Combination of Chemotherapy with Nivolumab plus Ipilimumab in First-Line Advanced NSCLC (CheckMate-9LA)

Combining nivolumab plus ipilimumab with a limited course of chemotherapy in first-line advanced NSCLC extends overall survival.

The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) has demonstrated improved overall survival (OS) versus chemotherapy in treatment-naïve patients with advanced NSCLC in CheckMate-227 part 1, regardless of programmed cell death-ligand 1 (PD-L1) expression.¹ Researchers hypothesized that a limited course of chemotherapy added to the combination could provide rapid disease control and enhance the durable OS benefit seen with the programmed cell death-1 (PD-1) and CTLA-4 inhibitor combination.² CheckMate-9LA is a phase 3 randomized study to evaluate the nivolumab plus ipilimumab combination plus 2 cycles of chemotherapy compared with chemotherapy alone in first-line patients with stage IV or recurrent NSCLC.² These data were reported at the 2020 ASCO Virtual Scientific Program and the 2020 North American Conference on Lung Cancer in October 2020.^2,3

In CheckMate-9LA, a total of 719 adults with treatment-naïve, histologically confirmed, stage IV recurrent NSCLC without EGFR or ALK aberrations 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 (pemetrexed plus cisplatin or carboplatin for nonsquamous tumors, and paclitaxel plus carboplatin for squamous tumors; N = 361) or 4 cycles of chemotherapy alone (N = 358).² Patients were stratified based on PD-L1 expression level (<1% vs ≥1%), sex, and histology (squamous vs nonsquamous).² 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.²

The primary end point of CheckMate-9LA was OS, whereas secondary end points included progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review and efficacy by PD-L1 subgroups. Exploratory end points included safety and tolerability.²

At a preplanned interim analysis with a minimum follow-up of 8.1 months, OS was significantly prolonged with nivolumab plus ipilimumab plus chemotherapy compared with chemotherapy alone (hazard ratio [HR], 0.69; 96.71% confidence interval [CI], 0.55-0.87; P = .0006).² The addition of chemotherapy to the nivolumab plus ipilimumab combination also resulted in significant improvements in PFS and ORR.²

After follow-up of at least 12.7 months, nivolumab plus ipilimumab plus chemotherapy continued to provide longer OS: median OS for nivolumab plus ipilimumab plus chemotherapy was 15.6 months compared with 10.9 months for chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80).² One-year OS rates were 63% and 47% for nivolumab plus ipilimumab plus chemotherapy and chemotherapy alone, respectively.² Clinical benefit was consistent across all efficacy measures in key patient subgroups, including by PD-L1 expression level and tumor histology.² Severe (grade 3/4) treatment-related adverse events were reported in 47% of patients receiving nivolumab plus ipilimumab plus chemotherapy and in 38% of patients receiving chemotherapy alone, respectively.²

The CheckMate-9LA investigators concluded that a significant improvement in OS was observed with the nivolumab plus ipilimumab combination combined with a limited course of chemotherapy compared with 4 cycles of chemotherapy in first-line advanced NSCLC. No new safety signals were reported. Nivolumab plus ipilimumab combined with a limited course of chemotherapy should be considered as a new first-line option for patients with advanced NSCLC without EGFR or ALK aberrations.²

References
1. Hellmann MD, Paz‑Ares L, Caro LB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.
2. Reck M, Ciuleanu T-E, 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(15_suppl). Abstract 9501.
3. Carbone DP, Reck M, Ciuleanu T-E, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment for stage IV/recurrent NSCLC: CheckMate 9LA. Presented at: International Association for the Study of Lung Cancer North America Virtual Congress; October 16-17, 2020. Abstract 24.