Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).
Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).
Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.
Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).
Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.
Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).
With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).
Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.
Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies . Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years .