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E. Felip
Moderator of
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PC02 - By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV (ID 324)
- Event: WCLC 2016
- Type: Pro Con
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 4
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PC02.01 - Introduction & Vote (ID 6887)
14:30 - 14:45 | Author(s): G. Pall
- Abstract
- Presentation
Abstract not provided
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PC02.02 - Pro Chemotherapy (ID 6596)
14:45 - 15:05 | Author(s): N. Hanna
- Abstract
- Presentation
Abstract:
Despite the reduction in cigarette consumption in many parts of the world, the incidence and mortality rate of lung cancer will remain high in the year 2030[1]. Over the last 50 years major advances in the treatment of lung cancer have included early detection by screening CT, improved cure rates with neo-adjuvant and adjuvant chemotherapy, the successful integration of chemotherapy with radiation for locally advanced disease, and prolonged survival times with chemotherapy in the metastatic setting. More recently, the discovery of targetable mutations and development of a myriad of small molecule tyrosine kinase inhibitors have transformed the natural history of lung cancer in select subsets. Furthermore, immunotherapy is now a reality in the treatment of patients with stage IV non-small cell lung cancer (NSCLC). Today, the integration of targeted agents and immunotherapy are being investigated in earlier stages of disease. With these recent advances, what does the future of chemotherapy hold in the treatment of stage I-IV NSCLC? Is there a future at all? Can we eliminate the need for chemotherapy altogether for most patients at any point in their disease history? The dream of replacing chemotherapy with more active, less toxic, and more convenient therapy for patients with stage I-IV NSCLC is a laudatory goal. Is it realistic by the year 2030? Certainly not. Chemotherapy is currently the only systemic therapy that has ever been known to cure patients in the neo-adjuvant or adjuvant setting for stage I-III NSCLC[2]. While many targeted agents can prolong life in the metastatic setting, to date all of those tested in the adjuvant setting have failed to improve upon standard therapy[3-5]. The graveyard of negative trials in the adjuvant setting includes those evaluating angiogenesis inhibition, epidermal growth factor tyrosine kinase inhibition, and vaccine therapy. The same can be said for locally advanced, unresectable NSCLC. While the integration of chemotherapy with radiation improves survival rates compared with radiation alone[6], thus far no other agents have successfully done so, including tyrosine kinase inhibitors, angiogenesis inhibitors, or monoclonal antibodies[7-8]. In the metastatic setting, chemotherapy improves survival whether given as induction therapy or as maintenance therapy. Chemotherapy is also more active than targeted therapy in the vast majority of patients who do not harbor targetable mutations. Even with the stunning success of immunotherapy for some patients with advanced NSCLC, it appears this will not be curative in this setting and nearly all patients will still be getting chemotherapy at some point of their disease history. In other words, chemotherapy works for patients with stage I-IV NSCLC. Just as we will do with targeted therapy and immunotherapy, we will not abandon what works, but rather we will improve upon it. Chemotherapy works in a broad group of patients with lung cancer. It targets DNA, topoisomerase, and the mitotic spindle, which are the key targets in all cells. The majority of patients’ tumors do not have targetable mutations and most patients do not respond to immunotherapy. While gains are expected over the next 15 years in targeted therapy and immunotherapy, it is likely that we will discover the plateau in the benefit to these strategies and eventually nearly all patients will develop resistance. While predicting the future is usually only a fool’s errand, the past is prologue. So, what is the future of chemotherapy in NSCLC? Better drug delivery systems; developing combination therapy with DNA repair agents, cell cycle checkpoint modulators, and immunotherapy; and improved biomarkers for efficacy and toxicity are each on the horizon. Improved targeting of the cancer cell, increased cancer cell drug concentrations, and reduction of normal cell toxicity can be accomplished through nano-carriers[9]. Nano-carriers can deliver chemotherapy directly to cancer cells by protecting these agents from being degraded in the circulation and being excessively protein bound, limiting active drug exposure. Nano-carriers include liposomes, carbon nanotubes, dendrimers, and polymeric compounds (micelles, conjugates, nanoparticles). These carriers are typically 100-150 nm in size but have large surface-to-surface volume ratios, enabling them to encapsulate cytotoxic agents and enhancing drug deliver to tumors. Thus far 8 have been FDA approved, including 2 polymer-protein conjugates, 5 liposomal formulations, and 1 polymeric nanoparticle, in various cancers. Another strategy to enhance drug delivery to tumors is through antibody-drug conjugates (ADC). These agents link an antibody to a protein overexpressed on the surface of a cancer cell to a potent cytotoxic such as a microtubule inhibitor or an alkylating agent. The cytotoxic is released only in the cancer cell after the ADC complex is internalized. Examples include TDM-1 and Brentuximab. Over 30 ADC’s are under clinical investigation, including several against lung cancer including Rova-T and Sacituzumab. Another promising strategy for the future treatment of lung cancer involves combining chemotherapy with drugs that interfere with DNA repair, silence DNA repair genes, or inhibit cell cycle arrest [10]. Examples of this approach include PARP inhibitors, DNA methylation agents, and checkpoint modulators. Combination trials of chemotherapy and immunotherapy are also underway. In this regard, ADC technology may prove a more effective strategy when combining cytotoxic drugs with immunotherapy. By improving chemotherapy drug delivery to cancer cells and reducing off-target toxicities, nanotechnology has the potential to most effectively combine chemotherapy with immunotherapy. Lastly, despite decades of clinical investigation, most patients are empirically treated with chemotherapy, regardless of the molecular characteristics of the tumor and the pharmacogenomics of the patient. Refinements in these areas are expected in the upcoming years. In conclusion, for better or worse, in the year 2030 chemotherapy will remain standard of care for the majority of patients with stage I-IV NSCLC. But, the year 2040 or 2050 may be a different story. References 1. Rahib L, Smith B, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancer in the United States. Cancer Res 2014;74(11):2913-2921. 2. Burdett S, Pignon J, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;2(3):doi: 10.1002/14651858.CD011430 3. Wakelee H, Dahlberg S, Keller S, et al. E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—Outcomes based on chemotherapy subsets. J Clin Oncol 2006;34(abstract 8507). 4. Kelly K, Altorki N, Eberhardt W, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non–Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-4014. 5. Van Steenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 Immunotherapy in Resected Non–Small-Cell Lung Cancer: Phase II Randomized Study Results. J Clin Oncol 2013;31(19):2396-2403. 6. O’Rourke N, Roque i Figuls M, Farre Bernado N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010; DOI: 10.1002/14651858.CD002140. 7. Kelly K, Chansky K, Gaspar L, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26(15):2450-6. 8. Bradley J, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16(2):187-199. 9. Fanciullino R, Ciccolini J, Milano G. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit Rev Onc Hemat 2013;88:504-513. 10. Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nature Rev 2008;8:193-204.
