David P. Carbone, MD, PhD

AS REPORTED BY David P. Carbone, MD, PhD, of The Ohio State University Comprehensive Cancer Center, Columbus, and colleagues in The New England Journal of Medicine, the phase III CheckMate 026 trial has shown no progression-free survival benefit for first-line nivolumab (Opdivo) vs platinum-based chemotherapy in patients with recurrent or stage IV non–small cell lung cancer (NSCLC) and programmed cell death ligand 1 (PD-L1) expression ≥ 5%.¹ 

Prior phase III trials showed nivolumab to provide superior overall survival vs docetaxel among patients with metastatic NSCLC and disease progression during or after platinum-based chemotherapy, with the benefit observed irrespective of PD-L1 expression level but greater in nonsquamous disease with increasing PD-L1 expression.^2,3 

Study Details 

IN THE OPEN-LABEL international trial, 541 patients with PD-L1 tumor-expression levels ≥ 1% were randomized between March 2014 and April 2015 to receive nivolumab at 3 mg/kg every 2 weeks (n = 271) or investigator’s choice of platinum doublet chemotherapy every 3 weeks for 4 to 6 cycles (n = 270). In the chemotherapy group, treatment consisted of pemetrexed (Alimta)/carboplatin in 44%, pemetrexed/cisplatin in 33%, gemcitabine/carboplatin in 13%, gemcitabine/cisplatin in 5%, and paclitaxel/carboplatin in 6%; 38% of patients received maintenance pemetrexed. 

Randomization was stratified according to PD-L1 expression level < 5% vs ≥ 5% and tumor histology of squamous vs nonsquamous. PD-L1 expression was determined by a centralized laboratory using anti–PD-L1 antibody (28-8 antibody). 

The primary endpoint was progression-free survival assessed by blinded independent central review among patients with PD-L1 expression ≥ 5%. Patients in the chemotherapy group with disease progression could cross over to receive nivolumab. The current report is based on the final analysis after database lock in August 2016. 

Patient Characteristics 

AMONG ALL RANDOMIZED PATIENTS, the percentage of patients who were women (32% vs 45%) and the percentage of patients with PD-L1 expression ≥ 50% (32% vs 47%) were lower in the nivolumab group vs the chemotherapy group; more patients in the nivolumab group had liver metastases (20% vs 13%), and median tumor burden (sum of target lesions diameter) was greater in the nivolumab group (median = 82 vs 68 mm). Other baseline characteristics were similar for the nivolumab and chemotherapy groups. 

In total, 77% of the nivolumab group vs 78% of the chemotherapy group had PD-L1 expression ≥ 5%. Baseline characteristics among patients with PD-L1 expression ≥ 5% were similar to those of the overall population, including lower proportions of women (32% vs 44%) and patients with PD-L1 expression ≥ 50% (42% vs 59%) and greater tumor burden (median = 83 vs 70 mm) in the nivolumab group. 

Primary and Secondary Analyses 

MEDIAN FOLLOW-UP was 13.5 months, with median follow-up for overall survival of 13.7 months. Among the 423 patients with PD-L1 expression ≥ 5%, median progression-free survival was 4.2 months in the nivolumab group vs 5.9 months in the chemotherapy group (hazard ratio [HR] = 1.15, P = .25). Median overall survival was 14.4 vs 13.2 months (HR = 1.02, 95% confidence interval [CI] = 0.80–1.30). 

After disease progression, 128 patients in the chemotherapy group (60%) received nivolumab. Response rates were 26% vs 33%, and 27% vs 10% had progressive disease as best response. Median duration of response was 12.1 vs 5.7 months. 

For progression-free survival, unstratified hazard ratios were 0.83 (95% CI = 0.54–1.26) among patients with squamous histology and 1.29 (95% CI = 1.02–1.63) among those with nonsquamous histology. For overall survival, the corresponding hazard ratios were 0.82 (95% CI = 0.54–1.24) and 1.17 (95% CI = 0.91–1.52). 

Among all randomized patients, median progression-free survival was 4.4 vs 5.8 months (HR = 1.17, 95% CI = 0.95–1.43), and median overall survival was 13.7 vs 13.8 months (HR = 1.07, 95% CI = 0.86– 1.33). Among the 214 patients with PD-L1 expression ≥ 50%, hazard ratios were 1.07 (95% CI= 0.77–1.49) for progression-free survival and 0.90 (95% CI = 0.63–1.29) for overall survival. Response rates were 34% vs 39%. 

In an exploratory analysis in patients with a high tumor mutation burden (30% of the nivolumab group and 39% of the chemotherapy group), nivolumab treatment was associated with a greater response rate (47% vs 28%) and better progression-free survival (median = 9.7 vs 5.8 months; HR = 0.62, 95% CI = 0.38–1.00). Overall survival was similar between treatment groups irrespective of the tumor mutation burden. In total, 68% of patients in the chemotherapy group with high tumor mutation burden received subsequent nivolumab. 

Adverse Events 

TREATMENT-RELATED adverse events of any grade occurred in 71% of the nivolumab group vs 92% of the chemotherapy group. The most common events were fatigue (21%) and diarrhea (14%) in the nivolumab group and nausea (48%) and anemia (43%) in the chemotherapy group. Treatment-related grade 3 or 4 adverse events occurred in 18% vs 51%. 

No individual adverse event of grade ≥ 3 occurred in > 1% of the nivolumab group. The most common adverse events in the chemotherapy group were anemia (17%) and neutropenia (11%). Serious treatment-related adverse events occurred in 17% vs 18%. Treatment-related adverse events led to discontinuation of treatment in 10% vs 13%. 

The investigators concluded: “Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals.” 

Dr. Carbone commented to The ASCO Post, “Exploratory analysis of tumor mutation burden in this study showed it to be a potent candidate predictor of clinical outcomes to immunotherapy, independent of PD-L1, and warrants prospective testing. 

DISCLOSURE: The study was funded by Bristol-Myers Squibb and others. For full disclosures of the study authors, visit www.nejm.org. 

REFERENCES 

1. Carbone DP, Reck M, Paz-Ares L, et al: First-line nivolumab in stage IV or recurrent non–small-cell lung cancer. N Engl J Med 376:2415-2426, 2017. 

2. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015. 

3. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373:1627-1639, 2015.