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    ES01 - What Is the Role of Chemotherapy in the Era of Immunotherapy in Advanced NSCLC? (ID 4)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 5
    • Now Available
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      ES01.01 - Chemotherapy is Strictly Additive to Immunotherapy (Now Available) (ID 3149)

      10:30 - 12:00  |  Presenting Author(s): Johan Vansteenkiste  |  Author(s): Els Wauters

      • Abstract
      • Presentation
      • Slides

      Abstract

      Historically, chemotherapy was the only systemic therapy for advanced NSCLC. Over the last decades, effective targeted therapy has been developed. EGFR is the prime target since 20 years now [1], and is followed by an increasing number of targetable rare oncogenic driver mutations. This decade, the phase I trial of nivolumab – including NSCLC patients – started recruitment on July 1, 2011 [2]. Since then, immunotherapy with immune checkpoint inhibition (ICI) has become the third pillar in our therapeutic armentarium, with a very rapid development for relapsed, and thereafter for untreated advanced NSCLC. Most patients with non-oncogene addicted advanced NSCLC will nowadays have both chemotherapy and ICI, either in a concurrent or sequential way. This raises the question whether their interaction is synergistic or additive, favoring the former versus the latter approach. We will look at this from the perspective of adverse events, mechanistic background, and clinical trial outcomes.

      There is not much overlap between the typical and common adverse events (AEs) of chemotherapy or ICI. The former are mostly bone marrow inhibition, nausea/vomiting, mucositis, hair loss and neuropathy. ICIs are well tolerated, with no or mild AEs in most patients, but may induce immune related AEs mostly in skin or endocrine organs, liver, lungs or kidneys. Hence, there is little difference in overall adverse event profiles when the chemotherapy+ICI (chemo+ICI) and chemotherapy+placebo (chemo+PL) arms from randomized trials are compared. In the Keynote-189 trial - an example with the anti-PD-1 agent pembrolizumab – overall grade 3 to 5 AEs were present in 67.2% and 65.8% of patients with chemo+ICI and chemo+PL, respectively [3]. Grade 3 to 5 immune-related AEs, as rated by investigators blinded to the assigned therapy, were 8.9% for chemo+ICI, while 4.5% for chemo+PL. AEs leading to discontinuation of all treatment were 13.8% and 7.9%, respectively. Hence, irAEs acted additive to the overall AE profile. The notable exception in this trial was renal toxicity. There was a low frequency of auto-immune nephritis (1.7%), but there was a 5.2% incidence of acute kidney injury in the chemo+ICI arm, compared to 0.5% in the control arm.

      In the IMpower-133 trial – an example with the anti-PD-L1 agent atezolizumab – overall grade 3 to 5 AEs were present in 67.2% and 63.8% of patients with chemo+ICI and chemo+PL, respectively [4]. All grade immune-related AEs, as rated by investigators blinded to the assigned therapy, were 39.9% for chemo+ICI, and 24.5% for chemo+PL. So, here again a rather additive pattern in AE profile is put forward.

      Chemotherapy has long time been regarded as immunosuppressive and incompatible with immuno­therapy. To improve on the rather low response rate with ICI alone, recent trials focused on the combination of chemo+ICI, trying to exploit the immune modulatory (synergistic) effects of chemotherapy both on the tumor cells and immune cells. The details of this interaction are beyond the scope of this abstract, but a central one is immunogenic cell death (ICD) by chemotherapy. In contrast with necrotic/apoptotic cell death, ICD is characterized by immune-promoting features on dendritic cells and macrophages, by means of inducing calreticulin expression on tumor cells, release of adenosine triphosphate in the extracellular space and of high mobility group box 1 protein from the nucleus of the cancer cell. ICD, however, has been associated with only a limited number of chemotherapeutic agents used in clinical practice, such as doxorubicin, mitoxantrone, oxaliplatin and cyclophosphamide [5]. None of these agents is part of the modern chemotherapeutic armentarium for NSCLC.

      Recent phase III trials with chemo+ICI versus chemo+PL demonstrated a convincing benefit in response rate, progression-free survival (PFS) and overall survival (OS) with the combination (e.g. [3]). Of note, there are no randomized data comparing the combination of chemo+ICI in a concurrent versus a sequential way. Ideally, such a trial should have several arms: one with the concurrent use of chemo+ICI in all PD-L1 tumors; a sequential one with pembrolizumab followed by chemotherapy in PD-L1 >=50% tumors; and one with the sequential use of a chemotherapy and then ICI in PD-L1 <50% tumors. The primary endpoint preferably should be PFS2 in a intention-to-treat analysis.

      In the absence of such data, there is no definitive evidence that one or the other strategy is superior, and we can only make speculations about this question. At the meeting, we will present suggested algorithms based on the comparison of PFS from several recent trials. Especially the PFS2 analysis of the Keynote-024 [6,7] and KN-189 [3,8] trials are helpful in this respect. Even if there are many caveats with this approach, it may be helpful to guide clinical practice between concurrent and sequential treatment strategies.

      References

      1. Vansteenkiste J, Wauters E. Tyrosine kinase inhibition of EGFR: A successful history of targeted therapy for NSCLC since 20 years. Ann Oncol 2018; 29 Suppl 1: i1-i2.

      2. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-54.

      3. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. N Engl J Med 2018; 378: 2078-92.

      4. Horn L, Mansfield AS, Szczesna A et al. First-line atezolizumab plus chemotherapy in extensive-stage small cell lung cancer. N Engl J Med 2018; 379: 2220-9.

      5. Bezu L, Gomes-de-Silva LC, Dewitte H et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 2015; 6: 187.

      6. Brahmer JR, Rodriguez-Abreu D, Robinson AG et al. Progression after the next line of therapy (PFS2) and updated OS among patients with advanced NSCLC and PD-L1 TPS >=50% enrolled in KEYNOTE-024. J Clin Oncol 2017;. 35S, abstr 9000.

      7. Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med 2016; 375: 1823-33.

      8. Gadgeel SM, Garassino MC, Esteban E et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic non-squamous NSCLC. J Clin Oncol 2019; 37S, abstract 9013.

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      ES01.02 - Chemotherapy Enhances the Efficacy of Immunotherapy (Now Available) (ID 3150)

      10:30 - 12:00  |  Presenting Author(s): Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract

      Combination chemotherapy with anti-PD-1 therapy has now become standard of care as first-line therapy in patients with advanced NSCLC. Several trials demonstrate the improvement of combination therapy versus chemotherapy alone, but trials comparing immunotherapy +/- chemotherapy are ongoing (e.g. INSIGNA, CCTG BR.34, Checkmate 9LA, Checkmate 227).

      Several preclinical studies suggest that adding chemotherapy to immunotherapy is additive. Chemotherapy has been shown to disrupt immunsuppressive cell activity, for example regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumour associated macrophages (TAM) in preclinical studies (reviewed in Yan et al. Frontiers in Immunology, 2018). Chemotherapy may also promote immune responses via induction of tumor cell death, upregulation of MHC Class 1 expression and dendritic cell maturation. Lara et al recently reported activity both preclinically and clinically when combining gemcitabine with anti-PD1 therapy in mesothelioma, despite lack of activity of either as a single agent (Lara et al. Clin Cancer Res 2018).

      A key question in the first-line setting for those eligible for anti-PD1 monotherapy (PDL1 TPS >=50%) is whether the addition of chemotherapy is of benefit. Keynote 024 demonstrates superior survival, progression-free survival and response in this population compared to platinum doublet therapy, with a response rate of 45%. Overall response rates in the Keynote 189 and 407 trials in the subgroup with PDL1 TPS>=50% were 60% and 63% for chemotherapy plus pembrolizumab. Despite consensus that some patients clearly benefit from combination therapy while others likely can receive anti-PD-1 monotherapy, it is unclear how to select patients for each strategy. Ongoing studies are currently examining this question, such as the US cooperative-group-led INSIGNA trial (NCT03793179). In this study, patients with advanced PDL1 TPS>=1% nonsquamous NSCLC will be randomized to receive either (1) pembrolizumab monotherapy followed by pemetrexed/platinum upon progression; (2) pembrolizumab monotherapy and upon progression, the addition of pemetrexed/platinum to pembrolizumab; and (3) pembrolizumab/pemetrexed/platinum followed by maintenance pembrolizumab/pemetrexed with investigator's choice of treatment upon progression. It is hoped that this study will provide answers in how to best select patients for either strategy.

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      ES01.03 - Chemotherapy Directly Targets the Immune System to Improve Efficacy  (Now Available) (ID 3151)

      10:30 - 12:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multiple phase III trials support the use of combination chemotherapy with immune checkpoint inhibitors in the first line setting. Yet the exact mechanism of synergy is poorly understood. In this third instalment of three talks dissecting this topic, the focus will be on the impact of chemotherapy on the immune system, ranging from its effect on recognition of tumor antigens, circulating immune cells and/or cytokines, as well as on immune cells in the tumor microenvironment. Elucidating the mechanism of action can delineate more tailored approaches to first line therapy, including the use of single agent checkpoint inhibitors or alternative/ additional combinations that further enhance the immune response.

