For now, initial management of small cell lung cancer continues to be driven by chemotherapy with platinum and etoposide. Meanwhile, management of small cell lung cancer post chemotherapy is undergoing a rapid and much-needed revolution.— Jeffrey Crawford, MD
Ever since the immune checkpoint agents arrived, the pace of clinical investigation in oncology has continued to accelerate with an ever-increasing number of trials of single-agent and combination therapies with novel designs that are transforming our drug-development process. However, even in this fast-forward world, we continue to rely on phase III studies for practice-changing vs practice-affirming results.
Phase III: The Reality of Results
As reported in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, Dr. Reck and colleagues have performed the largest randomized phase III trial ever conducted in extensive-stage small cell lung cancer to evaluate the addition of phased ipilimumab (Yervoy) to etoposide/platinum.1 Unfortunately, the trial did not demonstrate an overall survival benefit for the addition of ipilimumab to our standard of care for small cell lung cancer. A statistical difference was seen in progression-free survival, but the difference in median progression-free survival can be measured in days and is not clinically significant.
In addition to reconfirming that platinum/etoposide remains the standard of care for extensive-stage small cell lung cancer, there is more we can learn from this study. We have decades of experience in small cell lung cancer, adding additional agents to platinum/etoposide and not achieving better results.2 Often this has been due to the addition of cytotoxic agents, which lead to unacceptable levels of neutropenia and neutropenic complications. Of interest, however, in the current trial, the addition of ipilimumab was actually associated with a lower rate of neutropenia. Patients receiving ipilimumab had expected increased toxicities in terms of colitis and skin rash and a higher withdrawal from study of 18% vs 2% in the control group.
Despite the differential dropout rate, the majority of patients received the planned therapy, suggesting that the lack of survival difference was not due to increased toxicity, but rather lack of efficacy of the phased ipilimumab in addition to chemotherapy.
Phasing Out the Phased Approach?
The phased approach was based on phase II observations both in small cell lung cancer as well as non–small cell lung cancer.3,4 The hypothesis was that the cytotoxic effects of chemotherapy in early cycles would release tumor antigens, which would potentially enhance the immune effects of ipilimumab in later cycles. However, that was not realized in the study. The other concept, of course, is that chemotherapy itself is immunosuppressive and might be associated with reduced T-cell activation, making it a difficult environment to expect to see improvement with immune checkpoint inhibitors. For now, this appears to be the prevailing conclusion, at least in the front-line setting of small cell lung cancer.
A Promising Future in Small Cell Lung Cancer
In the second-line setting, promising results have been seen with immune checkpoint therapy in the absence of chemotherapy. In the KEYNOTE 28 trial, a subset of patients with programmed cell death ligand 1 (PD-L1)–positive small cell lung cancer, previously treated with chemotherapy, received pembrolizumab (Keytruda).5 In this small study, the overall response rate was 35%, with responses appearing durable.
Additionally, the phase I/II trial of nivolumab (Opdivo) alone and nivolumab plus ipilimumab has been reported in small cell lung cancer (CheckMate 032).6 In the setting of disease progression after prior platinum-based chemotherapy, 216 patients were enrolled and treated on a variety of different schedules. A 10% response rate was seen in patients receiving nivolumab at 3 mg/kg, and a 23% response rate was noted in patients receiving nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg induction, followed by nivolumab at 3 mg/kg maintenance. Again, in this setting, many responses appeared to be durable, leading the National Comprehensive Cancer Network® to add both nivolumab and nivolumab plus ipilimumab as potential treatment options in second-line small cell lung cancer while awaiting the results of ongoing confirmatory trials with these and other immune checkpoint inhibitors.
Meanwhile, the small cell lung cancer community is optimistic that we have a target in small cell lung cancer—delta-like protein 3 (DLL3). In a phase I trial of rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, a response rate of 39% was seen in patients with tumors that overexpressed DLL3.7 Ongoing clinical trials will hopefully confirm and expand this observation, potentially leading to a truly targeted therapy in small cell lung cancer.
The results of the phase III trial of Reck and colleagues are definitive. The addition of ipilimumab to platinum/etoposide chemotherapy did not improve outcomes for patients with extensive-stage small cell lung cancer. Clinical trials for patients with small cell lung cancer who have received prior platinum-based therapy have identified promising nonchemotherapeutic approaches, including immune checkpoint inhibitors and a targeted approach with an antibody-drug conjugate. Confirmatory trials and further studies in second-line treatment and beyond will help inform the next generation of front-line trials in small cell lung cancer. For now, initial management of small cell lung cancer continues to be driven by chemotherapy with platinum and etoposide. Meanwhile, management of small cell lung cancer post chemotherapy is undergoing a rapid and much-needed revolution. ■
Disclosure: Dr. Crawford is a scientific advisor for Merck, Novartis, and Pfizer; a data and safety monitoring board member for Genentech/Roche; and an investigator on clinical trials for AstraZeneca, Bayer, Bristol-Myers Squibb, and Stemcentrx.
1. Reck M, Luft A, Szczesna A, et al: Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. July 25, 2016 (early release online).
3. Reck M, Bondarenko I, Luft A, et al: Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 24:75-83, 2013.
4. Lynch TJ, Bondarenko I, Luft A, et al: Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046-2054, 2012.
5. Ott PA, Fernandez MEE, Hiret S, et al: Pembrolizumab (MK-3475) in patients with extensive-stage small cell lung cancer: Preliminary safety and efficacy results from KEYNOTE-028. 2015 ASCO Annual Meeting. Abstract 7502.
6. Antonia SJ, López-Martin JA, Bendell J, et al: Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol 17:883-895, 2016.
7. Rudin CM, Pietanza MC, Bauer TM, et al: Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate in recurrent or refractory small cell lung cancer. 2016 ASCO Annual Meeting. Abstract LBA8505. Presented on June 3, 2016.