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G. Pall
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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SH02 - WCLC 2016 Scientific Highlights - SCLC, Mesothelioma and Thymic Malignancies (ID 484)
- Event: WCLC 2016
- Type: Scientific Highlights
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 3
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SH02.01 - SCLC (ID 7120)
07:30 - 07:50 | Author(s): J. Schiller
- Abstract
- Presentation
Abstract not provided
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SH02.02 - Malignant Pleural Mesothelioma (ID 7121)
07:50 - 08:10 | Author(s): A. Nowak
- Abstract
- Presentation
Abstract not provided
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SH02.03 - Thymic Malignancies & Esophageal Cancer (ID 7122)
08:10 - 08:30 | Author(s): P. Hohenberger
- Abstract
- Presentation
Abstract not provided
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Author of
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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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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): G. Pall
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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P3.02c - Poster Session with Presenters Present (ID 472)
- 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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P3.02c-091 - Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC (ID 4735)
14:30 - 14:30 | Author(s): G. Pall
- Abstract
Background:
Preclinical studies demonstrated that local radiotherapy (RT) acts synergistically with RNActive[® ]vaccines to increase tumor-infiltrating immune cells and enhance anti-tumor effects. BI 1361849 (CV9202) is an immunotherapeutic cancer vaccine comprising optimized mRNA constituents (RNActive[®]) encoding six NSCLC-associated antigens. Here we report clinical outcomes and immune response data of a phase Ib study, employing local RT and BI 1361849 in advanced NSCLC.
Methods:
Patients (Pts) with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) were enrolled in three cohorts based on histological and molecular NSCLC subtypes (non-squamous vs. squamous vs. EGFR-mutated NSCLC). Pts received two initial vaccinations with BI 1361849 prior to local RT to the primary tumor or a metastatic lesion (four consecutive daily fractions of 5 Gy), followed by further vaccinations until start of another treatment. Maintenance Pemetrexed (mP) and EGFR-TKIs were continued according to the label. Primary endpoint was safety; secondary endpoints included objective response, PFS and OS. Cellular and humoral immune responses were measured ex vivo by multifunctional intracellular cytokine staining, IFN-γ ELISpot, and ELISA in pre- and post-treatment blood samples.
Results:
26 pts were enrolled. 15 pts received mP, two received EGFR TKIs. Most frequent AEs were mild to moderate injection-site reactions and flu-like symptoms. Two pts experienced BI 1361849-related grade 3 AEs (fatigue, pyrexia). No BI 1361849-related SAE or grade 4 AE was reported. Interim results indicate one confirmed PR in a patient receiving mP and SD in 13/25 evaluable pts (52%, 8 pts on mP, 3 pts without maintenance therapy, 2 pts on EGFR-TKI), with two pts showing remarkably long-lasting disease stabilization of up to 72 and 54 weeks, respectively. Shrinkage of lesions outside the irradiated field of ≥15% occurred in 7 pts, all but one receiving mP. Longitudinal assessment of tumor response allows for further insight into patterns of progression. BI 1361849 was capable of eliciting antigen-specific immune responses in the majority of the patients including both cellular and humoral immune responses.
Conclusion:
BI 1361849 elicits antigen-specific immune responses and can be safely combined with local RT and mP treatment. Shrinkage of non-irradiated lesions and prolonged disease stabilization was observed in a subset of pts, mainly in combination with mP. Final clinical outcomes and analyses of cellular and humoral immune responses will be presented.
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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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PC02.01 - Introduction & Vote (ID 6887)
14:30 - 14:45 | Author(s): G. Pall
- Abstract
- Presentation
Abstract not provided
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