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      ES01.04 - Immunotherapy, Radiotherapy and Chemotherapy Combination: A Potential New Standard? (Now Available) (ID 3152)

      10:30 - 12:00  |  Presenting Author(s): Maurice Perol

      • Abstract
      • Presentation
      • Slides

      Abstract

      The advent of immunotherapy in lung cancer with immune checkpoints inhibitors (CPIs) has first involved stage IV non-small cell lung cancer (NSCLC), recently in combination with cytotoxic chemotherapy in first-line setting. The rationale to combine chemotherapy with CPIs is theoretically based on the chemotherapy-induced immunogenic cell death triggering an immune response and the modification of the tumor microenvironment (TME) by depletion of immunosuppressive cells. Radiotherapy remains one of the main components of the NSCLC treatment, from early stages with stereotactic ablative radiotherapy (SABR) and locally advanced stage III NSCLC in combination with chemotherapy to stage IV disease for the local palliative treatment of metastatic sites. Radiation therapy (RT) techniques have been considerably improved with image-guidance, and technological developments in linear accelerators, allowing now a very precise delivery of radiation.

      Radiation biology has been mainly concentrated on radiation-induced DNA damage with irreparable double strand break, leading to cell cycle inhibition and cell death. There are also a rationale and a preclinical evidence to expect a synergy between RT and CPIs. RT can also cause immunogenic cell death by direct cytotoxic effects, resulting in the release of tumor-associated antigens (TAAs) and danger signals (DAMPs: damage associated molecular pattern) that can be recognized by toll-like receptors, thus facilitating the presentation of TAAs to CD8+ T cells by MHC I. The dendritic cell activation and up-regulation of interferon pathway also enhance TAAs presentation to immune cells and up-regulate MHC-1 expression on tumor cells. Radiotherapy can therefore act as an auto-vaccine, activating the dendritic cells, broadening up the immune repertoire of T cells and increasing the "visibility" of TAAs. Beside this promotion of priming and activation of cytotoxic T cells, RT upregulates PD-L1 expression in the TME. Nevertheless, the modification of TME induced by RT may be equivocal with on one hand an increase in the CD8+ T cells recruitment by up-regulation of adhesion molecules, but on the other hand, the promotion of immune tolerance via the recruitment of MDSCs and Treg cells. Moreover, RT activates the immunosuppressive TGF-β pathway by reactive oxygen species. In addition to the potential synergism in terms of local control, the RT might also mediate an abscopal effect, describing the tumor regression of lesions distant from the irradiated volume, due to circulating of T cells locally activated by RT. This phenomenon has been experimentally demonstrated in preclinical models and occasionally reported in case reports.

      In stage IV NSCLC, the impact of RT delivered on a metastatic site or on the primary tumor on CPIs anti-tumor effect has been suggested by the retrospective analysis of the Keynote 001 phase I trial of pembrolizumab showing that patients who received radiotherapy before pembrolizumab had a better overall survival (OS) and progression-free survival (PFS) than those patients who did not receive radiotherapy. Many ongoing trials are exploring the possibility to "boost" the activity of CPIs by the addition of local RT, especially SABR; these trials have to face many challenges in terms of treatment timing, radiation dosing, and minimization of the RT toxicity on local and circulating T-cells. The main advance was brought in stage III NSCLC by the Pacific study which evaluated the impact of a treatment consolidation with durvalumab (anti-PD-L1), administered during 1 year after completion of concurrent chemoradiation therapy. This trial was a double-blinded, 2:1 randomized versus placebo study; randomization was authorized between 1 and 42 days after the end of radiation therapy. PD-L1 status was not required for enrollment. The majority of the 713 included patients were male, smokers and received a dose of radiotherapy between 54 and 66 Gy. The addition of durvalumab after concurrent chemo-RTsignificantly improved both PFS (median 17.2 vs. 5.6 months, HR 0.51 95%CI, 0.41-0.63) and OS at the first interim analysis (median not reached vs. 28.7 months, HR 0.68 99.73%CI, 0.469-0.997). The effect of durvalumab was mainly due to a reduction of metastatic relapses, including brain metastases. Subgroups analysis showed a trend toward a greater magnitude of PFS and OS benefit for patients randomized early after completion of radiotherapy (<14 days). The exploratory analysis of the impact of PD-L1 expression on the magnitude of benefit was planned with a cutoff at 25% for tumor cells. Knowing that 37% patients had no PD-L1 assessment, the analysis showed a PFS benefit in both subgroups of patients and no OS benefit for patients with PD-L1<25%. At the request of EMA, an additional unplanned subgroup analysis at the cutoff of 1% showed no PFS benefit and a trend toward a worse survival with durvalumab for the PD-L1<1% tumors, due to an unexpected very good survival for patients randomized in the placebo group in this small subset of patients. While FDA approval of durvalumab was unrestricted, the European label is limited to the PD-L1≥1% tumors, even if the statistical validity of the subgroup analysis is questionable. The risk of pneumonitis after radiation therapy was slightly increased in the durvalumab arm without significant augmentation of grade ≥3 events.

      Pacific was the first study demonstrating the potential for CPIs to obtain a potential synergy with radiation therapy, defining a new standard of care for these patients. However, further already ongoing clinical research will have to address the questions of a similar benefit with sequential chemoradiation therapy and of the optimization of this potential synergy by administering immunotherapy concurrently with thoracic radiotherapy as suggested by preclinical data. Potential long term toxicities must also be carefully assessed. Another area of further development of RT and CPIs combinations actually investigated is the incorporation of immunotherapy after SABR in the treatment of early stage NSCLC.

      The combination of RT and immunotherapy has proven effective in preclinical studies and in stage III NSCLC. A lot of challenges still exist to harness the combination of chemotherapy, RT and CPIs, especially in terms of timing, irradiated volume, fractionation, and dose that likely play a major role in the modulation of the RT different effects on the tumor cells, the immune response and the TME.

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      ES01.05 - Future of Dual Anti-CTLA4 and PD1/PDL1 Blockade (Now Available) (ID 3153)

      10:30 - 12:00  |  Presenting Author(s): David R Spigel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ES23 - Optimal Management of N2 Disease in the Era Of IO (ID 26)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 5
    • Now Available
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      ES23.01 - Mediastinoscopy with Invasive Staging: Are They Still Crucial? (Now Available) (ID 3281)

      11:30 - 13:00  |  Presenting Author(s): Akif Turna

      • Abstract
      • Presentation
      • Slides

      Abstract

      There are more multiple treatment strategies for non-small cell lung cancer(NSCLC) that should be selected based on staging of the disease. Nodal status indicates N component of staging and studies invariably show that upfront surgical resection of patients with mediastinal lymph node involvement (i.e., N2 or N3) is not recommended. Evidence suggest that, T1-4N2-3M0-1c patients should firstly receive oncological treatment; otherwise, surgical treatment could be deemed to be futile.

      Accordingly, mediastinal lymph node involvement prediction as accurate as possible is recommended before any treatment planning. PET-CT, Endobronchial ultrasonography-transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound-guided-fine-needle aspiration(EUS-FNB) have all inherent limitations. Mediastinoscopy has been defined to be gold standard for preoperative disclosure of mediastinal lymph node metastasis. However, small biopsy material due to being an incisional biopsy, practically low number of explored mediastinal stations (usually median number of 2 or 3) led to approximately 10% of false negativity rate. Also studies showed that, even the fact that, mediastinoscopy has been recommended to be performed in all patients except the patients with non-discrete lymph node involvement or in the patients with peripheral cT1a-cN0M0 patients, a fraction of thoracic surgeons prefer to comply with the published guidelines.

      Video-assisted mediastinoscopy lymphadenectomy(VAMLA) was developed to reduce the false negativity rate below statistically non-significant levels (below 5%). It involves dissection of at least 5 lymph nodes stations and some evidence suggest that, VAMLA is associated with better survival rate beyond selection bias phenomenon. Transcervical extended mediastinal lymphadenectomy (TEMLA) is a technically more advanced mediastinal lymph node dissection procedure that is a definition of a resection of lymph nodes from #1-9 bilaterally including aorticopulmonary and anterior mediastinal lymph nodes. The accuracy of TEMLA has been reported to be 98.4%. Taking all those achievements into consideration, VAMLA or TEMLA or at least video-mediastinoscopy should be performed before selecting a therapeutical option in a patient with potentially resectable operable NSCLC.

      However, recent advancements in computational science could propose us that, possibly, there is enough information for us to predict mediastinal lymph node positivity without performing any invasive procedure. Artificial Intelligence (AI) is accomplished by computers that use algorithms, pattern matching, rules, deep learning and cognitive computing to approximate conclusions using previously defined analog or digital parameters. AI aimed to mimic the brain’s neural networks. It uses multiple layers of non-linear processing units to teach itself how to understand data classifying the record or making predictions.

