Tyler F. Stewart, MD
Sarah B. Goldberg, MD, MPH
Ipilimumab (Yervoy) is a fully human monoclonal antibody that inhibits cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and was the first checkpoint inhibitor approved after showing survival benefit in metastatic melanoma.1 Indeed, in the first-line setting for metastatic melanoma, ipilimumab was studied in combination with dacarbazine vs dacarbazine alone and demonstrated significantly better overall survival rates.2,3 Given the success of ipilimumab in melanoma, this prompted research in other diseases including non–small cell lung cancer (NSCLC).
In a randomized phase II study in patients with advanced NSCLC, patients received ipilimumab at 10 mg/kg with a platinum and paclitaxel, in either a concurrent (cycles 1–4) or phased-in (cycles 3–6) manner, followed by maintenance ipilimumab, or placebo.4 The phased-in group demonstrated improved immune-response progression-free survival compared with placebo, particularly in patients with squamous cell carcinoma. Based on these results, the phase III study of carboplatin plus paclitaxel with ipilimumab or placebo in patients with squamous NSCLC was undertaken.
Phase III Trial Findings
In the phase III study, reported by Govindan et al and reviewed in the October 25, 2017, issue of The ASCO Post, ipilimumab combined with chemotherapy failed to show improvement in overall survival in patients with squamous cell carcinoma of the lung (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.77–1.07]).5 Interestingly, the Kaplan-Meier curves suggested an initial worsening in overall survival in the first 8 months of therapy and then eventually crossing of the curves at 10 months. Serious grade ≥ 3 treatment-related adverse events occurred more frequently in the ipilimumab group (29% vs 8%), including seven treatment-related deaths (compared with one treatment-related death in the placebo group).
Failure to show a benefit in overall survival is likely to dissuade further studies of ipilimumab as a single agent or as the sole immunotherapy agent combined with chemotherapy in lung cancer.— Tyler F. Stewart, MD and Sarah B. Goldberg, MD, MPH
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The failure to improve overall survival in this trial may have been impacted by issues that are still being investigated, including the dose and frequency of ipilimumab. The dose of 10 mg/m2 was used based on data from the melanoma literature. More recently, this dose has been shown to have significantly more toxicity compared with lower doses, including a 24% treatment discontinuation rate vs 10% when dosed at 3 mg/m2 in advanced melanoma.6 The significant toxicity may have led to patients missing doses of chemotherapy, possibly leading to the initial worsening of overall survival.
Additionally, the frequency may have contributed to the poor results. In the CheckMate 012 study, which tested the combination of nivolumab (Opdivo) with ipilimumab in the first-line setting for patients with NSCLC, the dose of ipilimumab had to be de-escalated to every 6 or 12 weeks due to toxicity.7 A lower dose or change in the drug frequency may have been more tolerable and may have changed the outcome.
The results reported by Govindan et al mirror other results for anti–CTLA-4 agents in lung cancer. After promising results from a phase II study,8 the addition of ipilimumab to platinum/etoposide failed to improve overall survival in patients with extensive-stage small cell lung cancer.9 Serious grade ≥ 3 treatment-related adverse events were higher in the ipilimumab group (22% vs 11%), with five treatment-related deaths in the ipilimumab group and two deaths in the chemotherapy-alone group.
Tremelimumab, a fully human anti–CTLA-4 monoclonal antibody, has also been studied as maintenance after first-line platinum-containing doublet chemotherapy compared with best supportive care in NSCLC. Tremelimumab failed to show a benefit in 3-month progression-free survival (20.9% vs 14.3%), with 20% of patients reporting grade 3 or 4 adverse events.10
Ipilimumab: A Supporting Role in Lung Cancer
Failure to show a benefit in overall survival is likely to dissuade further studies of ipilimumab as a single agent or as the sole immunotherapy agent combined with chemotherapy in lung cancer. However, studies have already suggested a role in combination with other checkpoint inhibitors in NSCLC and small cell lung cancer.
Ipilimumab has been combined with both pembrolizumab (Keytruda)11 and nivolumab (Opdivo)7 in NSCLC, with objective response rates of 25% and 43%, respectively. In the CheckMate 032 study, ipilimumab in combination with nivolumab was tested in patients with small cell lung cancer whose disease progressed after one or more previous regimens, with a response rate of 23% (nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg) and a 2-year overall survival rate of 30% (compared with a response rate of 10% and a 2-year overall survival rate of 17% with nivolumab alone).12,13 However, these results come with an increased severity of toxicities. The incidence of grade 3 or higher toxicity when ipilimumab was combined with pembrolizumab was 49% compared with 10% with single-agent pembrolizumab.11,14 Similar results of efficacy and toxicity have been shown when tremelimumab is combined with durvalumab.15 Several ongoing trials are examining the combination of nivolumab and ipilimumab in both NSCLC and small cell lung cancer.
