There is no question that immune checkpoint inhibitors have a role in untreated advanced lung cancer. How they will be integrated into the upfront setting and which patients are likely to benefit are areas of active research.— Karen Kelly, MD
For the majority of patients who are diagnosed with advanced-stage non–small cell lung cancer (NSCLC), platinum-based doublets have been the standard of care for over 30 years. Recently, the immune checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) demonstrated superior survival compared with docetaxel in patients who failed to respond to first-line chemotherapy, transforming our approach to lung cancer treatment.1-3 The enthusiasm for immune checkpoint inhibitors is tempered, however, by the recognition that if our new treatment partner is going to make a dramatic impact, it will need to extend its superiority to the first-line setting and to earlier stages of disease.
This issue of The ASCO Post includes an article describing the phase I safety and efficacy data for nivolumab as monotherapy or in combination with chemotherapy in the first-line treatment of advanced lung cancer,4,5 giving us a glimpse at their potential role as upfront therapy in advanced disease. In the monotherapy trial reported by Gettinger and colleagues,4 nivolumab was safe, with a mild toxicity profile similar to that seen in the previously treated patient population. The overall efficacy data, however, were disappointing, with an objective response rate, median progression-free survival, and progression-free survival rate at 24 weeks that were comparable to those with cytotoxic chemotherapy. The striking 19-month median overall survival is noteworthy but may be more reflective of the highly selected patient population enrolled into the study.
There were a couple of encouraging findings. Four patients achieved a complete response, and responses, both partial and complete, were durable, with the median duration of response not reached. As seen in the majority of other trials, the frequency of response increased with increasing PD-L1 (programmed cell death ligand 1) expression levels, suggesting a biomarker strategy will be needed if nivolumab is to be effective in the front-line setting.
Indeed, this was the approach taken in the randomized phase III trial comparing nivolumab with investigator-choice platinum-based chemotherapy, whereby only patients whose tumors expressed PD-L1 were enrolled. Unfortunately, this trial failed to meet its primary progression-free survival endpoint in patients who had ≥ 5% PD-L1 tumor expression.6 In contrast, pembrolizumab met its primary progression-free survival endpoint and also showed a survival benefit in patients with PD-L1 tumor expression of 50% or greater.7 We anxiously await the presentations of the data from both these studies to provide clarity regarding PD-L1 expression and outcomes. Determining the minimal PD-L1 expression level that will predict a meaningful benefit for our patients will be an important question to answer.
Combining Chemotherapy and Immunotherapy
The evaluation of immune checkpoint inhibitors as upfront monotherapy is one of several approaches being evaluated to improve survival. Traditionally, promising novel agents are incorporated into the platinum-based regimen to enhance efficacy. Numerous triplet regimens have been evaluated in this manner, but only two agents—bevacizumab (Avastin; for patients with adenocarcinoma) and necitumumab (Portrazza; for patients with squamous cell carcinoma)—produced a modest overall survival benefit in combination with chemotherapy over chemotherapy alone.8,9
There is a rationale for combining chemotherapy with immunotherapy. In addition to the cytotoxic effects of chemotherapy, many chemotherapeutic agents induce immunogenic cell death (a form of regulated cell death that is capable of activating an adaptive immune response against dead cell–associated antigens and inducing immunologic memory) and/or influence the makeup of the immune microenvironment.10 Furthermore, there is preclinical evidence showing synergy between immune checkpoint inhibitors and chemotherapy. This evidence, coupled with the nonoverlapping toxicity profiles of immune checkpoint inhibitors and chemotherapy, provides the necessary justification for the clinical evaluation of immunochemotherapy combinations.
Rizvi and colleagues5 are the first to report their data combining nivolumab with the three most commonly used platinum doublets to treat NSCLC. Overall, the triplet combination was safe, with an adverse event profile related to the known individual toxicities of each agent. However, there were a few toxicities that were enhanced with the combination, such as pneumonitis, renal failure, and hypersensitivity/infusion reactions. These events will require a thorough case-by-case review to better understand their causality. Close follow-up of these adverse events in ongoing, and future studies are mandatory to decipher their true attribution to treatment.
The efficacy analysis hints at a benefit of a three-drug combination over a two-drug combination, but this conclusion must be viewed cautiously, given the small number of highly selected patients who participated in the trial. For example, the high objective response rate of 47% with pemetrexed (Alimta) plus cisplatin and paclitaxel plus carboplatin is notable but not surprising. Paclitaxel plus carboplatin produced objective response rates of 58% in a small phase II trial.11
The more impressive results were the progression-free and overall survival rates. All combinations were associated with a 24-week progression-free survival rate between 51% and 71%, which exceeds the 37% to 40% 24-week progression-free survival rate observed in randomized phase III trials of the doublets alone.9,12,13 Likewise the 1-year overall survival rate of 87% and 86% with the pemetrexed or paclitaxel combinations, respectively, is double the 1-year overall survival rate of 38% to 49% with chemotherapy in the same phase III trials.9,12,13 In contrast to the monotherapy studies, this study did not show a correlation between efficacy and PD-L1 expression levels, suggesting we need a better understanding of the interplay among the tumor, immune microenvironment, and treatment to identify patients who may benefit from combination therapy.
Despite this efficacy signal, randomized trials of chemotherapy with or without nivolumab are not being pursued in favor of evaluating an immune doublet, nivolumab plus ipilimumab (Yervoy) vs platin doublets. However, there are several ongoing randomized phase III trials of chemotherapy with or without other immune checkpoint inhibitors that will definitely address the role of an immunochemotherapy combination in first-line advanced NSCLC.
There is no question that immune checkpoint inhibitors have a role in untreated advanced lung cancer. How they will be integrated into the upfront setting—whether as monotherapy or in concurrent or sequential combination with chemotherapy or immune therapy—and which patients are likely to benefit—PD-L1 high expressers, low expressers, or negative expressers or patients with other yet-to-be-determined predictive biomarker(s)—are areas of active research. ■
Disclosure: Dr. Kelly receives royalties from UpToDate, is an advisor for Ariad, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Lilly, Novartis, and has received research funding from AbbVie, Celgene, EMD Serono, Genentech, Gilead, Lilly, Millennium, and Novartis.
5. Rizvi NA, Hellmann MD, Brahmer JR, et al: Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2969-2979, 2016.
6. Bristol-Myers Squibb announces top-line results from CheckMate -026, a phase 3 study of Opdivo (nivolumab) in treatment-naive patients with advanced non-small cell lung cancer. August 5, 2016. Available at investor.bms.com/investors/news-and-events/press-releases/press-release-details/2016/Bristol-Myers-Squibb-Announces-Top-Line-Results-from-CheckMate--026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. Accessed September 8, 2016.
7. Merck’s Keytruda (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. June 16, 2016. Available at www.businesswire.com/news/home/20160616005393/en/Merck’s-KEYTRUDA®%C2%A0-pembrolizumab-Demonstrates-Superior-Progression-Free-Survival. Accessed September 8, 2016.
9. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE). Lancet Oncol 16:763-774, 2015.
12. Herbst RS, Redman MW, Kim ES, et al: A randomized, phase III study comparing carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non-small cell lung cancer (NSCLC). 2015 World Conference on Lung Cancer. Abstract 3612.
13. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008.
Scott Gettinger, MD
Naiyer A. Rizvi, MD
The phase I CheckMate 012 study examined the effects of nivolumab (Opdivo) monotherapy and nivolumab combined with platinum-based doublets as first-line treatments in patients with advanced non–small cell lung cancer (NSCLC). Encouraging...!-->!-->!-->!-->