      In a study, we aimed to evaluate the value of artificial neural network(ANN) for mediastinal nodal metastasis, by using only clinical and radiologic data. In our data set, ANN predicted mediastinal nodal involvement perfectly (AUC:1) in both training and test groups. When we used ‘traditional’ univariate and multivariate analyses, younger age (<65) (AUC:0.59) and higher SUVmax (>2.5)(AUC:0.67) were associated to be mediastinal nodal involvement. ANN prediction was better and it was even more sensitive than VAMLA! However, specificity of ANN resulted to be less than 0.9 in some training analyses.

      The major limitations of ANN include its variability, non-transparency and non-consistency. Nevertheless, there is a possibility that, ANN could provide better predictions and it may help us to identify and narrow down the patients who need invasive staging. However, the usage of ANN in medicine has been continuously expanding. Future studies are needed to understand the exact place of ANN in mediastinal staging.

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      ES23.02 - Which N2 Patients Are Candidates to Surgery in the Era If I/O? (Now Available) (ID 3282)

      11:30 - 13:00  |  Presenting Author(s): Eric Vallieres

      • Abstract
      • Presentation
      • Slides

      Abstract

      The role of surgery in patients with pre-resection documented N2 disease remains a subject of controversy. In some institutions, any clinical N2 disease identified preoperatively is considered non-surgical and these patients are offered upfront definitive chemoradiation therapy (DefCRT) without planned resection. In other institutions, a selective approach to N2 patients will consider surgery as part of a multimodality approach where surgery may be offered first followed by adjuvant cytotoxic chemotherapy (AC) with or without sequential post-operative radiation therapy (PORT), or where surgery will be offered after induction chemotherapy or induction chemoradiation therapy. Due to variability in N2 disease presentation, factors determining this selective approach vary between institutions and may include the bulk of N2 nodal involvement (size), extent of N2 involvement (single vs multistation, microscopic vs macroscopic), the presence or absence of extracapsular nodal involvement, the need to perform a pneumonectomy or not, and mediastinal sterilization after induction therapy. Historically, response to induction therapy with clearance of N2 nodal involvement following induction therapy has been shown to bode for a better prognosis after surgical resection. Unfortunately, even after complete resection following induction therapy, many patients develop distant metastases, with brain metastases prevailing.

      In 2018, the PACIFIC trial showed that adding an immune checkpoint inhibitor (IO) durvalumab for up to one year after completion of DefCRT in non-surgical stages cIIIa and cIIIB patients led to a significant and unprecedented overall survival in this population of patients. (Antonia, NEJM 2018) In patients with resectable NSCLC (cIIIA and less), recent small phase I clinical trials of either single-agent induction IO (Forde, NEJM 2018) or concurrent induction chemoimmunotherapy (Provencio, JTO abst. 2018) given before surgery have demonstrated feasibility, acceptable toxicity, and unprecedented pathological response rates. It remains to be seen if these pathologic responses will translate into improved overall survival in this patient population.

      Extrapolating from these early observations, one may think that induction IO (likely with concurrent cytotoxic chemotherapy) may possibly allow us to offer surgery to a larger proportion of patients with clinical N2 disease in the future as we observe higher response rates to induction therapies which may translate in better survival. Others may want to extrapolate from the Pacific trial results and hypothesize that surgery followed by adjuvant IO may become a desirable option. Though encouraging, there is a paucity of data to help guide us in the incorporation of IO therapy perioperatively for patients with clinical N2 disease. As such, the role for IO in multimodality treatment for N2 disease remains undefined. Unknown are the true impacts of periop IOs in this patient population and what is the optimal combination and timing of these multimodality treatments. There are more unanswered questions than established guidelines: (1) whether “IO first then surgery” is superior to “surgery first then adjuvant IO”, (2) whether an induction IO strategy followed by resection would be superior to DefCRT followed by IO in this population of potentially resectable cN2 IIIA patients, (3) if induction IO is shown to be superior, how many cycles preop, (4) do we need to continue IOs post op, if so, for how long, (5) whether there will be a role for surgery after major response to IO, and (6) how will we select patients for resection when major pathological response rates will be in the 80% range (7) do we need to utilize biomarkers, tumor mutation burden, or genotyping in patient selection, (8) What is the best biomarker to predict response, among other questions .

      The easy answer at this stage is to treat these patients on trials where the impact of IOs can be rigorously studied. Ideally, I personally would want to compare: (1) Induction vs adjuvant IOs for surgical patients with cN+ disease, (2) Induction IO followed by resection vs DefCRT followed by IO. The duration of periop IO also needs to be evaluated and these studies should include cost analysis as well. For the surgeons, as systemic treatments improve, our duty is to perform sound oncological surgery with minimal morbidity and minimal to absent mortality. I believe that preop IO may allow us to consider surgical resection for a larger proportion of cIIIA N2 patients in the future.

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      ES23.03 - Is CT/RT Followed by I/O the Standard of Care for All N2 and Selected N3 Patients? (Now Available) (ID 3283)

      11:30 - 13:00  |  Presenting Author(s): Wilfried Ernst Erich Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background: Immunotherapy consolidation with PD-L1-Ab has changed the current standard treatment for unresectable patients with stage III NSCLC (in Europe with PD-L1-exp by IHC > or = 1%) who are not progressing following definitive chemoradiotherapy1,2,3. More and more issue comes up for which patients this new strategy should be adopted, and for whom these data do not represent the new standard. Here we will try to analyze current evidence of stage selection for this multimodality approach.

      Methods: We analyzed the existing evidence on outcome results of stage III NSCLC subsets based on the new 8th-version of the IASLC/UICC staging classification and expert consensus4,5 and current outcome data on stage III subsets within large landmark randomized trials,6,7,8,9,10 and possible permutations of chosen multimodality treatment approaches.

      Results: The PACIFIC Trial included only unresectable patients with stage IIIA and stage IIIB (based on the old UICC7 staging classification)1,2,3. No detailed data on T- and N-subgroups as well as transferring the data to the new UICC8 stage subsets IIIA/IIIB/IIIC were given in the manuscript1. Definition of "unresectable stage IIIA and IIIB" was probably best carried out as "individual local descision within tumor boards including thoracic surgeons to define disease resectability status". Nevertheless, no clear definition on selection for unresectable disease is given in the trial description of the PACIFIC publication. The overall two- and three-year-survival results were excellent and showed a significant and clinically meaningful benefit for patients receiving PD-1-antibody consolidation for one year2,3. Based on current evidence and consensus4,5 about 15 to 20% of stage III patients are still ocnsidered to be potentially resectable. The majority of these belong to the IIIA(N2) diasease subset. Only one recently published clinical phase-III trial included subgroups with T4N0 (stage IIIB UICC7/stage IIIA/UICC8)8. Outside of multimodality groups with specific expertise, stage IIIB(UICC8) and stage IIIC(UICC8) are considered unresectable and would definitely be put on definitive chemoradiotherapy protocols. Only three large randomized trials6,7,8 included resectable patients subsets of stage IIIA(N2)-disease (INTERGROUP 0137, SAKK, ESPATUE). The treatment strategies within these trials were induction chemotherapy followed by surgery versus induction chemotherapy followed by radiation and followed by surgery6, induction chemoradiotherapy followed by surgery versus definitive chemoradiotherapy7or induction chemotherapy followed by concurrent chemoradiotherapy and surgery versus induction chemotherapy followed by concurrent chemoradiotherapy and definitive chemoradiation boost8. All three trials including surgery in at least one of the randomization arms gave a detailed description of T- and N-subgroups in their overall patient characteristics. All three clinical trials had PET-CT and detailed mediastinal staging techniques included into the initial patient selection descision (either mediastinoscopy or recently EBUS). All three trials had excellent overall survival outcomes in each of their randomization arms. Five-year survival results were somewhere betweeen 20% and 44% observed in the three randomized trials. In all three trials no significant difference was noted for OS between the different randomization arms while the OS results in all treatment groups of the studies can be considered excellent. However, in all three trials a low accrual rate was generally noted, and the overall duration of the clinical trials was around six to eight years in all three, pointing to a considerable selection procedure of patient inclusion. The two large randomized clinical phase-III trials investigating modern chemoradiation techniques9,10 included per definition only "unresectable stage IIIA and IIIB patients subsets" (following the old UICC7/UICC6 classification). However, in both trials (PROCLAIM and RTOG 0617) no detailed TN-subgroups were given, but they included rather IIIA and IIIB definitions based on PET-CT staging as well as biopsy confirmation of N2- or N3-tumor-positive lymph nodes at staging work-up. FIve-year overall survival data turned out somewhere around 30% of the initially included patient groups within the two trials. The only group that showed a significantly worse outcome was that with the higher total radiation dose of 74 Gy in the RTOG study (no comment on this issue here). Nevertheless, all survival outcomes showed overall excellent five-year survival data in these two chemoradiation trials, too. Median OS data were between 25 and 29 months observed. There are considerable difficulties to compare all six randomized trials (PACIFIC, RTOG 0617, PROCLAIM, SAKK-TRIAL, INTERGROUP 0139, ESPATUE) based on the difficulties to compare patient selection and included TN-subgroups. Thus the above mentioned relevant differences in patient selection and accrual between the pure chemoradiation trials and the randomized trials including surgical arms cannot be overcome by comparing TN-data from these studies. All three definitive chemoradiation trials did only give IIIA and IIIB subset numbers of their patient population. However, patient accrual was much faster in all three definitive chemoradiation studies, pointing to a less selective patient inclusion into these trials. Some of the differences in the observed OS and PFS results noted could in fact be based on these different patient selection procedures rather than on differences between the individual treatment strategies.

