PC02.03 Contra Chemotherapy

Abstract

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 adenocarcinoma3 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. 1. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009, 361:947-57. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. MERCK press release, July 2016. 8. 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). Immunotherapy, Targeted therapy, lung cancer