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Susana Cedres
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ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)
- Event: WCLC 2019
- Type: Educational Session
- Track: Advanced NSCLC
- Presentations: 4
- Now Available
- Moderators:Susana Cedres, Oliver Gautschi
- Coordinates: 9/08/2019, 13:30 - 15:00, Vienna (2016)
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ES06.01 - Recent Advances in Second Line Treatment (Now Available) (ID 3181)
13:30 - 15:00 | Presenting Author(s): Roy S. Herbst
- Abstract
- Presentation
Abstract
Despite advances in the treatment of cancer and reductions in smoking rates, lung cancer continues to be one of the leading causes of cancer death worldwide. Over the past decade, a handful of immune-checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) have been shown to improve survival and changes have been made to the standard of care for first-line treatment of patients with non-small cell lung cancer (NSCLC). However, only a minority of patients respond to these treatments and even these patients acquire resistance to the therapy. Continued investigation and research for second-line therapy options are vital to provide treatment options to patients who progress. Master protocols, like LUNGMAP, are efficient trial designs used to quickly and safely investigate new therapies or combinations. LUNGMAP is the first major trial, supported by the National Cancer Institute (U.S.) to simultaneously test multiple treatments under an umbrella design. LUNGMAP was launched in 2014 to investigate new therapies for squamous cell lung cancer, enrolling over 2000 patients. In 2018, the trial underwent a major expansion to include all non-small cell lung cancer patients. Treatments being tested include immunotherapy combinations and targeted therapies that are associated with specific genomic alterations. This allows for the identification of potential biomarkers which can help identify the treatments that would most likely benefit a patient. LUNGMAP is an unprecedented public-private partnership that is more flexible and efficient and will help to speed-up the development process for new lung cancer drugs.
References:
RS Herbst et al. Clin Cancer Res. 2015 Apr 1;21(7):1514-24 doi: 10.1158/1078-0432.CCR-13-3473. Epub 2015 Feb 13.
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ES06.02 - What Is the Best Strategy in Progressive Disease After Consolidation with Durvalumanb, or Rapid Progressors to First Line? (Now Available) (ID 3182)
13:30 - 15:00 | Presenting Author(s): Fabrice Barlesi
- Abstract
- Presentation
Abstract
Immune Check Points Inhibitors (ICIs) have dramatically changed the management of locally advanced and advanced NSCLC patients. While the survival improvement compared to previous standard of care is undoubtable, several patients still progress on or relapse after ICIs. How should these patients be managed?
To better understand how to manage these patients, we should probably try to better understand the underlying mechanism(s) of resistance to ICIs. Schematically, we can propose three main categories, with primary resistances, occurring early after ICIs initiation, secondary resistances, occurring after a previous response or disease stabilization on ICIs, and follow-up resistances, occurring after stopping ICIs, either per protocol or severe adverse event(s).
Management of primary resistances to ICIs. Although no validated definition is available, primary resistances might include hyperprogressors and progressors within the first 12- (to 18) weeks of treatment with ICIs. It represents approximately 20 to 30% of stage III NSCLC patients receiving durvalumab after concomitant chemo-radiation, 30% of stage IV patients PD-L1 50% or more NSCLC patients treated with pembrolizumab and 20 to 30% of stage IV patients NSCLC patients treated with a combination of chemotherapy and ICIs.
Few data are available on the underlying biological mechanisms to explain these primary resistances.
Considering clinical data of the PACIFIC trial, 41% of patients in the durvalumab arm (without precise characterization of the time or progression) received a subsequent therapy. For the patients who already received durvalumab as a consolidation treatment, 20 patients received a subsequent ICI. The response rate in this case was 0%. With a longer follow, different patients’ profiles will certainly be reported in this setting, with possibly responses to ICIs alone or in combination for patients relapsing a long time after stopping Durvalumab.
Considering clinical data for stage IV NSCLC patients treated in the first line setting in monotherapy, a recent long term analysis of the Keynote 024 trial. The management of patients with an early progression on Pembrolizumab was not specifically detailed. Globally, 56 out of 154 patients received a subsequent oncologic treatment, mainly chemotherapy.
Considering clinical data for stage IV NSCLC patients treated in the first line setting with combination of chemotherapy and ICIs, few results are available to date on the management of early progressors.
Finally, all trials assessing the efficacy of new IO agents or new ICI-based combinations as a rescue treatment after failure of a previous line of ICIs are globally disappointing. A summary of ongoing trials will be presented at the meeting.
In summary, the best strategy to date for early progressors on ICIs, alone or in combination, unfortunately remains a standard chemotherapy; a participation in a clinical trials should be also discussed giving the efficacy of rescue treatments in this situation.