      Conclusion: Based on a differential analysis of the recent five largest randomized phase-III trials with multimodality treatment of stage III NSCLC, we cannot readily compare the patient selection for "pure" concurrent chemoradiotherapy trials on one hand, to that within multimodality trials including surgery in at least one trial arm on the other side. This strongly points to the fact, that we cannot currently widen up any indication for an inclusion of immunotherapy for subsets of patients with potentiallly resectable stage III NSCLC. Patient with resectable stage III (mostly IIIA) should either be treated within multimodality protocols including surgery (based on the local expertise) or should be offered to participate within clinical trials that try to implement immunotherapy with PD-1 or PD-L1 antibodies into this multimodality setting including surgery. Several clinical studies wirth induction chemoimmunotherapy followed by surgery or induction chemoimmunotherapy/chemoradiationimmunotherapy followed by surgery are currenlty being performed by different multimodality treatment groups. The practice-changing results of the PACIFIC trial for unresectable stage III disease leave us very enthusiastic, that this new approach could also improve the results for potentially resectable stage III patients groups in NSCLC.

      1Antonia, NEJM 2017 2 Antonia, NEJM 2018 3 Gray, ASCO 2019 4Goldstraw, J Thorac Oncol 2016 5Eberhardt, Ann Oncol 2015 6Pless, Lancet 2015 7Albain, Lancet 2009 8Eberhardt, J Clin Oncol 2015 9Senan, J Clin Oncol 2016 10 Bradley, Lancet Oncol 2015

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      ES23.04 - Optimal Supportive Care During and After Concurrent Chemoradiotherapy and I/O (Now Available) (ID 3284)

      11:30 - 13:00  |  Presenting Author(s): Dirk De Ruysscher  |  Author(s): Kristiaan Nakaerts

      • Abstract
      • Presentation
      • Slides

      Abstract

      Concurrent chemotherapy and radiotherapy (CCRT) is the treatment of choice for most fit patients with locally advanced NSCLC. Recently, adjuvant durvalumab has improved the overall survival further.

      However, CCRT is a toxic treatment. Treatment-related deaths occur in a few percent of patients and many suffer severe side effects that require medical interventions and even in-patient care.

      In contrast to extensive research on infections and emesis, most data on other important side effects are scant.

      Two examples of this are acute esophagitis and cough and dyspnea.

      Correlation between dysphagia and endoscopic findings

      In a prospective trial with 38 patients receiving radiotherapy alone for lung cancer, an endoscopy was done during radiotherapy when patients had received a dose of 30-40 Gy on the esophagus. Eighteen patients (47 %) had dysphagia of any grade, but only in 12 of them (67 %) endoscopy showed esophagitis. Of the remaining 20 patients without complaints, 5 (25 %) had endoscopic signs of esophagitis. Gastritis was found in 18 patients (47 %), with or without esophagitis.

      In another study, 82 NSCLC patients were evaluated by endoscopy. There was a good correlation between the RTOG clinical score for dysphagia and the endoscopic findings (Spearman rank correlation coefficient 0.428; p< 0.0001). All patients with clinical grade 3 dysphagia had endoscopic grade 2 or 3 esophagitis. Also in case of RTOG grade 2 dysphagia, all patients had endoscopic esophagitis, although 40 % had endoscopic grade 1 and 27 % had endoscopic grade 3 esophagitis. Of patients with or without only mild (grade 1) dysphagia, 11 % showed grade 3 endoscopic esophagitis. Sixteen percent of patients has esophageal candidiasis, but its relation with dysphagia or endoscopic grade of esophagitis was not reported. No data on the incidence of gastritis were given.

      Effect of radiotherapy on esophageal motility

      An impaired esophageal motility may also lead to dysphagia.

      The esophageal transit time (ETT) before and during (10 Gy and 30 Gy) radiotherapy alone was evaluated in 11 patients. An increase in the ETT was seen in 9 of 11 patients (82%) (p<0.05).

      The ETT was also investigated in 18 breast cancer patients receiving radiotherapy to the inner quadrants of the breast using a dose of 50 Gy/ 25 fractions. The cranial part of the esophagus received a mean dose of 6 Gy/ 25 fractions, and the distal two-thirds a mean dose of 15.3 Gy/ 25 fractions. Comparing the ETT before and after radiotherapy, for the upper third and the distal two-thirds of the esophagus, the ETT increased from 4.77 ± 1.08 sec. to 6.92 ± 2.15 sec., from 11.22 ± 2.85 sec to 23.30 ± 5.65 sec. and from 11.61 ± 2.97 sec. to 23.74 ± 5.70 sec., respectively (p<0.001).

      Because of the motility impairment even at very low radiotherapy doses, the use of proton pump inhibitors is logical.

      Prevention and treatment of acute esophagitis

      In a randomized study with advanced NSCLC patients, treated with radiotherapy alone or radiotherapy plus amifostine, amifostine reduced the incidence of esophagitis in week 4 during radiotherapy from 42 % (31/73) to 4 % (3/73) (p<0.001), without decreasing the tumor response 2 months after treatment. In a larger randomized series of the RTOG, 243 stage II-III NSCLC patients were enrolled and randomized between carboplatin-paclitaxel concurrent chemo-radiotherapy with or without amifostine. No significant differences between the arms regarding overall survival, disease-free survival or long-term toxicity were observed.

      In another study, 60 stage III NSCLC patients were randomized between concurrent carboplatin-paclitaxel and radiotherapy with or without amifostine. No significant difference in esophagitis was observed.

      Therefore, amifostine has no consistently proven effect of preventing acute radiation-induced esophagitis.

      In a small double-blind study, 14 stage III NSCLC patients were randomized between placebo or prophylactic indomethacin. Endoscopically-assessed esophagitis seemed to be milder, but no firm conclusions could be drawn.

      Another small, placebo-controlled randomized trial, investigated naproxen in 28 stage III NSCLC patients receiving radiotherapy alone. There were no differences in clinical or endoscopic esophagitis rates. Eight patients (29 %) developed esophageal candidiasis, with no difference between the groups.

      A placebo-controlled randomized trial could not demonstrate a beneficial effect of sucralfate on dysphagia.

      In NRG/ RTOG 1012, patients were randomized between prophylactic Manuka honey, either in liquid or in lozenge form, and standard supportive care during concurrent chemo-radiotherapy for NSCLC. Standard supportive care consisted of a compound containing viscous lidocaine, an antacid such as magnesium aluminum oxide, and liquid or solid oxycodone, 5–10 mg, every 3 hours as needed. The primary endpoint was patient-reported pain on swallowing utilizing an eleven point (0–10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). Fifty-three patients were randomized to supportive care, 54 randomized to liquid honey and 56 to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms (p=0.03), with 52 % vs. 67 % of patients experiencing no pain with liquid honey. No difference was observed with lozenge honey. with more patients on the supportive care arm taking opioids. However, the differences were only observed at 4 weeks and not at the end of radiotherapy.

      From this example, already, it is clear that more in-depth knowledge of the physiopathology of radiation injury is needed. A joint task force between ESTRO and ESMO members will address a spectrum of supportive care interventions in patients receiving concurrent chemotherapy and radiotherapy for lung cancer.

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      ES23.05 - The Future of Systemic Therapy in Stage III (Now Available) (ID 3285)

      11:30 - 13:00  |  Presenting Author(s): Pilar Garrido

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stage III NSCLC comprises a very heterogeneous group of patients with regard to tumor extent, prognosis, and treatment options. It represents between 25-30% of NSCLCs and the majority of them are unresectable. Potentially curative treatment of unresectable stage III necessitates adequate locoregional control as well as control of the micrometastatic disease that is likely to be present in most patients. Several randomized clinical trials dating back as far as 20 years and metanalysis have shown the superiority of cisplatin-based chemotherapy and radiotherapy over radiotherapy alone. Sequential versus concomitant approach has been directly compared in several trials; almost all of them showed a trend in favor of concomitant treatment. These results clearly supported the use of concomitant chemoradiotherapy as standard of care for these patients1 fit enough to tolerate the risk of severe toxicity, particularly grade 3-4 esophagitis that is the most common adverse effect of the concomitant approach.

