As reported in The Lancet Oncology by Luis Paz-Ares, MD, and colleagues, the phase III CheckMate 9LA trial has shown improved overall survival with first-line nivolumab/ipilimumab plus two cycles of chemotherapy vs four cycles of chemotherapy alone in patients with stage IV or recurrent non–small cell lung cancer (NSCLC) without EGFR or ALK aberrations.

A preplanned interim analysis of the trial, at which the study endpoint was met, supported the May 2020 approval of nivolumab/ipilimumab for use with two cycles of platinum doublet chemotherapy as first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations. The current report includes findings from the interim analysis as well as from an exploratory longer-term follow-up analysis.

Luis Paz-Ares, MD

Study Details

In the open-label trial, 719 patients from sites in 19 countries were randomly assigned between August 2017 and January 2019 to receive nivolumab/ipilimumab with two cycles of histology-based platinum doublet chemotherapy (n = 361) or four cycles of chemotherapy alone (control group, n = 358). Overall, approximately 40% of patients had tumor PD-L1 expression < 1%.

Treatment consisted of nivolumab at 360 mg every 3 weeks plus ipilimumab at 1 mg/kg every 6 weeks combined with chemotherapy every 3 weeks for two cycles, or chemotherapy alone every 3 weeks for four cycles. Chemotherapy consisted of carboplatin at area under the curve (AUC) = 6 plus paclitaxel at 200 mg/m² for patients with squamous histology, or carboplatin at AUC = 5 or 6 plus pemetrexed at 500 mg/m² or cisplatin at 75 mg/m² plus pemetrexed at 500 mg/m² for patients with nonsquamous histology.

Treatment with nivolumab/ipilimumab was continued until disease progression (unless prespecified criteria were met for treatment beyond progression), unacceptable toxicity, or for up to 2 years.

The primary endpoint was overall survival in all randomly assigned patients.

Overall Survival

At the preplanned interim analysis, at a median follow-up of 9.7 months (interquartile range [IQR] = 6.4–12.8 months), median overall survival was 14.1 months (95% confidence interval [CI] = 13.2–16.2 months) in the nivolumab/ipilimumab group vs 10.7 months (95% CI = 9.5–12.4 months) in the control group (hazard ratio [HR] = 0.69, 96.71% CI = 0.55–0.87, P = .00065).

In longer-term follow-up, with a median duration of 13.2 months (IQR = 6.4–17.0 months), median overall survival was 15.6 months (95% CI = 13.9–20.0) in the nivolumab/ipilimumab group vs 10.9 months (95% CI = 9.5–12.6) in the control group (HR = 0.66, 95% CI = 0.55–0.80). Overall survival benefit in the nivolumab/ipilimumab group was observed across all PD-L1 expression levels, and similar benefit was observed among patients with nonsquamous histology and those with squamous histology.  

At interim analysis, median progression-free survival was 6.8 months vs 5.0 months (HR = 0.70, 97.48% CI = 0.57–0.86, P = .00012). With longer-term follow up, median progression-free survival was 6.7 months vs 5.0 months (HR = 0.68, 95% CI = 0.57–0.82). Objective response was observed in 38.2% vs 24.9% of patients (complete response in 2% vs 1%), and median duration of response was 11.3 vs 5.6 months.

Adverse Events

Grade 3 to 4 treatment-related adverse events occurred in 47% vs 38% of patients, with the most common in the nivolumab/ipilimumab group being neutropenia (7% vs 9% in control group), anemia (6% vs 14%), increased lipase (6% vs 1%), and diarrhea (4% vs 1%). Serious treatment-related adverse events of any grade occurred in 30% (25% grade 3–4) vs 18% (15% grade 3–4) of patients, with the most common in the nivolumab/ipilimumab group being diarrhea (3%), febrile neutropenia (3%), and anemia (2%). The most common treatment-related grade 3 to 4 immune-mediated adverse events in the nivolumab/ipilimumab group were gastrointestinal (6%), skin (4%), and hepatic (4%) events.

Treatment-related death occurred in seven patients (2%) in the nivolumab/ipilimumab group, with causes consisting of acute kidney failure, diarrhea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia. Treatment-related death occurred in six patients (2%) of the control group, with causes consisting of anemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis.

The investigators concluded, “Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival vs chemotherapy alone and had a favorable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.”

Dr. Paz-Ares, of Hospital Universitario 12 de Octubre, Madrid, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.