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ES06.03 - Future Strategies in Second Line Treatment (Now Available) (ID 3183)
13:30 - 15:00 | Presenting Author(s): Gregory J Riely
- Abstract
- Presentation
Abstract
With the continued refinement of molecularly targeted therapy and the dramatic changes in initial therapy for patients with newly diagnosed NSCLC without a molecular target, the concept of "second line" therapy has largely become outdated. For the more than one-third of patients who have a targetable oncogenic driver (with aberrations in genes such as EGFR [exon 19 deletion, exon 21 point mutation, or exon 20 insertion], ALK, ROS1, BRAF, RET, MET exon 14, or TRK), multiple lines of targeted therapy are possible prior to receiving a platinum-based combination chemotherapy combination (sometimes with the addition of an anti-PD-1/PD-L1 antibody). In such patients, "second line treatment" could actually be the fifth treatment regimen. Similarly, for patients with PD-L1 that is 50% or greater, the second-line treatment is typically platinum-based doublet chemotherapy. Practically, "second line treatment" is that given after a regimen that contains platinum-based chemotherapy. Despite the difficulties in defining second line treatment, it is an area with critical need for development of new treatments.
Some new approaches to development of second line therapies are dependent upon a molecular evaluation of the patient’s tumor, typically selecting for targets that are not oncogenic drivers but rather other, non-driver, vulnerabilities found in a patient's tumor. This approach is best exemplified by the Lung MAP (Lung Cancer Master Protocol). This NCI-sponsored trial that began by enrolling only patients with squamous cell lung cancer but now enrolls patients with any NSCLC, uses the results of a comprehensive genomic profiling platform that looks at over 200 cancer-related genes for genomic alterations to assign patients to a genetically matched sub-study or randomize patients to an immunotherapy treatment. Cohorts have included patients with PI3KCA mutations receiving GDC-0032, patients with FGFR amplifications receiving AZD4547, patients with homologous repair deficiency receiving PARP inhibitors, and patients with STK11 alterations receiving talazoparib + avelumab. Critically, this trial uses staged evaluation of an arm to minimize the number of patients treated with relatively ineffective therapies.
There is a great deal of interest in identifying new immunologic approaches for patients with NSCLC who have progressed after initial treatment with anti-PD-1/PD-L1 therapy. These approaches include the exploration of antibodies against such targets as the T-cell inhibitory receptor Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) or small molecule inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in tryptophan catabolism alone or in combination with anti-PD-1 or PD-L1 antibodies. Beyond this, there are attempts to improve the efficacy of single-agent anti-PD-1 antibodies by adding MEK inhibitors. Building off great successes in hematologic malignancies, there are new effort that seek to use cell-based therapies in patients with solid tumors. These include clinical trials of autologous T-cells that have been transduced with vectors expressing T-cell receptors against such targets as NY-ESO-1 and LAGE-1a for patients with NSCLC as well as trials exploring ex vivo expansion of tumor infiltrating lymphocytes.
Treatment of patients who have progressed on available targeted therapies as well as platinum-based chemotherapies remains a notable challenge, with current treatments having limited activity. While none have yet proven effective, there are a broad array of treatments under study, whether using targeted therapies, chemotherapy combinations, or immunologic approaches.
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ES06.04 - The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt (Now Available) (ID 3184)
13:30 - 15:00 | Presenting Author(s): Juergen Wolf
- Abstract
- Presentation
Abstract
The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt
Jürgen Wolf
Most current guidelines recommend molecular testing of activating alterations in EGFR, ALK, ROS1 and BRAF before first line treatment decision in advanced NSCLC. These recommendations mostly are based on the approval status of the respective targeted therapies. For the remaining patients combinations of immunecheckpoint inhibitor (ICI) therapy and platinum-based chemotherapy (CT) has become standard for patients with a PD-L1 tumor proportion score (TPS) of below 50% and may also be used for patients with a higher score in case of aggressive tumor growth and good performance score (PS). Patients with a TPS of 50% and more may be treated with ICI alone. Tumor mutational burden (TMB) is currently evaluated as new predictive marker for either ICI mono- or combination therapy, the definitive value of this approach in first or second line so far, however, is still unclear.
If these (EGFR-, ALK-, ROS1-, BRAF wildtype) patients relapse after ICI monotherapy, platinum-based CT, eventually with the addition of bevacizumab, widely is considered standard treatment. By comparison, for patients with relapse after ICI/CT combination systemic treatment options are quite unsatisfying. Docetaxel monotherapy has only marginal efficacy which may be modestly increased by the addition of antiangiogenic agents. Numerous immunotherapeutic approaches are evaluated In this situation (next generation ICIs and other immunomodulatory drugs), preferably in combinations. However, so far, no convincing results have been reported from these clinical trials.
It is therefore particularly important to identify from these patients the subgroup with a possible benefit from driver-mutation directed treatments – either within a clinical trial or a compassionate use program or as off-label treatment. Numerous such approaches are in clinical evaluation. Examples are kinase inhibitors against RET-fusions, TRK-fusions, MET exon 14 skipping mutations, MET amplification, HER2 mutations, EGFR-/HER2 exon 20 mutations, NRG-1 fusions. High response rates and clinical significant duration of responses have already been reported for many of these personalized treatment options, some of them are already in accelerated approval procedures. Many of them will forge ahead towards first line treatment in particulary, since ICI therapy partly seems not to work well here.
