As reported in The Lancet Oncology by Luis Paz-Ares, MD, of the Universidad Complutense & CiberOnc, Madrid, 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.1
Luis Paz-Ares, MD
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 in the interim analysis and in an exploratory longer-term follow-up analysis.
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). Randomization was stratified by tumor histology, sex, and PD-L1 expression. 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 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. Nivolumab/ipilimumab was continued until disease progression (unless prespecified criteria were met for treatment beyond disease progression), unacceptable toxicity, or for up to 2 years. The primary endpoint was overall survival in all randomly assigned patients.
For the nivolumab/ipilimumab group vs the control group, median patient age was 65 vs 65 years (51% vs 50% ≥ 65 years), 70% vs 70% were male, 59% vs 60% were from Europe and 8% vs 8% from Asia, and 99% vs 99% had an Eastern Cooperative Oncology Group performance status of 0 or 1 (68% vs 68%). Overall, 87% vs 86% were former or current smokers, and 31% vs 31% had squamous and 61% vs 61% nonsquamous histology. Metastatic sites included the liver in 19% vs 24%, bone in 27% vs 31%, and central nervous system in 18% vs 16%. Among 94% vs 93% with quantifiable PD-L1 expression, 40% vs 39% had expression < 1% and 60% vs 61% expression ≥ 1%, with 38% vs 32% having expression of 1% to 49% and 22% vs 29% ≥ 50%.
At the preplanned interim analysis, 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 months) in the nivolumab/ipilimumab group vs 10.9 months (95% CI = 9.5–12.6 months) in the control group (HR = 0.66, 95% CI = 0.55–0.80).
Hazard ratios for overall survival favored the nivolumab/ipilimumab group in nearly all subgroups. For stratification factors, hazard ratios were 0.62 (95% CI = 0.45–0.86) for squamous and 0.69 (95% CI = 0.55–0.87) for nonsquamous histology; 0.66 (95% CI = 0.53–0.82) for men and 0.68 (95% CI = 0.47–1.00) for women; and 0.62 (95% CI = 0.45–0.85) for PD-L1 expression < 1%, 0.64 (95% CI = 0.50–0.82) for ≥ 1%, 0.61 (95% CI = 0.44–0.84) for 1% to 49%, and 0.66 (95% CI = 0.44–0.99) for ≥ 50%.
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.
Subsequent systemic therapy was received by 31% of patients in the nivolumab/ipilimumab group vs 40% of the control group, including immunotherapy in 5% vs 30% and chemotherapy in 29% vs 22%.
Grade 3 to 4 treatment-related adverse events occurred in 47% vs 38% of patients, 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, 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 in one patient each. Treatment-related death occurred in six patients (2%) in the control group, with causes consisting of anemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis in one patient each.
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.”
DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Paz-Ares has received research support from Bristol Myers Squibb and AstraZeneca; has received honoraria as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Genomica, Merck Sharp & Dohme, Roche, Eli Lilly, Merck, Novartis, Amgen, Incyte, Takeda, Blueprint Medicines, Bayer, PharmaMar, and Ipsen; is a board member for Genomica; and is a founder of and holds stock options in Altum Sequencing.
1. Paz-Ares L, Ciuleanu TE, Cobo M, et al: First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol 22:198-211, 2021.
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