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PC02.03 - Contra Chemotherapy (ID 6597)
15:05 - 15:25 | Author(s): K. Kelly
- Abstract
Abstract:
By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV: Contra Chemotherapy Cytotoxic chemotherapy has undeniably provided benefit for our patients with non-small cell lung cancer (NSCLC). However its nondiscriminatory application based on general tumor biology principles and not on the underlying biology of lung cancer has hampered its ability to dramatically improve survival and cures for lung cancer. Over the last twenty years we have seen multiple examples of how molecular characterization of lung tumors coupled with advances in drug development, have led to astonishing improvements in cancer outcomes. Hence, it is time to set a course toward abandoning chemotherapy. In addition to their superior efficacy, targeted therapies and immunotherapy have milder toxicity profiles compared to chemotherapy that all patients appreciate. We have already made significant progress in this quest. Our journey began with the discovery of EGFR (epidermal growth factor receptor) mutations and their exquisite sensitivity to EGFR-TKI (tyrosine kinase inhibitors). This observation was confirmed in the landmark IPASS trial that demonstrated the superiority of EGFR-TKIs over platinum-based chemotherapy for the first line treatment of patients whose tumors harbor these mutations (1). On the heels of this therapeutic advancement came the discovery of ALK (anaplastic lymphoma kinase) gene rearrangements and the replacement of doublet chemotherapy with an ALK-TKI in patients with ALK positive tumors (2). To date actionable driver mutations are found in at least 50% of patients with adenocarcinoma (3) and inhibitors to all of these mutations are in clinical development with the hope that they will have similar success as their predecessors. Of particular interest is developing inhibitors to KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) because it is the most frequent driver mutation occurring in approximately 20-25% of tumors. Today there is optimism that we will achieve this goal given it is the focus of the Stand Up To Cancer (SU2C) lung cancer dream team initiative and several novel agents are in development including direct KRAS therapy. Driver mutations are typically identified in patients who are never smokers, light former smokers or have a lengthy quit time. The remaining groups of patients’ (i.e. current smoker or recent former smokers) have a different biology that has been successfully exploited with immunotherapy. Immune checkpoint inhibitors have replaced single agent docetaxel as the standard of care for second line treatment of lung cancer for all histological subtypes of NSCLC (4-6). Most recently the KEYNOTE-024 a randomized trial of pembrolizumab versus doublet chemotherapy for untreated patients with advanced NSCLC whose tumor have > 50% PD-L1 (programmed death-ligand 1) IHC (immunohistochemistry) expression met its primary progression-free survival (PFS) endpoint and also improved overall survival (7). This will represent a new standard of care for approximately 25% of patients and will serve as the backbone for immune combinations. We are anxiously awaiting the results of a randomized trial of a PD-1 (programmed cell death protein 1) inhibitor plus a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor versus platinum-based chemotherapy that is expected to report out in mid 2017. A similar study is actively accruing patients. The preliminary results on this dual immune combination were very promising and if positive would increase the number of patients receiving upfront immune therapy over chemotherapy (8). Additionally, there are numerous immune combinations involving drugs that target immune evasion and even more drugs that stimulate the immune system including cellular therapies that are being evaluated. The success of targeted therapy and immunotherapy in the advanced setting has quickly led to their evaluation in earlier stages of disease. There is a lot of enthusiasm for combining immunotherapy with radiation for patients with locally advanced lung cancer given the well-known immune modulatory effects of radiation. Moreover the bar for replacing weekly low dose concurrent chemotherapy with immunotherapy is low. In the adjuvant setting our Asian colleagues designed and conducted two randomized phase III trials in patients whose tumors have an EGFR sensitizing mutation to replace chemotherapy with an EGFR-TKI. Accrual is completed and we are awaiting the results. In regard to immunotherapy, enrolling phase III trials are evaluating immune checkpoint inhibitors as maintenance therapy but the pursuit of immunotherapy as a replacement for chemotherapy will follow. Beyond treatment of lung cancer, on the horizon is the exploration of targeted agents and immunotherapy as preventive agents. It is important to emphasize that our current and future success is the consequence of many factors: 1) the exponential advances in technology that has driven the science and drug development 2) rapid trial accrual and 3) regulatory authorities’ responsiveness to bringing efficacious treatments to patients as quickly as possible. This momentum is what will lead us to replacing chemotherapy for lung cancer. With 20%+ of patients with driver mutations and 25% of all NSCLC with high PD-L1 already benefiting from non-chemotherapy treatment, we are well on our way to ousting chemotherapy in NSCLC by 2030. References Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009, 361:947-57. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013, 368:2385-94. Vigneswaran J, Tan YH, Murgu SD, et al. Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation. Oncotarget 2016, 7:18876-86. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373:123-35. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373: 1627-39. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016, 387:1540-50. MERCK press release, July 2016 Hellman MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001).