      Attempts to improve outcomes have included studies of radiotherapy dose escalation and new chemotherapy combinations, as well as adding biological agents and cancer vaccines to existing regimens. Technical radiotherapy modifications, including intensity-modulated radiotherapy and particle beam therapy, have also been investigated. In spite of it, the long-term survival has remained largely unchanged for many years, with only 15% of patients are alive at 5 years.

      In the last years, immune-checkpoints blockade revolutionized the standard of care of metastatic NSCLC. The PACIFIC study is an randomized, double-blind, placebo-controlled, multi-centre, phase 3 study to evaluate the efficacy and safety of durvalumab compared with placebo, as sequential therapy in patients with locally advanced, unresectable stage III NSCLC who have not progressed following definitive, concurrent platinum-based chemotherapy and thoracic RT. The study was positive for both primary endpoints progression- free survival (HR=0.51; 95%CI: 0.41-0.63)) and overall survival (HR=0.68; 95%CI: 0.49-0.99; p=0.00251)2. This benefit was observed in both non-squamous and squamous histology as well as in both stages IIIA and IIIB NSCLC. Based on this study, there is a new standard of care for unresectable stage III NSCLC patients. Nevertheless, improving outcomes for patients with stage III disease remains a challenge and many questions have to address in well-designed clinical trials.

      1.- 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 Suppl 4: iv1-iv21.

      2.-Antonia SJ, Villegas A, Daniel D et al. Overall survival with Durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018; 379: 2342-50

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    IS02 - Symposium by Ology Medical Education: Spotlight On Emerging Immunotherapy Approaches And MET Inhibitors In Advanced NSCLC (Not IASLC CME Accredited) (ID 366)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS07 - Symposium by Daiichi Sankyo: Targeting Her Pathways In Advanced NSCLC: Emerging Concepts And Future Opportunities (Not IASLC CME Accredited) (ID 371)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS10 - Symposium by Boehringer Ingelheim: Treatment Sequencing For Advanced NSCLC (Not IASLC CME Accredited) (ID 374)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS12 - Symposium by Medscape: Expanding the Therapeutic Landscape Of Advanced NSCLC Targeting HER2 (Not IASLC CME Accredited) (ID 376)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS15 - Symposium by Medscape: Immune Checkpoint Inhibitor Treatment for Frontline Metastatic NSCLC: The Evolving Role of Biomarkers in Guiding Decisions (ID 379)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS16 - Symposium by Novartis: The Road Ahead: New Horizons In The Treatment Of NSCLC (Not IASLC CME Accredited) (ID 380)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 12
    • Now Available
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      MA11.01 - Multifactorial Model to Predict Response to PD-(L)1 Blockade in Patients with High PD-L1 Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 2322)

      14:00 - 15:30  |  Presenting Author(s): Kathryn C. Arbour  |  Author(s): Miruna Oprescu, Joe Hakim, Hira Rizvi, Mark Leiserson, Michelle Ginsburg, Andrew J. Plodkowski, Jennifer Sauter, Isabel Preeshagul, Sharon Gillett, Philip Rosenfield, Lester Mackey, Miroslav Dudik, Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      High PD-L1 expression (≥50%) is a routine biomarker but is incompletely predictive, with response rates to PD-1 monotherapy only 35-45% in patients with lung cancer. Beyond PD-L1, additional individual pre-treatment variables, including clinical (smoking history, BMI), genomic (TMB, STK11, EGFR), and laboratory features (baseline dNLR), individually associate with response but have not been comprehensively examined in combination. We hypothesized that a multifactorial model incorporating routinely available clinical, pathologic, and genomic variables could improve prediction of response in high PD-L1 patients receiving first line anti-PD-(L)1 monotherapy.

      Method

      190 patients from MSKCC with advanced, PD-L1 high NSCLC (PD-L1 ≥50%) treated with PD-1 or PD-L1 inhibitor were identified and separated into training (n=134, 70%) and validation cohorts (n=56, 30%). In addition to PD-L1 expression, 39 variables were collected, including histology, clinical (age, gender, performance status, smoking, clinical trial vs standard of care treatment), molecular (TMB, EGFR, KRAS, STK11, KEAP1, TP53, ALK, ROS1, BRAF), and baseline CBC (including dNLR). Radiologic response assessments were performed according to RECIST 1.1. To distinguish responders vs. non-responders, a logistic regression classifier with an elastic net penalty was used to restrict the number of variables considered and to optimize generalizability to independent cohorts. The parameters of the model were optimized using only the training cohort and its performance was measured on the validation cohort.

      Result

      In PD-L1 high NSCLC patients treated with PD-(L)1 blockade, the ORR was 43%. In the training cohort, 5 features (PD-L1 expression, current smoking status, lymphocyte count, platelets, total WBC) associated with response . Three features (EGFR mutation, STK11 mutation, standard of care treatment) associated with lack of response. TMB was not predictive within this selected PD-L1 high cohort. In the training cohort, the eight identified features were used to develop a multifactorial model which improved BOR prediction (AUC 0.83) compared to PD-L1 alone (AUC 0.65), p=0.02. Improved performance of the model was confirmed in the validation cohort (AUC 0.66 for multifactorial model vs. AUC 0.52 for PD-L1 alone).

      Conclusion

      Among patients with high PD-L1 expression, multiple clinical, molecular, and baseline laboratory features impact response to PD-(L)1 monotherapy. The addition of these routinely available variables to PD-L1 in a multifactorial model improves prediction of response to PD-(L)1 blockade in patients with high PD-L1. This approach may help further stratify patients within the PD-L1 high population and identify which patients are likely to benefit from PD-(L)1 monotherapy vs those who should consider chemotherapy + immunotherapy.

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      MA11.02 - KEYNOTE-042 China Study: First-Line Pembrolizumab vs Chemotherapy in Chinese Patients with Advanced NSCLC with PD-L1 TPS ≥1% (Now Available) (ID 1772)

      14:00 - 15:30  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Li Zhang, Yun Fan, Jianying Zhou, Li Zhang, Qing Zhou, Wei Li, ChengPing Hu, Gongyan Chen, Xin Zhang, Caicun Zhou, Thao Dang, Justina Penrod, Debra A. Kush, Yun Qin, Ben Li, Tony Mok

      • Abstract
      • Presentation
      • Slides

      Background

      In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies.

      Method

      The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ~350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients.

      Result

      As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.

      Overall Survival

      n

      Median (95% CI), mo

      HR (95% CI)

      PD-L1 TPS ≥50%

      Pembrolizumab

      72

      20.0 (15.5–NR)

      0.62 (0.38–1.00)

      Chemotherapy

      74

      14.0 (10.0–17.9)

      PD-L1 TPS ≥20%

      Pembrolizumab

      101

      20.0 (17.4–NR)

      0.62 (0.41–0.95)

      Chemotherapy

      103

      13.7 (10.1–17.9)

      PD-L1 TPS ≥1%

      Pembrolizumab

      128

      20.0 (17.4–NR)

      0.65 (0.45–0.94)

      Chemotherapy

      134

      13.7 (10.1–17.9)

      PD-L1 TPS 1–49%a

      Pembrolizumab

      56

      19.9 (11.9–NR)

      0.69 (0.40–1.20)

      Chemotherapy

      60

      10.7 (8.3–20.9)

      NR, not reached. aExploratory analysis.

      Conclusion

      Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.

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      MA11.03 - Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer Patients (Now Available) (ID 2017)

      14:00 - 15:30  |  Presenting Author(s): Oscar Gerardo Arrieta  |  Author(s): Feliciano Barrón, Amir Carmona, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain Barrón, Andrés Felipe Cardona, Yolanda Bautista, Fernando Aldaco, Miguel Lazaro, Renata Baez, Raquel Gerson, Carolina Blanco

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy is now the standard of care for non-small cell lung cancer patients without actionable mutations, due to a clear survival benefit in large phase III trials, further this benefit can be translated into the first-line setting, alone or in combination with chemotherapy. Nonetheless, due to several circumstances many patients do not receive immunotherapy as first-line. The effect of the combination therapy with pembrolizumab plus docetaxel in previously-treated NSCLC patients has not been prospectively assessed.

      Method

      In this phase II clinical trial, we evaluated the effect of a combination therapy with pembrolizumab plus Docetaxel (PD) compared with Docetaxel (D) for the treatment of advanced NSCLC patients who had progressed to previous lines of therapy. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety profile.