Until the approval of these new treatment options it is of particular importance to test patients at the latest upon failure of ICI with or without chemotherapy on the presence of driver mutations in their tumors and to try hard to bring them into a clinical trial or to enable off-label treatment.
Given the dynamics in the field, this treatment algorithm will change in the near future not only by the approval of several of these new driver-mutation directed treatments, but also by the development of more effective and more tailored immunotherapies as well as by the availability of potent KRAS inhibitors.
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Author of
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-05 - Incidence and Outcome of Multiple Primary Cancers (MPC) in a Series of Lung Cancer (LC) Patients (ID 1030)
09:45 - 18:00 | Presenting Author(s): Susana Cedres
- Abstract
Background
The number of cancer survivors has increased as a result of significant progress in prevention, diagnosis and treatment of malignant tumors. The risk of developing a second neoplasm, after treatment of an initial primary cancer, is increasing and indeed lung cancer represents a commonly diagnosed second primary malignancy. This study investigates the co-occurrence of MPC among patients (p) diagnosed with lung cancer (LC).
Method
Review of clinical data of all consecutive patients with histologically confirmed LC visited at our institution between October 2017 and August 2018
Result
Out of 1386 p with LC, two primary cancers occurred in 206 cases (15%), including 41 p (3%) with three primary cancers. Patients with MPC were predominantly males (67%), smokers (88%), statin users (40%) and 28% had known family history. Second cancer was detected in a routine follow-up in 62%, whereas 27% were symptomatic patients. Median age at the first tumor diagnosis was 61 years (27-85). LC occurred as first neoplasm in 34% of the cases, as subsequent neoplasm in 41% and as two consecutive primary neoplasm in 25%. The most common primary cancer was LC in 34%, followed by breast (16%), colorectal (15%), prostate (9%), bladder (8%) and head and neck (6%). Treatment received for the first cancer included surgery in 80%, chemotherapy in 47% and radiotherapy in 32%. As a second tumor LC represented 41%, followed by bladder (19%), colorectal (10%), prostate (9%) and breast (7%). Surgery was performed in 70% of the cases with a second cancer. Regarding only patients with LC as two primary tumours (first and second tumour), 25 pts (89%) were not metastatic at second tumour, surgery was performed in 82% and 7 pts (24%) developed a third tumour. Overall, median time of diagnosis between the first and the second neoplasm was 4.2 years (CI95% 3.2-5.2), without significant differences if primary tumor was LC or another neoplasm (p=0.82). Smoking was associated with a shorter time of the second neoplasm diagnosis (3.8 years vs 7.9 years for non-smokers, p=0.09), whereas taking statins exhibited longer time of diagnosis of the second neoplasm (5.1 vs 3.3 year, p=0.05). With a median follow up of 7.3 years after diagnosis of the first neoplasm, the 5-year survival rate was 97.2% (94.8-99.7%).
Conclusion
In our series, the frequency of the MPC co-occurrence among LC p is 15%, indicating that surveillance strategies are recommended. Many p are treated with curative intent. Moreover, smoking and taking statins influences the time interval between tumors
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-01 - STELLAR Trial: Radiological Response Patterns of TTFields Plus Chemotherapy in First-Line Treatment of Malignant Pleural Mesothelioma (ID 2533)
10:15 - 18:15 | Author(s): Susana Cedres
- Abstract
Background
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of glioblastoma patients. In-vitro, human malignant pleural mesothelioma (MPM) cells were highly susceptible to TTFields. In the STELLAR trial [NCT02397928], patients with unresectable MPM treated with first-line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 Vs. 12.1 months). We analyzed radiological data from STELLAR patients whose tumors responded while receiving the combined therapy.
Method
The trial accrued 80 patients with unresectable, previously untreated mesothelioma who were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria: ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. EOCG status and cancer-related pain were assessed until disease progression using a visual analog scale.
Result
Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of patients. The median time between treatment start and PR was 1.8 (1.4-4.4) months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial/pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within median response duration of 5.7 (1.4-13) months, per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Median time to deterioration in performance status was 13.1 months. Average pain score was lower compared to baseline during the first 7 months of treatment and higher later with a median time to a clinical significant 33% increase in pain of 8.4 months. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. No TTFields-related other than expected dermatitis below the arrays were reported.
Conclusion
The STELLAR study showed significant survival extension in previously untreated MPM patients. Response rates were similar to that of current SOC treatment, but lasted longer with the addition of TTFields. TTFields was not associated with a decrease in performance status or an increase in pain. TTFields in combination with chemotherapy are efficacious in MPM vs chemotherapy alone reported in historical data.