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PC02.04 - Discussion & Vote (ID 6888)
15:25 - 15:45 | Author(s): E. Felip
- Abstract
- Presentation
Abstract not provided
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Author of
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ISS07 - Industry Supported Symposium: Immuno-Oncology and Lung Cancer: Emerging Data and Recent Developments - Bristol-Myers Squibb (ID 440)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 1
- Moderators:M.D. Hellmann
- Coordinates: 12/05/2016, 12:45 - 14:15, Hall D (Plenary Hall)
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ISS07.02 - Developments in the Use of I-O Monotherapy in Lung Cancers (ID 7141)
12:55 - 13:10 | Author(s): E. Felip
- Abstract
Abstract not provided
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 3
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MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)
11:30 - 11:36 | Author(s): E. Felip
- Abstract
- Presentation
Background:
ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.
Methods:
Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.
Results:
In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).
Conclusion:
Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.
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MA07.08 - Discussant for MA07.05, MA07.06, MA07.07 (ID 7081)
11:48 - 12:00 | Author(s): E. Felip
- Abstract
- Presentation
Abstract not provided
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MA07.11 - Safety and Efficacy of Lorlatinib (PF-06463922) in Patients with Advanced ALK+ or ROS1+ Non-Small-Cell Lung Cancer (NSCLC) (ID 5053)
12:12 - 12:18 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Patients with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC often become resistant to tyrosine kinase inhibitor (TKI) therapy; central nervous system (CNS) relapse is common. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI, active against most known resistance mutations.
Methods:
In Ph I of the ongoing Ph I/II study NCT01970865, patients had ALK+ or ROS1+ NSCLC ± brain metastases and were treatment naïve or had disease progression after ≥1 TKIs. Patients received lorlatinib on day –7 and then once or twice daily from day 1. Primary objective was identification of MTD and recommended Ph II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1 including intracranial activity.
Results:
Of 54 patients treated in Ph I (cutoff Jan 15, 2016), 41 were ALK+, 12 ROS1+, and 1 had mutation status unconfirmed for ALK+ or ROS1+. Patients were heavily pretreated: 27 had received ≥2 prior TKIs and 20 had 1 prior TKI; 39 patients had CNS metastases at baseline. Patients were treated across 10 dose levels (total daily dose of 10–200 mg). Response rates were:
Median duration of response was 10.5 months (95% CI 2.9– not reached [NR]) and 12.4 months (95% CI 6.5–NR) for ALK+ and ALK+/ROS1+ pts, respectively. 26 patients remain on treatment. The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade ≥3 TRAE. No patient discontinued due to a TRAE. Analyses of ALK resistance mutations in archival tumor tissue and plasma circulating free DNA collected before lorlatinib treatment are ongoing.N CR PR uCR uPR Overall RR (CR + PR) n (%) ORR in ALK+ and ROS1+ 53 3(6) 22(42) - 1(2) 25(47) ORR in ALK+ with 1 prior TKI 14 1(7) 7(50) - - 8(57) ORR in ALK+ with ≥2 prior TKI 26 2(8) 9(34) - 1(4) 11(42) IC ORR (target + non-target lesions) in ALK+ and ROS+ 39 10(26) 4(10) 1(3) 2(5) 14(36) IC ORR (target lesions) in ALK+ and ROS+ 23 7(30 4(17) - 2(9) 11(47) ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed
Conclusion:
Lorlatinib was well tolerated and demonstrated durable responses, including intracranial responses, in ALK+ and ROS1+ NSCLC, most of whom had CNS metastases and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph II is ongoing.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
15:26 - 15:32 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 2
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OA03.02 - Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1–Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study (ID 4799)
11:10 - 11:20 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients.
Methods:
1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Results:
With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented.
Conclusion:
With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.
NE, not estimable.[a ]TC ≥50% or IC ≥10% PD-L1–expressing cells.[b ]TC or IC ≥5% PD-L1–expressing cells.Endpoint(95% CI) TC3 or IC3[a](n=65) TC2/3 or IC2/3[b](n=139) INV ORR, % 32% (21.2–45.1) 24% (16.9–31.7) EGFR mutant/wild-type, % 25%/29% 31%/20% KRAS mutant/wild-type, % 38%/27% 27%/21% mDOR, mo 13.1 (8.5–NE) 13.1 (9.9–17.5) mOS, mo NE (12.0–NE) 20.1 (20.1–NE) 12-mo OS rate, % 61% (48.8–73.8) 66% (57.9–74.5) mPFS, mo 7.3 (4.9–12.0) 7.3 (5.6–9.1) 12-mo PFS rate, % 36% (23.8–48.8) 32% (24.0–40.7)
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OA03.05 - Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 (Abstract under Embargo until December 5, 7:00 CET) (ID 4392)
11:45 - 11:55 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.
Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.
Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.
Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.01 - Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer: Updated Survival Results from KEYNOTE-028 (Abstract under Embargo until December 5, 7:00 CET) (ID 6198)
14:20 - 14:30 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present updated safety and efficacy data, including survival, for patients with ED SCLC enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.
Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and overall survival (OS).
Results:
24 patients with ED SCLC and tumor PD-L1 positivity were enrolled and received ≥1 dose of pembrolizumab. At the data cutoff date (June 9, 2016), median follow-up duration was 9.8 months (range, 0.5-24.0 months); 3 patients (12.5%) remain on treatment. The ORR was 37.5% (95% CI, 18.8%-59.4%), including 1 complete and 8 partial responses in 24 evaluable patients. Median duration of response was 9.0 months (range, 1.9-19.9+ months). Median PFS was 1.9 months (95% CI, 1.7-5.9 months); the 6- and 12-month PFS rates were 29.8% and 24.8%, respectively. Median OS was 9.7 months (95% CI, 4.1 months-not reached); the 6- and 12-month OS rates were 66.0% and 35.7%, respectively. No new safety concerns were noted. Sixteen of 24 (66.7%) patients experienced treatment-related AEs. Two patients experienced grade 3-5 treatment-related AEs: 1 patient had blood bilirubin increased (grade 3) and 1 patient experienced grade 3 asthenia and grade 5 colitis.
Conclusion:
Pembrolizumab demonstrated promising antitumor activity in this pretreated, PD-L1–positive ED SCLC population. The responses were found to be durable and may have led to an OS benefit for the subset of patients who achieved objective responses with pembrolizumab.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.03 - Second-Line Afatinib for Advanced Squamous Cell Carcinoma of the Lung: Analysis of Afatinib Long-Term Responders in the Phase III LUX-Lung 8 Trial (ID 4711)
14:40 - 14:50 | Author(s): E. Felip
- Abstract
- Presentation
Background:
Squamous cell carcinoma (SCC) of the lung is a genetically complex and difficult-to-treat cancer. In LUX-Lung 8, afatinib (40mg/day) significantly improved OS (median 7.9 vs 6.8 months, HR=0.81 [95% CI, 0.69‒0.95], p=0.008), PFS (2.6 vs 1.9 months, HR=0.81 [0.69‒0.96], p=0.010) and DCR versus erlotinib (150mg/day) in patients with relapsed/refractory SCC of the lung (n=795). Notably, 12-month (36 vs 28%; p=0.016) and 18-month survival (22 vs 14%; p=0.016) was significantly higher with afatinib than erlotinib, indicating that some patients derive prolonged benefit from afatinib. Here, we present post-hoc analysis of baseline characteristics and efficacy/safety of afatinib in long-term responders (treatment for ≥12 months). Hypothesis-generating analysis of archived tumor samples and blood serum was undertaken to identify possible molecular/clinical biomarkers.
Methods:
Tumor samples were retrospectively analyzed using FoundationOne[TM] next-generation sequencing (NGS); EGFR expression was determined by immunohistochemistry. Pre-treatment serum samples were analyzed with VeriStrat[®], a MALDI-TOF mass spectrometry test, and classified as VeriStrat-Good or VeriStrat-Poor-risk.
Results:
15/398 patients treated with afatinib were long-term responders. Median duration of treatment was 16.6 months (range: 12.3‒25.8). Patient characteristics were similar to the overall dataset (median age: 65 years [range: 54‒81]; male: 80.0%; Asian: 13.3%; ECOG 0/1: 40.0%/60.0%; best response to chemotherapy CR or PR/SD: 53.3%/46.7%; current and ex-smokers: 80.0%). Median PFS was 16.2 months (range: 2.8‒24.0); median OS was 23.1 months (range: 12.9‒31.5). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (73.3%/6.7%); rash/acne (66.7%/6.7%); stomatitis (13%/7%). AEs generally occurred soon after treatment onset (median onset, days [range]: diarrhea 11 [5‒48]; rash/acne 17 [9‒107]; stomatitis 15 [11‒19]). Four patients required a dose reduction to 30mg/day due to treatment-related AEs (diarrhea, rash, stomatitis, diarrhea/rash). NGS was undertaken in 9 patients and details will be presented at the meeting. Genomic aberrations in the ErbB/FGF gene families were identified in 44.4%/55.6% of long-term responders (overall dataset: 29.4%/58.0%). Of 14 patients assessed by VeriStrat, 85.7% were VeriStrat-Good (overall dataset: 61.6%). Immunohistochemistry data was available for two patients; one overexpressed EGFR (≥10% positive cells; H-score ≥200)
Conclusion:
Baseline characteristics of long-term responders to afatinib were similar to the overall dataset. In this sub-group, afatinib conferred a survival benefit of nearly 2 years. Afatinib was well tolerated with predictable and transient AEs that occurred soon after treatment onset. The dataset was too small to identify any clear NGS/VeriStrat predictive signals. Further studies are required to predict long-term response to afatinib.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-025 - Evaluation of NGS and RT-PCR Methods for ALK Assessment in European NSCLC Patients: Results from the ETOP Lungscape Project (ID 5001)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%, depending on population and detection method. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This is one of the first studies comparing all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort.