      Result

      Eighty patients met the inclusion criteria and were enrolled in the study, among which 78 were randomized 1:1. Forty patients were allocated to receive PD, while thirty-eight were allocated to receive D. Baseline characteristics, including sex, age, tobacco index, performance status and EGFR mutation were well-balanced between both arms of the trial. We found a statistically significant difference in terms of ORR (42.5% vs. 15.8%; OR: 3.9 [95%CI: 1.34-11.5]; p=0.01), in patients receiving PD compared with D alone. Further, patients receiving PD had a significantly longer PFS compared with those receiving D monotherapy (9.5 months [95%CI: 4.2-NR] vs. 3.9 [95%CI: 3.2-5.7]; HR: 0.24 [95%CI: 0.13-0.46]; p<0.001). In the multivariate analysis the therapeutic intervention was an independently associated factor with better PFS (Figure). In terms of safety, a total of 22.5% vs. 5.3% of patients experienced any-grade pneumonitis in the PD and D arm of the trial respectively (p=0.048), while 27.5% vs. 16% experienced any-grade hypothyroidism (p=0.20). No new safety signals were identified.

      Conclusion

      Patients who receive the combination therapy have a significantly increased ORR and PFS, with a significant decrease in the hazard of progressing. This work was performed through a grant from MSD (Investigator Initiated Study). The sponsor did not have any role in the acquisition or interpretation of the data.


      pfs_figure 1.png
      Figure. Kaplan-Meier curve for the progression-free survival of patients in the experimental (P+D) vs. the control (D) arm of the trial.

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      MA11.04 - Platinum Doublet + Durvalumab +/- Tremelimumab in Patients with Advanced NSCLC: A CCTG Phase IB Study - IND.226 (Now Available) (ID 927)

      14:00 - 15:30  |  Presenting Author(s): Rosalyn Anne Juergens  |  Author(s): Peter M Ellis, Dongsheng Tu, Desiree Hao, Scott A Laurie, Mihaela Mates, Glenwood D. Goss, John Goffin, Penelope A Bradbury, Mustapha Tehfe, Christian Kollmansberger, Pamela Brown-Walker, Martin Smoragiewicz, Ming Sound Tsao, Lesley Seymour

      • Abstract
      • Presentation
      • Slides

      Background

      Studies of single agent immune checkpoint inhibitors with platinum-based chemotherapy in non-small cell lung cancer (NSCLC) have demonstrated survival benefit over chemotherapy alone. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, +/- tremelimumab (Tr), a CTLA-4 inhibitor, with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract updates the results in the NSCLC cohort in this study.

      Method

      Patients (pts), regardless of tumour PD-L1 status, were enrolled into one of six dose levels (Table 1). Dose escalation was according to a Rolling Six type design. Concurrent enrollment of cohorts was allowed. ind 226 abstract wclc methods.png

      Result

      Seventy-three pts (median age=63 (range 34-80); 52% female; 77% non-squamous) were enrolled. The majority of drug-related adverse events (AEs) were grade 1 or 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr (immune related AEs (irAEs)) were mainly grade 1 or 2. The most common irAEs were fatigue (64%), rash/itch (42%), diarrhea/colitis (34%), anorexia (22%), thyroid dysfunction (19%), and nausea/vomiting (21/12%). The most common grade 3 or 4 irAEs were diarrhea/colitis (11%), fatigue (10%), and rash (5%). No treatment related grade 5 toxicities were reported. Twenty pts (27%) discontinued treatment due to an AE. Twelve pts (16%) discontinued treatment for toxicity related to D+/-T. Objective response rate (ORR) was 50.7% (95% CI = 38.7-62.6%). Median progression free survival (mPFS) was 6.5 months (95% CI = 5.5-9.4). Median overall survival (mOS) was 19.8 months (95% CI = 14.8-not yet reached). ORR was similar for all levels of PD-L1 staining including PD-L1 negative patients. ORR for pts with EGFR mutations (N=5) was similar to the ORR of wild type pts. Exploratory analyses suggest mPFS and mOS were longer in patients who experienced irAEs.

      Conclusion

      In this PD-L1 unselected patient population, Du and Tr can be safely combined with full doses of platinum-doublet chemotherapy. The ORR, mPFS and mOS are similar to results reported from other immunotherapy + chemotherapy combination trials. A randomized trial, CCTG BR.34, is evaluating the incremental benefit of adding platinum doublet to Du+Tr.

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      MA11.05 - Discussant - MA11.01, MA11.02, MA11.03, MA11.04 (Now Available) (ID 3764)

      14:00 - 15:30  |  Presenting Author(s): Lizza Hendriks

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA11.06 - A PII Study of Toripalimab, a PD-1 mAb, in Combination with Chemotherapy in EGFR+ Advanced NSCLC Patients Failed to Prior EGFR TKI Therapies (Now Available) (ID 1160)

      14:00 - 15:30  |  Presenting Author(s): Jie Zhang  |  Author(s): Caicun Zhou, yanqiu Zhao, Xiaoqian Mu, Jianying Zhou, Zhang Bao, Yun Fan, Yanjun Xu, Yongqian Yong Shu, Renhua Guo, Xiaoqing Liu, Hong Wang, Helong Zhang, Lin Deng, Ningqiang Ma, Jianxing He, Yalei Zhang, mo Chen, Yinrui Jiang

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR TKI is the standard 1st line therapy for the patients (pts) with advanced NSCLC harboring EGFR mutations. While PD-1 checkpoint blockade has become an integral component of disease management for EGFR wild type NSCLC pts at various settings, platinum-based chemotherapy is still the standard of care for EGFR mutated NSCLC pts who progress after EGFR targeting therapy. Early attempts to combine EGFR TKI with checkpoint blockade had resulted in exacerbated immune related toxicity in the lung. Here we aimed to prospectively evaluate toripalimab, a humanized PD-1 mAb approved for 2nd line treatment of melanoma, in combination with chemotherapy to treat EGFR mutated NSCLC pts after failure of EGFR targeting therapy.

      Method

      This is a phase II, multicenter, open-label, single-arm study for pts with EGFR activating mutations who have failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment. Pts were treated with 240mg or 360mg fixed dose toripalimab once every 3 weeks in combination with carboplatin and pemetrexed for up to 6 cycles, followed by toripalimab plus pemetrexed maintenance therapy until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) at week 12 as assessed by investigator per RECIST v1.1 once every 6 weeks. Secondary endpoints were safety, ORR, DOR, DCR, TTR, PFS, OS, PK and immunogenicity.

      Result

      f14_2_1_3_pub.png

      Forty pts were enrolled from Apr 25, 2018 to March 22, 2019 with 52.5% female pts and a median age of 57.5. 57.5% pts harbored EGFR exon19 deletion while 42.5% pts had exon21 L858R mutation. Only 1 pt had T790M mutation who progressed after osimertinib treatment. In ITT population, 13 confirmed partial response (PR) and 22 stable disease (SD) were observed at week 12 for a 32.5% ORR. As of Jul 25 2019, among 40 pts, 20 confirmed PR and 15 SD were observed for a 50% ORR (95% CI, 33.8% to 66.2%) and an 87.5% DCR (95% CI, 73.2% to 95.8%). Median progression free survival (PFS) was 7.0 months, and median duration of response (DOR) was 7.0 months. Treatment emergent adverse events (TEAE) occurred in 39 (97.5%) of the pts, grade 3 or higher events occurred in 25 (62.5%) of pts including two deaths. Most common AE included leukopenia, neutropenia, thrombocytopenia, anemia, nausea, and loss of appetite. Treatment discontinuation due to AE occurred in 4 (10%) of the pts.

      Conclusion

      Anti-PD-1 mAb, toripalimab in combination with carboplatin and pemetrexed has shown a promising anti-tumor efficacy with a tolerable safety profile for advanced NSCLC patients with EGFR mutated who progressed after EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (DOR, PFS and OS). A phase III registration study will be initiated in May 2019.

      (Clinical trial information: NCT03513666)

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      MA11.07 - Efficacy of Immune-Checkpoint Inhibitors and EGFR-TKIs in NSCLC Patients with High PD-L1 Expression (Now Available) (ID 667)

      14:00 - 15:30  |  Presenting Author(s): Ken Masuda  |  Author(s): Hidehito Horinouchi, Midori Tanaka, Ryoko Higashiyama, Yuki Shinno, Jun Sato, Tatsuya Yoshida, Yuji Matsumoto, Yasushi Goto, Shintaro Kanda, Noboru Yamamoto, Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Background

      Recently, several studies have demonstrated that patients with non-small cell lung carcinoma (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations show poor clinical outcomes in response to treatment with anti-programmed cell death-1 (PD-1) inhibitors. Conversely, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are not effective in NSCLC showing high programmed death ligand 1 (PD-L1) expression levels. In this study, we retrospectively investigated the relationship between high PD-L1 expression and the efficacy of PD-1 inhibitors and EGFR-TKIs in patients with NSCLC.

