not cross the boundary for statistical significance. Clinically meaningful OS improvement was observed in the PD-L1–high subgroup, despite not being formally tested. No new or unexpected safety signals were reported.

      Arm B

      Atezolizumab + Carboplatin
      + Nab-Paclitaxel

      (n = 343)

      Arm C

      Carboplatin +
      Nab-Paclitaxel

      (n = 340)

      HR (95% CI)

      Median OS, mo

      ITT

      14.2

      13.5

      0.88 (0.73, 1.05); P = 0.16

      PD-L1 high (TC3 or IC3)

      23.4

      10.2

      0.48 (0.29, 0.81)

      PD-L1 positive (TC1/2/3 or IC1/2/3)

      14.8

      15.0

      0.86 (0.67, 1.11)

      PD-L1 negative (TC0 or IC0)

      14.0

      12.5

      0.87 (0.67, 1.13)

      Median PFS, mo

      6.5

      5.6

      0.75 (0.64, 0.88)

      Confirmed ORR, n/N (%)a

      170/342 (49.7)

      139/339 (41.0)

      a Patients were classified as missing or unevaluable when no post-baseline response assessments were available or all post-baseline response assessments were unevaluable.

      CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; OS, overall survival; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TC, tumour cell.
      TC3 or IC3: PD-L1 expression on ≥50% of TC or ≥10% of IC; TC1/2/3 or IC1/2/3: PD-L1 expression on ≥1% of TC or IC; TC0 and IC0: PD-L1 expression on <1% of TC and IC.

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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Presenting Author(s): Janna Claire Minehart  |  Author(s): Takashi Eguchi, Aurore Morello, Prasad S Adusumilli

      • Abstract
      • Slides

      Background

      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.

      Method

      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.

      Result

      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.

      Conclusion

      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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      OA14.05 - Discussant - OA14.01, OA14.02, OA14.03, OA14.04 (Now Available) (ID 3799)

      11:30 - 13:00  |  Presenting Author(s): Jay M Lee

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA14.06 - Hyperprogressive Disease in Advanced Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (Now Available) (ID 1835)

      11:30 - 13:00  |  Presenting Author(s): Giuseppe Lo Russo  |  Author(s): Diego Signorelli, Claudia Proto, Giulia Galli, Arsela Prelaj, Roberto Ferrara, Michele Sommariva, Massimo Moro, Valeria Cancila, Monica Ganzinelli, Silvia Brich, Sabina Sangaletti, Giancarlo Pruneri, Claudio Tripodo, Mario Paolo Colombo, Licia Rivoltini, Andrea Balsari, Gabriella Sozzi, Mattia Boeri, Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).

      Method

      We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 12/2018. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). (Table). All ICIs administered for ≥1 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.

      Table HPD definition on the basis of 3 concomitant out of the five possible criteria

      HPD CLINICAL & RADIOLOGICAL CRITERIA

      Time-to-treatment failure < 2 months

      Increase of ≥ 50% in the sum of target lesions major diameters between baseline and first radiological evaluation

      Appearance of at least two new lesions in an organ already involved between baseline and first radiological evaluation

      Spread of the disease to a new organ between baseline and first radiological evaluation

      Clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment

      Result

      We reviewed 301 cases and 257 were evaluable for response. We identified four categories: responders (R, 57 cases, 22.2%), patients with stable disease as best response (SD, 69 cases, 26.8%), patients with progressive disease as best response (P, 78 cases, 30.4%) and patients with HPD (53 cases, 20.6%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,5 vs 2,3 vs 1,5 months ( p < 0.0001) and 32,5 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.448, 95% CI 2.137-2.899, p<0.0001) and OS (HR 2.481, 95%CI 2.092-2.950, p < 0.0001) confirmed the worse outcome of HPD group.

      Conclusion

      Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients. The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.

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      OA14.07 - Clinical and Genetic Characterization of Hyperprogression Based on Volumetry in Advanced NSCLC Treated with Immunotherapy (Now Available) (ID 1067)

      11:30 - 13:00  |  Presenting Author(s): Youjin Kim  |  Author(s): Chu Hyun Kim, Se-Hoon Lee, Ho Yun Lee, Hong Sook Kim, Kyunga Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD), characterized by accelerated tumor progression, has been proposed as a new pattern of progression following immune checkpoint inhibitor (ICI) treatment. The aim of this study was to describe the characteristics of HPD and investigate its predictive markers.

      Method

      Clinical and radiological findings of 335 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy were retrospectively analyzed. Radiological data were quantitatively and longitudinally analyzed for tumor size and volume by comparing baseline and follow-up computerized tomography results. The findings were matched to individual genomic profiles generated by deep sequencing of 380 genes.

      Result

      Among 135 patients with progressive disease (PD), as assessed by RECIST, 48 (14·3% of total and 35·6% among PD) and 44 (13·1% of total and 32·6% among PD) were found to have HPD by volumetric (HPDV) and one-dimensional (HPDR) analysis, respectively. HPDV patients were associated with significantly inferior overall survival (OS) compared with non-HPDV PD patients (median OS (months), 4·7 [95% confidence interval (CI), 3·5–11·9)] vs. 7·9 [95% CI, 6·0–13·5], p=0·004); OS did not differ between HPDR and non-HPDR patients. HPDV status was an independent OS factor. Derived neutrophil-to-lymphocyte ratio (dNLR) greater than 4 and lactate dehydrogenase (LDH) greater than the upper normal limit were significantly associated with HPDV. Moreover, we identified coinciding KRAS and STK11 mutations in the HPDV cohort (3/16), while none were found in the non-HPDV cohort (0/28).

      Conclusion

      Defining HPD treated with ICI based on volumetric measurement is more precise than that based on one-dimensional analysis. Pre-ICI dNLR, LDH, and concurrence of STK11 and KRAS mutations could, thus, be used as potential biomarkers for HPD prediction.

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      OA14.08 - Discussant - OA14.06, OA14.07 (Now Available) (ID 3800)

      11:30 - 13:00  |  Presenting Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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