Methods:
96 cases from the ETOP Lungscape iBiobank (N=2709) selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK) were examined by FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014), central RT-PCR and NGS. H-score 120 is used as cutoff for IHC+. For both RT-PCR and NGS, RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers were used covering the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used, allowing simultaneous sequencing of 70 ALK, RET and ROS1 specific fusion transcripts associated with NSCLC, as well as novel ALK translocations using 5’-3’ ALK gene expression ‘Imbalance Assay’.
Results:
NGS provided results for 90 cases, while RT-PCR for 77. Overall, 70 cases have results for all 4 methods, with fully concordant 60 (85.7%) cases (49 ALK-, 11 ALK+). Before employing the ‘Imbalance Assay', in 5 of the remaining 10 cases, NGS differs from the other methods (3 NGS-, 2 NGS+), while in the other 5, NGS agrees with RT-PCR in all, IHC in 2, and FISH in 1. Using the concordant result of at least two of the three methods as true negative/positive, the specificity and sensitivity of the fourth is 96/94/100/96% and 94/94/89/72% for IHC/FISH/RT-PCR/NGS, respectively (incorporating imbalance: NGS sensitivity=83%). Imbalance scores are presented here for 18 NGS- cases: 9 ‘NGS-/FISH+/IHC+’, 9 ‘NGS-/FISH-/IHC-‘. Among the ‘NGS-/FISH+/IHC+’, there is strong evidence of imbalance in 4 cases (score’s range: 0.0144-0.0555), uncertain in 5 (range: 0.0030-0.0087), and no evidence (scores≤0.0004) in the 9 negative cases.
Conclusion:
NGS is a useful screening tool for ALK rearrangement status, superior to RT-PCR when RNA yield is limited. When using NGS, it is critically important to integrate the 5’-3’ imbalance assay and to confirm with one or more additional methods in the ‘imbalance’ cases. Data further highlight the possibility of missing actionable rearrangements when only one screening methodology is available.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.
Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-024 - Tedopi vs Standard Treatment as 2nd or 3rd Line in HLA-A2 Positive Advanced NSCLC Patients in a Phase 3, Randomized Trial: ATALANTE-1 (ID 5329)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
HLA-A2 is expressed in 40 to 50% of NSCLC patients. TEDOPI is a combination of neoepitopes that generates cytotoxic T lymphocytes responses. It consists of nine HLA-A2 supertype binding epitopes covering five tumor-associated antigens overexpressed in advanced NSCLC and the universal helper pan-DR epitope. In a phase II trial (NCT00104780, Barve et al. JCO 2008), TEDOPI showed a promising median overall survival of 17.3 months with a manageable safety profile in pre-treated HLA-A2 positive patients with advanced NSCLC. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy.
Methods:
Section not applicable
Results:
Trial design: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements, with progressive disease to first-line platinum-based chemotherapy or second-line immune checkpoint inhibitors (IC) are eligible if they have HLA-A2 positivity and ECOG PS 0-1. Treated and asymptomatic brain metastases are allowed. Patients are randomized 1:1 to receive 1 ml TEDOPI subcutaneously Q3W for 6 cycles, then every two months for the reminder of the year and finally every three months or standard treatment with: 75 mg/m[2] docetaxel Q3W or 500 mg/m[2] pemetrexed Q3W (in non-squamous histology and pemetrexed-naïve patients). In both arms, treatment continues until progression, intolerable toxicity, consent withdrawal, or investigator decision. In TEDOPI arm, treatment may continue beyond initial radiographic disease progression in case of clinical benefit. Randomisation is stratified by histology (squamous vs. non-squamous), initial response to first-line chemotherapy (partial or complete response vs. stabilization or progression), and previous treatment with IC (yes vs. no). Tumor assessment is performed every 6 weeks and adverse events are collected throughout the study and for 60 days and 90 days thereafter and graded per NCI CTCAE v4.0. Archival biopsies samples are required for assessing PD-L1 status (IHC22C3 pharmDx from Dako). Primary endpoint is overall survival; and secondary are progression free survival based on RECIST 1.1 criteria, objective response rate, disease control rate, duration of response, and quality of life measured by QLQ-C30 and QLQ-LC13 global scores. This is a superiority study with a hazard ratio of 0.7391, two-sided alpha 5% and power 80%, after 356 events are observed over 500 patients. The first patient was enrolled on 25th January 2016. Enrolment is ongoing in Europe and the US. Clinical trial identification: NCT02654587 Legal entity responsible for the study & Funding: OSE Immunotherapeutics, France
Conclusion:
Section not applicable
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-015 - Ceritinib as First-Line Therapy in Patients with ALK-Rearranged Non-Small Cell Lung Cancer: ASCEND-1 Subgroup Analysis (ID 5686)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
In the open-label, phase 1 ASCEND-1 study (NCT01283516), ceritinib demonstrated durable whole body and intracranial responses in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) (Kim et al. Lancet Oncol 2016). Median progression-free survival (PFS) was promising in ALK inhibitor (ALKi)-naïve patients (18.4 months), most of whom had received one or more lines of chemotherapy. Here, efficacy and safety of ceritinib are summarized in a subset of treatment-naïve patients enrolled in ASCEND-1.