      Method

      The subjects of this study were patients with NSCLC who had received treatment with PD-1 inhibitors at the National Cancer Center Hospital between March 2017 and December 2018. The PD-L1 expression in the tumor cells was divided into two groups based on the tumor proportion score (TPS): <50% (low) and ≥50% (high).

      Result

      Of the 414 patients treated with PD-1 inhibitors, the 263 patients in whom the PD-L1 expression levels could be evaluated were considered as being eligible for inclusion in this study. Among the 153 patients with high PD-L1 expression, we assessed the efficacy of PD-1 inhibitors according to the EGFR mutation status. The objective response rate (ORR) was 29.4% (95% confidence interval [CI], 1.3 to 53.1) in the EGFR-mutated patients and 43.4% (95% CI, 35.4 to 51.8) in the EGFR wild-type patients. The median progression-free survival (PFS) was 5.3 months (95% CI, 1.3 to 12.4) in the EGFR-mutated patients and 8.3 months (95% CI, 6.0 to 11.7) in the EGFR wild-type patients (hazard Ratio [HR] = 0.62; 95% CI, 0.62 to 1.14). A total of 33 patients received EGFR-TKI therapy. We assessed the efficacy of EGFR-TKIs according to the PD-L1 expression level. The ORR was 50.0% (95% CI, 28.0 to 72.0) in the high PD-L1 expression group and 52.9% (95% CI, 31.0 to 73.8) in the low PD-L1 expression group. The median PFS was 18.8 months (95% CI, 2.8 to 35.7) in the high PD-L1 expression group and 12.7 months (95% CI, 7.2 to 20.9) in the low PD-L1 expression group (HR = 0.83; 95% CI, 0.38 to 1.81).

      PD-L1 High

      EGFR+

      PD-L1 High

      EGFR−

      PD-L1 Low

      EGFR+

      PD-L1 Low

      EGFR−

      Total N

      17

      136

      18

      92

      Median age, years (range)

      62 (47–85)

      62 (33–87)

      64.5 (37–83)

      62 (33–83)

      Sex (n)

      Female

      Male

      7

      10

      36

      100

      15

      3

      25

      67

      ECOG PS (n)

      0, 1

      2

      14

      3

      125

      11

      16

      2

      81

      11

      Smoking history (n)

      Never-smoker

      Smoker

      7

      10

      21

      115

      12

      6

      13

      79

      EGFR mutation status (n)

      Ex 19 del

      L858R

      Others

      7

      6

      4

      13

      2

      3

      ICI agent used (n)

      Pembrolizumab

      Nivolumab

      11

      6

      105

      31

      4

      14

      21

      71

      Line of ICI therapy (n)

      First-line

      Second-line

      Third-line or more

      2

      3

      12

      85

      42

      9

      5

      64

      23

      0

      2

      16

      Efficasy

      ORR (%)

      PD-1 inhibitors

      EGFR-TKIs

      PFS (months)

      PD-1 inhibitors

      EGFR-TKIs

      29.4

      50.0

      5.3

      18.8

      43.4

      8.3

      0

      52.9

      1.6

      12.7

      16.3

      3.8

      Conclusion

      Even in a population of NSCLC patients showing high PD-L1 expression, the efficacy of PD-1 inhibitors tended to be lower in the EGFR-mutated patients as compared to the EGFR wild-type patients. In regard to EGFR-mutated patients with a PD-L1 TPS of ≥50%, our findings suggested that high PD-L1 expression might not predict a poor efficacy of EGFR-TKIs.

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      MA11.08 - Discussant - MA11.06, MA11.07 (Now Available) (ID 3765)

      14:00 - 15:30  |  Presenting Author(s): Qing Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
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      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Presenting Author(s): John Victor Heymach  |  Author(s): Ferdinandos Skoulidis, Kathryn C. Arbour, Matthew Hellmann, Pradnya Dinkar Patil, Melina E Marmarelis, Dwight Hall Owen, Mark Awad, Joseph C. Murray, Benjamin Philip Levy, Jessica Hellyer, Justin F. Gainor, Tyler Stewart, Sarah B. Goldberg, Anastasios Dimou, Christine M Bestvina, Amy Lauren Cummings, Yasir Elamin, Vincent Lam, Jianjun Zhang, Catherine Shu, Jonathan Wesley Riess, Collin M Blakely, Chad V. Pecot, Laura Mezquita, Fabrizio Tabbò, Adrian G Sacher, Matthias Scheffler, Biagio Ricciuti, Deepti Venkatraman, Hira Rizvi, Corinne Liu, Rocio Perez Johnston, Ying Ni, Joseph Azok, Melanie Wain Kier, Sharyn I Katz, Kurtis D. Davies, Jeremy P Segal, Lauren Ritterhouse, Hiram Shaish, LUDOVIC Lacroix, Regan Memmott, John R Madrigal, Jonathan Goldman, Sally CM Lau, Jonathan Killam, Zenta Walther, Brett Carter, Mark Woodcock, Jack Roth, Stephen Swisher, Natasha B Leighl, Subba Digumarthy, Meghan Mooradian, Julia Rotow, Juergen Wolf, Giorgio Vittorio Scagliotti, David Planchard, Benjamin Besse, Trever G Bivona, David R Gandara, Edward Garon, Naiyer A Rizvi, D. Ross Camidge, Kurt A Schalper, Roy S. Herbst, Alice T. Shaw, Joel W Neal, Heather A Wakelee, Julie R Brahmer, Pasi A Jänne, David P Carbone, Charu Aggarwal, Nathan Pennell, Charles M Rudin, Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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      MA11.12 - Discussant - MA11.09, MA11.10, MA11.11 (Now Available) (ID 3766)

      14:00 - 15:30  |  Presenting Author(s): Ana Zimmer Gelatti Gelatti

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
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      MA14.01 - Clinical and Genomic Features of Chinese Lung Cancer Patients with Germline Mutations (Now Available) (ID 682)

      15:45 - 17:15  |  Presenting Author(s): Wenying Peng  |  Author(s): Jin Li, Lian-peng Chang, Jing Bai, Yanyan Zhang, Yan-Fang Guan, Xingxiang Pu, Meilin Jiang, Jun Cao, Bolin Chen, Xuefeng Xia, Xin Yi, Jianjun Zhang, Lin Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Recent studies on next generation sequencing (NGS) data from cancer patients have demonstrated that germline mutations in genetic predisposition genes were more common than previous known in many cancer types including lung cancer. However, most previous studies have focused on western patient population and the germline mutation landscape in Asian lung cancer patients and the clinical and genomic features in these patients are largely unknown.

      Method

      NGS data from a targeted panel of 1,021 known cancer genes from paired cancer and germline DNA of 1,797 Chinese lung cancer patients was analyzed to identify pathogenic or likely pathogenic (P/LP) germline variants in predisposition genes based on American College of Medical Genetics and Genomics (ACMG) 2015 guideline.

      Result

      Totally, 5.95% of lung patients were found to harbor germline variants in 35 cancer predisposition genes. The prevalence of germline mutations was higher in patients under 40 compared to older counterparts (10.1% vs 5.74%, p=0.103, Chi-Square test ) although it did not reach statistical significance. However, germline BRCA1/2 mutations were associated with earlier age of onset (median 52.5 vs 60 years-old, p=0.0080 by Mann-Whitney test). Furthermore, patients with P/LP germline mutations had significantly more somatic mutations in KRAS (p=0.012, fisher’s exact test) and c-MET (p=0.018, fisher’s exact test) oncogenes, but less in tumor suppressor gene TP53 (p=0.019, fisher’s exact test). Compared to western lung cancer patients enrolled in TCGA, P/LP germline mutations in BRCA2, FANCA, ATM, MUTYH, BLM, TP53, BRCA1, CHEK2, PMS2, NBN and FANCC were identified in both current Chinese cohort and TCGA cohort with BRCA2 germline mutations significantly more common in Chinese cohort than TCGA cohort (p=0.015, Fisher’s exact test). In addition, RAD51D, FANCD2, BRIP1, MSH6, PMS1, PALB2, RAD51C, SDHA, TSC2, BAP1, CDH1, FLCN, NF1 and RUNX1) were exclusively identified in Chinese patients, while RET, ERCC3, FANCG and VHL were only detected in TCGA cohort.

      Conclusion

      These results implied that there might be both common and unique cancer predisposition germline mutations for lung cancer between Asian and Western patient populations.

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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): Rafal Dziadziuszko, Alexander Drilon, Tom John, Matthew G Krebs, George Demetri, Alice T. Shaw, Salvatore Siena, Juergen Wolf, Anna F Farago, Brian Simmons, Chenglin Ye, Xinhui Huang, Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Presenting Author(s): D. Ross Camidge  |  Author(s): Fabrice Barlesi, Jonathan Goldman, Daniel Morgensztern, Rebecca S Heist, Everett E. Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S. Hong, John H. Strickler, Monica Motwani, Zhaowen Sun, Apurvasena Parikh, Philip Komarnitsky, Jun Wu, Karen Kelly

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

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      MA14.04 - Discussant - MA14.01, MA14.02, MA14.03 (Now Available) (ID 3777)

      15:45 - 17:15  |  Presenting Author(s): Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
      • Presentation
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      Background

      Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).