Emerging Role for Immunotherapy Plus Chemotherapy
Despite advances in NSCLC with anti–programmed cell death protein 1 (anti–PD-1) or anti–programmed cell death ligand 1 (anti–PD-L1) therapies, most patients do not respond to such treatment. To that end, several studies are currently ongoing involving checkpoint inhibition with a secondary agent. Secondary agents include the addition of dual anti-checkpoint inhibitors, targeted agents, cytokines, and chemotherapy.
The disappointing results of this phase III study of ipilimumab in combination with chemotherapy for patients with squamous cell lung cancer is in distinct contrast with the randomized phase II study of carboplatin and pemetrexed with or without pembrolizumab for patients with nonsquamous NSCLC.— Tyler F. Stewart, MD and Sarah B. Goldberg, MD, MPH
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The addition of chemotherapy to immunotherapy is an important area of research, and mechanisms by which this approach may enhance immunotherapy include the elimination of T-regulatory cells, increased penetration of T cells into the tumor microenvironment, and creation of neoantigens.16 This strategy comes at the risk of cytotoxic destruction of T-effector cells by chemotherapy.
The disappointing results of this phase III study of ipilimumab in combination with chemotherapy for patients with squamous cell lung cancer is in distinct contrast with the randomized phase II study of carboplatin and pemetrexed (Alimta) with or without pembrolizumab for patients with nonsquamous NSCLC (KEYNOTE 021-G).17
In this study, 123 patients were randomly assigned to receive 4 cycles of carboplatin and pemetrexed with or without pembrolizumab. Pembrolizumab was continued up to 24 months, and maintenance pemetrexed was optional.
Objective responses were seen in 33 of 60 patients (55%) with the combination of chemotherapy plus pembrolizumab vs 18 of 63 patients (29%) with chemotherapy alone. The objective response rate for patients with < 1% PD-L1 expression who received pembrolizumab was 57%, compared with 13% for those who did not receive pembrolizumab. Updated results after a median of 18.7 months showed a significant improvement in progression-free survival with pembrolizumab (19.0 vs 8.9 months) and an 18-month overall survival rate of 70% and 56%, respectively.18 Treatment-related adverse events that were more common in the pembrolizumab group included fatigue, nausea, rash, endocrinopathies (hyper- and hypothyroidism), and pneumonitis (5% vs 0%).
Guarded Optimism and Significant Debate
The results of KEYNOTE 021-G have been met with guarded optimism and significant debate about the role of chemotherapy with immunotherapy. Based on this study, the U.S. Food and Drug Administration approved the combination of carboplatin/pemetrexed/pembrolizumab for patients with nonsquamous NSCLC, and the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) have been updated to include this combination as an option for first-line therapy in advanced nonsquamous NSCLC with < 50% PD-L1 expression and no targetable mutations. This is in contrast to the 2017 ASCO practice guidelines for stage IV NSCLC, which do not recommend the combination of immune checkpoint therapy with chemotherapy.19
Although ipilimumab alone plus chemotherapy will likely not have a place in the treatment of NSCLC, we anxiously await the results of several phase III trials exploring the efficacy of PD-1 or PD-L1 inhibitors combined with ipilimumab, other checkpoint inhibitors, or chemotherapy in the first-line setting in both advanced NSCLC and small cell lung cancer. These trials will help clarify the utility of combination therapy in the first-line treatment of patients with lung cancer. ■
Dr. Stewart is a fellow and Dr. Goldberg is Assistant Professor of Medicine in the Department of Medicine (Medical Oncology), Yale Cancer Center, New Haven, Connecticut.
DISCLOSURE: Drs. Stewart and Goldberg reported no conflicts of interest.
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3. Maio M, Grob JJ, Aamdal S, et al: Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol 33:1191-1196, 2015.
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10. Zatloukal P, Heo DS, Park K, et al: Randomized phase II clinical trial comparing tremelimumab with best supportive care following first-line platinum-based therapy in patients with advanced non-small cell lung cancer. 2009 ASCO Annual Meeting. Abstract 8071.
11. Gubens MA, Sequist LV, Stevenson J, et al: Phase I/II study of pembrolizumab plus ipilimumab as second-line therapy for NSCLC. 2016 ASCO Annual Meeting. Abstract 9027.
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18. Borghaei H, Langer CJ, Gadgeel S, et al: Updated results from KEYNOTE-021 cohort G: A randomized phase 2 study of pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. ESMO 2017 Congress. Abstract LBA49. Presented September 8, 2017.
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