Methods:
Patients with ALK+ NSCLC enrolled worldwide received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had not received any prior systemic antineoplastic therapy. Data cut-off was 16 November 2015.
Results:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom 16 had not received any prior systemic antineoplastic therapy. Among the 16 treatment-naïve patients, three (18.8%) had baseline brain metastases, five (31.3%) an ECOG performance status of 0, and all had stage IV disease. Median time from primary site diagnosis to ceritinib initiation (range) was 1.8 months (1.0–35.9). At data cut-off, median duration of exposure (range) was 18.5 months (0.9–35.7) and median duration of follow-up (range) was 29.6 months (4.7–39.1). In these 16 treatment-naïve patients, per investigator assessment, the overall response rate was 68.8% (95% confidence interval [CI]: 41.3, 89.0) and the disease control rate was 87.5% (95% CI: 61.7, 98.4). Median duration of response was 21.1 months (95% CI: 5.5, 31.1). Median investigator-assessed PFS was 19.3 months (95% CI: 4.2, 26.3), and median overall survival was 39.1 months (95% CI: 19.1, 39.1). Among three patients with baseline brain metastases, one had brain metastases selected as target lesion and achieved a partial intracranial response. The most frequently reported any-grade adverse events (AEs), regardless of study drug relationship, were diarrhea (93.8%), nausea (81.3%), ALT or AST increase (each 81.3%), and vomiting (62.5%). AEs requiring intervention were predominantly managed with dose reduction/interruption. Overall, 13 patients (81.3%) discontinued treatment, due to disease progression (n=6), consent withdrawal (n=3), AEs (n=2), administrative problems or death (each n=1).
Conclusion:
Ceritinib demonstrated durable efficacy in treatment-naïve patients with ALK+ NSCLC. Safety was consistent with the overall ASCEND-1 study population. An ongoing, prospective, phase 3 study (ASCEND-4) in which patients are randomized to receive either ceritinib or chemotherapy will provide further evidence for the clinical benefit of ceritinib in previously untreated patients with ALK+ NSCLC.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-003 - Second-Line Afatinib versus Erlotinib for Patients with Squamous Cell Carcinoma of the Lung (LUX-Lung 8): Analysis of Tumour and Serum Biomarkers (ID 5627)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
LUX-Lung 8 compared second-line afatinib (40 mg/day; n=398) and erlotinib (150 mg/day; n=397) in patients with stage IIIB/IV squamous cell carcinoma (SCC) of the lung. PFS (median 2.6 vs 1.9 months, HR=0.81 [95% CI, 0.69–0.96], p=0.010) and OS (median 7.9 vs 6.8 months, HR=0.81 [0.69–0.95], p=0.008) were both significantly improved with afatinib versus erlotinib. Here we report exploratory molecular (n=245) and immunohistochemical (n=288) analyses of tumour samples to assess the frequency of short variants (SVs) and copy number alterations (CNAs) in cancer-related genes and whether these tumour genomic alterations, or EGFR expression levels, have clinical utility as prognostic/predictive biomarkers in patients with SCC of the lung. We also assessed the predictive utility of the prospectively validated VeriStrat®, a serum protein test (n=675).
Methods:
Archived tumour samples were retrospectively analysed using next-generation sequencing (FoundationOne™). Tumour EGFR expression was assessed by immunohistochemistry; EGFR positivity was defined as staining in ≥10% of cells. Pretreatment serum samples were assigned as VeriStrat-Good or VeriStrat-Poor according to a mass spectrometry signature. Cox regression analysis was used to correlate OS/PFS with genomic alterations (individual or grouped into gene families e.g. ErbB family), EGFR expression levels and VeriStrat status.
Results:
The frequency of ErbB family alterations was low (SVs: EGFR 6.5%, HER2 4.9%, HER3 6.1%, HER4 5.7%; CNAs: EGFR 6.9%, HER2 3.7%). No individual genetic alterations, or grouped ErbB family aberrations, were prognostic of OS/PFS. Treatment benefit from afatinib versus erlotinib was consistent in all molecular subgroups. Most tumours were EGFR-positive by immunohistochemistry (afatinib: 82%; erlotinib: 86%). EGFR expression was not predictive of OS or PFS benefit (EGFR-positive PFS: HR=0.76 [0.57‒1.02]; OS: HR=0.84 [0.63‒1.12]; EGFR-negative PFS: HR=0.87 [0.45‒1.68]; OS: HR=0.77 [0.40‒1.51]). In afatinib-treated patients, both PFS (HR=0.56 [0.43‒0.72], p<0.0001) and OS (HR=0.40 [0.31‒0.51], p<0.0001) were improved in the VeriStrat-Good versus the VeriStrat-Poor group. VeriStrat-Good patients had significantly longer OS and PFS when treated with afatinib versus erlotinib (median OS: 11.5 vs 8.9 months, HR=0.79 [0.63‒0.98]; PFS: HR=0.73 [0.59‒0.92]). In VeriStrat-Poor patients there was no significant difference in OS between afatinib and erlotinib (HR=0.90 [0.70‒1.16]). However, there was no significant interaction between treatment arms and VeriStrat classification.