      Method

      From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.

      Result

      Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).

      Conclusion

      The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.

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      MA14.06 - Nintedanib-Docetaxel in 2nd Line Treatment in No Squamous Non-Small Cell Lung Cancer Patients, Refractory to First Line Treatment (GFPC02-15) (Now Available) (ID 558)

      15:45 - 17:15  |  Presenting Author(s): Alain Vergnenegre  |  Author(s): Jean Bernard Auliac, Isabelle Monnet, acya Bizieux, Laurent Greillier, Lionel Falchero, Gilles Robinet, Regien Lamy, Pierre-Alexandre Hauss, Florian Guisier, Hervé Lena, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Second line chemotherapy used in advanced Non Small Cell Lung Cancer (NSCLC) have demonstrated a slight survival benefit in patient refractory to a first line platinum based doublet chemotherapy. In exploratory analysis, Nintedanib in combination with docetaxel have shown interesting result in second line setting for refractory NSCLC patients.

      Objective: To assess the efficacy in terms of progression-free survival (PFS) of the nintedanib - docetaxel combination in second-line treatment in refractory no squamous NSCLC (NsqNSCL) patients

      Method

      This prospective, multicentric open-label phase II trial, included patients with advanced Nsq NSCLC (EGFR, ALK wild-type), PS 0-1, progressing during the first four cycles of cisplatin-based induction chemotherapy. Patients received Nintedanib (200 mg X2 /d d2-d20)- Docetaxel (75 mg/m2 d1-d21) combination until progressive disease or unacceptable toxicity.

      The primary endpoint was the PFS rate at 12 weeks. Secondary endpoints included median PFS, median overall survival (OS), overall response rate (ORR) and tolerability. Based on a A’Hern’s single-stage phase II design trial (sample size determination is based on exact binomial distribution), the Nintedanib-Docetaxel strategy will be rejected if the primary endpoint was below 22/53 patients at the end of study.

      Result

      The analysis included 53 evaluable patients managed in 21 centers; last patient included at the end of January 2019. Mean age 58.4 years, male 73 %, adenocarcinoma 97.5%, current/former smokers: 42/50 %, PS 0/1: 25%/75%; weight loss >5% : 19%, stage IV: 100% (38% with brain metastasis, median metastasis 2). All patients received for induction chemotherapy, a platin doublet (22% with bevacizumab), number of cycle 1-2/ 3-4: 57%/ 43%.

      Interim analysis reviewed by the independent committee conducted as planned, after the 27 first inclusions concluded that there was no sign of unexpected toxicity (adverse events grade 3-4 :22%, grade 5 :0%) or futility (9 patients meet primary end point on 25 evaluable). The results of the final analysis on the whole population (PFS at 12 weeks (primary end point), median PFS, median OS and toxicity) will be presented at the meeting

      Academic grant from Boehringer Ingelheim

      Conclusion

      Section not applicable

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      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Presenting Author(s): Roy S. Herbst  |  Author(s): Hendrik Tobias Arkenau, Johanna Bendell, Edward Arrowsmith, Martin Wermke, Andres Soriano, Nicolas Penel, Rafael Santana-Davila, Helge Bischoff, Ian Chau, Bo Chao, David Ferry, Gu Mi, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

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      MA14.08 - Discussant - MA14.05, MA14.06, MA14.07 (Now Available) (ID 3778)

      15:45 - 17:15  |  Presenting Author(s): Mirjana Rajer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.09 - Real-World Survival of Relapsed Compared to De-Novo Stage IV Diagnosis of Advanced Non-Small Cell Lung Cancer (Now Available) (ID 529)

      15:45 - 17:15  |  Presenting Author(s): Katie Kerrigan  |  Author(s): Benjamin Haaland, Blythe Adamson, Shiven Patel, Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      Differences in tumor biology and cancer therapy in early stage lung cancer may affect overall survival (OS) of patients with relapsed stage IV disease compared to others with de-novo stage IV disease. This study aimed to compare real-world survival of these patients.

      Method

      We selected patients with advanced NSCLC diagnosed between 2011 and 2017, who received at least one line of therapy, from the US Flatiron Health electronic health record-derived database. Patient data was collected through June 2018, providing at least 6 months of follow-up.

      OS was defined as time from advanced or metastatic diagnosis to the event of death, censored at last clinic visit or end of oral therapy. The unadjusted OS of patients was estimated using the Kaplan-Meier method. We fit multivariable Cox proportional hazards models to compare the hazard of death between groups.

      Result

      de-novo vs relapsed image final.jpg

      The study included 30,310 patients with median age of 68.8 years, 46.7% female, and 76.8% non-Hispanic white. We observed 22.8% had relapsed and 77.2% were de-novo stage IV. Relapsed patients had median OS of 15.5 months (95% CI: 14.9-16.2). Patients with de-novo stage IV had median overall survival of 12.0 months (95% CI: 11.7-12.2). The force of mortality among relapsed stage IV patients was 24% lower than the rate of death among de-novo stage IV patients (Hazard Ratio [HR]: 0.76; 95% CI 0.73-0.79; p <0.001), adjusting for age, gender, state, histology, smoking, race/ethnicity, and stratifying by year of diagnosis. Sensitivity analyses of an unadjusted model (HR 0.79, p <0.001) and a sub-group analysis of patients with advanced diagnoses in 2016-2017 (HR 0.74, p <0.001) suggested the results were robust.

      Conclusion

      Among patients with stage IV NSCLC that received at least one treatment, those who relapsed had better OS than those who presented with de-novo stage IV disease. These findings have implications for future clinical trial design.

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      MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)

      15:45 - 17:15  |  Presenting Author(s): Whitney Elizabeth Lewis  |  Author(s): George R Simon, Frank E Mott, Vassiliki A Papadimitrakopoulou, Waree Rinsurongkawong, Jeff Lewis, Jack Lee, Jack Roth, Stephen Swisher, John Victor Heymach, Jianjun Zhang, Vincent Lam

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.

      Method

      We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.

      Result

      Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).

      Conclusion

      Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous lung cancer.

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      MA14.11 - CareTrack: An Application-Based Method of Documentation for Improving Patient Communication in Cancer Care (Now Available) (ID 1933)

      15:45 - 17:15  |  Presenting Author(s): Jawaid Younus  |  Author(s): Jacques Raphael, Phillip Blanchette, Fahad Khan, Vineet Sharma, Morgan Black, Mark Vincent, Sara Kuruvilla, Michael Sanatani

      • Abstract
      • Presentation
      • Slides

      Background

      Patients being able to accurately understand and recall medical information correctly has been shown to improve outcomes, however, most studies suggest that patient information understanding in oncology tends to be poor with as much as 40-80% of information being relayed by healthcare professionals being forgotten (Kessels, 2003).

      Method

      Our study aimed to implement the use of ‘CareTrack’, an easy-to-use iPad application, as a simple yet complete app-based information package that provides an appointment summary sheet with no identifying information for patients to take home. An iPad pre-loaded with the CareTrack application was provided to oncologists and they filled in the form for their patients at the end of the initial consultation for lung cancer. A hard printout copy was provided to the patient to take home and the option of an email copy was sent as well. Approximately one-week later a patient satisfaction questionnaire was administered over the phone to patients who participated in the study.

      Result

      Six oncologists were recruited to the study with 35 patients consented to the study and 25 of these patients completing the follow-up surveys. Our primary objective was to assess feasibility of the CareTrack application. The average physician time to complete the CareTrack form for each patient was 1 minute and 29 seconds thus demonstrating that this is a quick and easy tool for physician use. Our secondary objective was to assess patient satisfaction with a brief survey. Ninety-six percent (24/25) of patients found the CareTrack information provided useful and 100% (25/25) of patients found the information easy to understand. Most patients did not require frequent review of the CareTrack form (28%, 7/25) nor needed the form to remember the information (56%, 14/25) or when discussing diagnosis/stage/treatment at home (44%, 11/25). Importantly, 96% (24/25) of patients were comfortable seeing their cancer information and treatment plan displayed on the CareTrack tool and 84% (21/25) of patients would like to receive additional CareTrack information in the future if their staging and/or treatment planned is changed/updated.

      Conclusion

      To conclude, the CareTrack application was found to be easy to use and was able to effectively provide new lung cancer patients with a comprehensive yet easy-to-understand summary of their initial consult. In the future, we envision this project expanding province- and nation-wide as well as expanding to other disease sites (e.g. breast, colorectal etc.).

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      MA14.12 - Discussant - MA14.09, MA14.10, MA14.11 (Now Available) (ID 3779)

      15:45 - 17:15  |  Presenting Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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