Adding ipilimumab to nivolumab does not improve outcomes in patients with advanced, pretreated, immunotherapy-naïve squamous non-small cell lung cancer (SqNSCLC), according to results from the Lung-MAP S14001 phase III randomized clinical trial.
These results, published in JAMA Oncology, led researchers to conclude that combination therapy with nivolumab and ipilimumab is still currently only indicated as first-line therapy in patients with advanced NSCLC.
An immune checkpoint inhibitor targeting cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), ipilimumab is approved for use as monotherapy in metastatic melanoma, according to Scott N. Gettinger, MD, of Yale Cancer Center in New Haven, Connecticut, and colleagues.
“Phase 1 and 2 studies in patients with untreated advanced NSCLC showed promising early results with nivolumab plus ipilimumab, and 2 recent phase 3 trials in this population demonstrated superiority of the combination either alone or with chemotherapy compared with chemotherapy alone. Nivolumab plus ipilimumab is currently approved in the first-line setting for patients with metastatic PD-L1–expressing NSCLC and in combination with 2 cycles of platinum-doublet chemotherapy regardless of tumor PD-L1 expression,” they added.
For the phase III, open-label Lung Cancer Master Protocol (Lung-MAP) S14001 trial, Gettinger and colleagues randomized 252 patients (mean age: 67.5 years; 67% men; 82% White) with advanced immunotherapy-naïve SqNSCLC, a Zubrod score of 0 to 1, and disease progression after standard platinum-based chemotherapy to treatment with nivolumab monotherapy or nivolumab plus ipilimumab. Patients were followed for a median of 29.5 months.
“At the time this study was designed, nivolumab was approved as salvage therapy but not as initial treatment in patients with advanced NSCLC,” they explained.
The primary endpoint of the study was overall survival (OS), and secondary endpoints included investigator-assessed progression-free survival (IA-PFS) and responses assessed with RECIST guidelines, version 1.1.
At the planned interim analysis, the study was halted for futility, as between-group OS did not differ significantly (HR: 0.87; 95% CI: 0.66-1.16; P=0.34). Median survival was also similar in the two groups: 10 months (95% CI: 8.0-14.4 months) in patients treated with combination therapy, compared with 11 months (95% CI: 8.6-13.7 months) in those treated with nivolumab monotherapy.
Results in secondary endpoints were also similar:
- IA-PFS: Hazard ratio of 0.80 (95% CI: 0.61-1.03; P=0.09).
- median IA-PFS: 3.8 months (95% CI: 2.7-4.4 months) in the nivolumab/ipilimumab group vs 2.9 (95% CI: 1.8-4.0) months in the nivolumab monotherapy group.
Response rates were similar between the two groups as well, at 18% (95% CI: 12%-25%) in patients treated with combination nivolumab/ipilimumab versus 17% (95% CI: 10%-23%) with nivolumab. Median response duration was 28.4 versus 9.7 months, respectively.
Finally, the incidence of grade 3 or higher treatment-related adverse events was 39.5 in patients treated with nivolumab/ipilimumab versus 33.3% in those treated with nivolumab. Treatment discontinuation occurred in 25% versus 15% of patients, respectively.
“In this multicenter, open-label, phase 3 randomized clinical trial and substudy of Lung-MAP (S1400), ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor–naive SqNSCLC. At present, there is no immunotherapy option for patients who experience disease progression on PD-1 axis inhibitor therapy,” concluded Gettinger and fellow researchers.
They added that there are “at least” two ongoing clinical trials assessing the combination of nivolumab plus ipilimumab as salvage therapy in NSCLC after PD-1 axis inhibitor treatment in patients with acquired and primary resistance to PD-1 axis inhibitor treatment.
“In this multicenter, open-label, phase 3 randomized clinical trial and substudy of Lung-MAP (S1400), ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor–naive SqNSCLC. At present, there is no immunotherapy option for patients who experience disease progression on PD-1 axis inhibitor therapy,” they concluded.
The primary limitation of the study was that the control group of nivolumab is no longer commonly used as salvage therapy for patients with advanced lung cancer—first-line treatment in most patients is PD-1 axis inhibitor therapy. In addition, adequate tissue samples for assessing tumor PD-L1 status was not require, and only 64% of patients had successful tumor PD-L1 analysis. Finally, the low number of patients who had both tumor PD-L1 and mutational burden results limit conclusions from the combined subset analyses for outcomes.
The addition of ipilimumab to nivolumab did not improve survival in patients with advanced chemotherapy-pretreated squamous non-small cell lung cancer.
Combination therapy with nivolumab and ipilimumab is currently only indicated as first-line therapy in patients with advanced non–small cell lung cancer.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
Gettinger reported receiving grants and research support for trials (to Yale Cancer Center) from Bristol Myers Squibb and research support for trials (to Yale Cancer Center) from NextCure, IOVANCE, Genentech/Roche, and Takeda/Ariad outside the submitted work.
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