Conclusion:
Despite comprehensive, multifaceted analysis, no biomarkers were identified that predicted the benefit with afatinib over erlotinib in patients with SCC of the lung. Afatinib is a treatment option in this setting irrespective of patients’ tumour genetics or EGFR expression levels. However, patient outcome strongly depends on VeriStrat status.
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P3.02b-117 - Phase Ib Results from a Study of Capmatinib (INC280) + EGF816 in Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 5012)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
Among patients with EGFR-mutant NSCLC who progress on EGFR tyrosine kinase inhibitors (EGFR-TKIs), the most common (50%) resistance mechanism is secondary T790M mutation. cMET dysregulation is the second most common mechanism, with amplification occurring in 5‒22% of resistant patients. This study evaluates targeting these two mechanisms to overcome acquired resistance to EGFR-TKIs. Capmatinib (INC280) is a highly selective, potent cMET inhibitor with clinical activity in patients with cMET dysregulation. EGF816 is an irreversible EGFR-TKI that selectively inhibits T790M and EGFR-activating mutations, with antitumor activity in EGFR[T790M]-mutated NSCLC. In this open-label Phase Ib/II study, capmatinib was combined with EGF816 in patients with EGFR-mutated, EGFR-TKI resistant NSCLC.
Methods:
The Phase Ib primary objective is estimation of the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of the combination using an adaptive Bayesian logistic regression model. Eligible patients (≥18 years; ECOG PS ≤2) must have documented EGFR-mutated (exon19del and/or L858R) NSCLC and documented progression (RECIST v1.1) while on EGFR-TKI treatment. Patients received capmatinib (starting dose 200 mg BID) plus EGF816 (starting dose 50 mg QD).
Results:
At the data cut-off (Aug 1, 2016), 33 patients were enrolled at five capmatinib BID/EGF816 QD mg dose levels (200/50 [n=4]; 200/100 [n=5]; 400/75 [n=3]; 400/100 [n=16]; 400/150 mg [n=5]); 18/33 (55%) patients discontinued treatment, mainly (13 [39%] patients) due to disease progression. Dose-limiting toxicities (DLTs) occurred in 4 patients: in 1 patient at the 200/50 dose level (increased alanine aminotransferase), 1 patient at the 400/100 dose level (anaphylactic reaction), and 2 patients at the 400/150 dose level (pyrexia, maculopapular rash, and allergic dermatitis). The most frequent (≥30%) any-grade adverse events (AEs), regardless of causality, were nausea (55%), peripheral edema (45%), increased amylase (42%), increased blood creatinine (36%), decreased appetite and diarrhea (both 30%). The most frequent (>10%) Grade ≥3 AEs were maculopapular rash (18% [mainly in the 400/150 cohort]) and increased amylase (12%). Capmatinib and EGF816 exposure increased with dose; preliminary data indicate a ~35% increase in EGF816 exposure (AUC) at steady state when co-administered with the capmatinib RP2D, compared with single-agent exposure. The investigator-assessed overall response rate was 42% (2/33 complete responses; 12/33 partial responses) across all dose levels and 50% (8/16 patients) at the 400/100 dose level, regardless of molecular status of resistance.
Conclusion:
The RP2D of the combination was declared as capmatinib 400 mg BID + EGF816 100 mg QD. Preliminary antitumor activity was observed across dose levels, independent of T790M status.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-050 - IMpower010: Phase III Study of Atezolizumab vs BSC after Adjuvant Chemotherapy in Patients with Completely Resected NSCLC (ID 6098)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
Early-stage non-small cell lung cancer (NSCLC) is treated surgically, but 30%-70% of patients experience post-resection recurrence and succumb to disease. Adjuvant chemotherapy is the standard of care for fully resected NSCLC (stages IB [tumors ≥4 cm]-IIIA), and although cisplatin-based chemotherapy provides some benefit, the 5-year absolute survival benefit is ≈5%, underscoring the unmet need. Atezolizumab is an anti-PD-L1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. Atezolizumab monotherapy has demonstrated promising efficacy and tolerable safety in patients with previously-treated advanced NSCLC, with a survival benefit observed across all PD-L1 expression levels. Given the need to improve survival for patients with early-stage NSCLC, IMpower010 (NCT02486718), a global Phase III randomized, open-label trial, has been initiated to compare the efficacy and safety of atezolizumab with best supportive care (BSC), following adjuvant cisplatin-based chemotherapy in patients with resected stage IB (tumors ≥4 cm)-IIIA NSCLC.
