The combination of nivolumab combined with ipilimumab (NIVO + IPI) has demonstrated improved overall survival (OS) and durability of response versus chemotherapy in treatment-naïve patients with advanced non–small-cell lung cancer (NSCLC) in CheckMate-227 Part 1, regardless of PD-L1 expression. Researchers hypothesized that a limited course of chemotherapy added to NIVO + IPI could provide rapid disease control and enhance the durable OS benefit seen with the PD-1 and CTLA-4 inhibitor combination. CheckMate-9LA was designed as a phase 3 randomized study to evaluate NIVO + IPI plus 2 cycles of chemotherapy compared with chemotherapy alone in first-line patients with stage IV or recurrent NSCLC.
In CheckMate-9LA, a total of 719 adults with treatment-naïve, histologically confirmed, stage IV recurrent NSCLC were randomized to receive either nivolumab (360 mg every 3 weeks) combined with ipilimumab (1 mg/kg every 6 weeks) and 2 cycles of chemotherapy (N = 361) or 4 cycles of chemotherapy alone (N = 358). Patients were stratified based on PD-L1 expression level (<1% vs ≥1%), sex, and histology (squamous vs nonsquamous). Chemotherapy in both study arms was selected based on tumor histology; those with nonsquamous NSCLC could receive pemetrexed maintenance in the chemotherapy-alone arm. Patients were treated with immunotherapy until disease progression or unacceptable toxicity, or for 2 years.
The primary end point of CheckMate-9LA was OS, while secondary end points included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review and efficacy by PD-L1 subgroups. Exploratory end points included safety and tolerability.
At a preplanned interim analysis with a minimum follow-up of 8.1 months, OS was significantly prolonged with NIVO + IPI + chemotherapy compared with chemotherapy alone (hazard ratio [HR], 0.69; 96.71% confidence interval [CI], 0.55-0.87; P = .0006). The addition of chemotherapy to NIVO + IPI also resulted in statistically significant improvements in PFS and ORR.
After longer follow-up of at least 12.7 months, NIVO + IPI + chemotherapy continued to provide longer OS: median OS for NIVO + IPI + chemotherapy was 15.6 months compared with 10.9 months for chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80). One-year OS rates were 63% and 47% for NIVO + IPI + chemotherapy and chemotherapy alone, respectively. Clinical benefit was consistent across all efficacy measures in key patient subgroups, including by PD-L1 expression level and tumor histology.
Severe (grade 3/4) treatment-related adverse events were reported in 47% of patients receiving NIVO + IPI + chemotherapy and in 38% of patients receiving chemotherapy alone, respectively.
The CheckMate-9LA investigators concluded that the study met its primary end point: a statistically significant improvement in OS was observed with NIVO + IPI combined with a limited course of chemotherapy compared with 4 cycles of chemotherapy in first-line advanced NSCLC. No new safety signals were reported. NIVO + IPI combined with a limited course of chemotherapy should be considered as a new first-line option for patients with advanced NSCLC.
Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38:suppl (abstract 9501).