Methods:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathologic stage IB (tumors ≥4 cm)–IIIA NSCLC. Patients must have adequately recovered from surgery, be eligible to receive cisplatin-based adjuvant chemotherapy and have an ECOG PS 0-1. Exclusion criteria include the presence of other malignancies, use of hormonal cancer or radiation therapy within 5 years, prior chemotherapy, autoimmune disease or exposure to prior immunotherapy. Approximately 1127 patients, regardless of PD-L1 expression status, will be enrolled. Eligible patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + either vinorelbine [30 mg/m[2] IV days 1, 8], docetaxel [75 mg/m[2] IV day 1] or gemcitabine [1250 mg/m[2] IV days 1, 8], or pemetrexed [500 mg/m[2] IV day 1; non-squamous NSCLC only]). Adjuvant radiation therapy is not permitted. Following adjuvant treatment, eligible patients will be randomized 1:1 to receive atezolizumab (1200 mg q3w, 16 cycles) or BSC. Stratification factors will include sex, histology (squamous vs non-squamous), extent of disease (stage IB vs II vs IIIA) and PD-L1 expression by IHC (TC, tumor cell; IC, tumor-infiltrating immune cell; TC2/3 [≥5% expressing PD-L1] and any IC vs TC0/1 [<5%] and IC2/3 [≥5%] vs TC0/1and IC0/1 [<5%]). The primary endpoint is disease-free survival, and secondary endpoints include overall survival and safety. Exploratory endpoints include PD-L1 status, immune and tumor related biomarkers before, during and after treatment with atezolizumab and at radiographic disease occurrence or confirmation of new primary NSCLC.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c-063 - Lactate Dehydrogenase (LDH) as a Surrogate Biomarker to Checkpoint-Inhibitors for Patient with Advanced Non–Small-Cell Lung Cancer (NSCLC) (ID 5073)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
Effectiveness of immunotherapy has been observed in around 20% of cases, nowadays there is no accurate biomarker to select those patients (pts) who will benefit the most.
Methods:
We evaluated retrospectively pretreatment (baseline) and post-treatment (every 2 months) serum-LDH in 94 pts with NSCLC treated with anti-PD1/PDL1. Repeated measures ANOVA, Kaplan-Meier and the proportional COX model were used to examine the association of LDH with overall survival (OS). The cutoff level of LDH was 400 based on the median of the sample. (normal range 105-333 UI/L).
Results:
From July 2013 to February 2016, 94 pts were treated with immunotherapy based in anti-PD1 (77,6%) and anti-PDL1 (22,4 %), in trials at VHIO. Median age was 62 (39-86). Histological subtypes were: adecocarcinoma 53.2%, squamous 42.5%, others 4.2 %. The OS was significantly different in pts treated with immunotherapy according to baseline LDH, if LDH ≥ 400 median OS was 8.2 months, while in pts with LDH <400 median survival was not reached (Figure 1) Figure 1 There were statistically significant differences in the evolution of LDH, with better responses if there was a downward trend in LDH levels. In long responding pts (45 of 94 pts), defined as ≥ 3 evaluations (6 months), a LDH level at the time of 6 months treatment below than the baseline LDH predicts better responses (22/45 pts): 68.2% partial response (RP); 18.2% stable disease (SD); 13.6% disease progression (PD). In contrast, when LDH at third evaluation was higher than baseline LDH (23/45 pts): 39.1% PR; 56.5% SD; 4.3% PD, (p=0.022). There were differences between the level of LDH pre and post-progression. 66.67% of patients who progressed had a higher level of LDH at the time of progression than at the previous assessment (p=0.03).
Conclusion:
LDH may be a potential predictive biomarker of survival benefit conferred by immunotherapy in patients with NSCLC.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-019 - Molecular Characterization of Malignant Pleural Mesothelioma (MPM) by next Generation Sequencing (ID 4881)
14:30 - 14:30 | Author(s): E. Felip
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite treatment. Chromosomal abnormalities are abundant in MPM and the most frequently mutated genes are BAP1, NF2 and CDKN2A. Expanded molecular profile in MPM may provide targetable molecular aberrations and improve treatment options for these patients (p).
Methods:
Thirty two MPM patients who progressed to standard chemotherapy underwent genetic tumor profiling in a molecular prescreening program at our institution between 2006 and 2015. Paraffin-embedded biopsies were used for the analysis. Mass detection (MassARRAY, Sequenom) including analysis of mutations in 25 oncogenes was used and since June 2014 multiplexed amplicon sequencing (AmpliSeq, Illumina) was implemented assessing mutations in 59 oncogenes. No patients received systemic treatment prior to obtain the tumor sample.
Results:
Demographics: male/female (22/10); median age 60.5 (range 32-83 years); histology epithelial/no epithelial (24/8); PS 0/1 (15/17); stage III/IV (14/13). All patients were treated with chemotherapy. Sequenom was performed in 21 p and AmpliSeq in 11 p. Median follow up was 23.3 months and median overall survival (OS) for entire cohort was 30.2 months. The median OS for patients with epitheliod and no-epithelioid histology was 31.5 vs 21.4 months (p=0.033). Genetic alterations were detected in 5 patients (4 p with AmpliSeq and 1 p with Sequenom).The mutations detected were RNF43/ZNRF3 (2p), PI3KCA (1p), APC (1p) and P53 (1p). We did not identify significant association between mutations with histology, gender and clinical stage (p>0.05). Median survival for patients with mutations was not reached and for patients without mutations was 30.2 m (p=0.462)
Conclusion:
This study shows genetic alterations are not frequent in MPM and AmpliSeq detected more genetic alterations than Sequenom. With a limited number of patients, we suggest further investigations about the role of mutations in Wnt pathway in MPM
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PC02 - By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV (ID 324)
- Event: WCLC 2016
- Type: Pro Con
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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PC02.04 - Discussion & Vote (ID 6888)
15:25 - 15:45 | Author(s): E. Felip
- Abstract
- Presentation
Abstract not provided
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