Patrick M. Forde, MB, BCh

As reported in The New England Journal of Medicine by Patrick M. Forde, MB, BCh, of Johns Hopkins Kimmel Cancer Center, and colleagues, the phase III CheckMate 816 trial has shown improved pathologic complete response rate and event-free survival with the addition of nivolumab to platinum-based chemotherapy in the neoadjuvant treatment of resectable non–small cell lung cancer (NSCLC).¹

The trial supported the March 2022 approval of nivolumab combined with platinum-doublet chemotherapy for resectable NSCLC in the neoadjuvant setting. The approval is the first for neoadjuvant therapy for early-stage NSCLC.

Study Details

In the open-label international trial, 358 patients with stage IB to IIIA resectable disease were randomly assigned between March 2017 and November 2019 to receive neoadjuvant treatment with nivolumab at 360 mg plus platinum-doublet chemotherapy (n = 179) or platinum-doublet chemotherapy alone (n = 179) every 3 weeks for three cycles before definitive surgery. Surgery was planned to occur within 6 weeks after the completion of neoadjuvant treatment. Patients in both groups could receive up to four cycles of adjuvant chemotherapy, radiotherapy, or both. The primary endpoints were event-free survival and pathologic complete response, both on blinded independent review.

For the nivolumab vs control groups, 47.5% vs 51.4% of patients were from Asia, 36.3% vs 34.6% had stage IB or II disease and 63.1% vs 64.2% had stage IIIA disease, 49.7% in both groups had tumor PD-L1 expression ≥ 1% and 43.6% vs 43.0 had PD-L1 < 1% (status unknown in 6.7% vs 7.3%). Moreover, 69.3% vs 74.9% received cisplatin and 21.8% vs 18.4% carboplatin as part of doublet chemotherapy.

Pathologic Complete Response and Event-Free Survival

Pathologic complete response was achieved in 43 patients (24.0%, 95% confidence interval [CI] = 18.0%–31.0%) in the nivolumab group vs 4 patients (2.2%, 95% CI = 0.6%–5.6%) in the control group (odds ratio = 13.94, 99% CI = 3.49–55.75, P < .001). Among all randomly assigned patients, 149 (83.2%) of those in the nivolumab group and 135 (75.4%) of those in the control group underwent surgery.

Adjuvant chemotherapy was received by 11.9% of the patients in the nivolumab group and 22.2% of the control group. Any subsequent cancer therapy was received by 21.2% vs 43.6% of patients, including systemic therapy in 17.3% vs 36.3%.

Minimum follow-up was 21 months. Median event-free survival was 31.6 months (95% CI = 30.2 months to not reached) in the nivolumab group vs 20.8 months (95% CI = 14.0–26.7 months) in the control group (hazard ratio [HR] = 0.63, 97.38% CI = 0.43–0.91, P = .005). Rates at 1 and 2 years were 76.1% vs 63.4% and 63.8% vs 45.8%. The benefit of nivolumab was maintained in analysis adjusted for optional receipt of adjuvant therapy (HR = 0.65, 95% CI = 0.47–0.90).

In a subgroup analysis, median event-free survival was 25.1 vs 18.4 months among patients with PD-L1 expression < 1% (HR = 0.85, 95% CI = 0.54–1.32) and not reached vs 21.1 months among those with PD-L1 ≥ 1% (HR = 0.41, 95% CI = 0.24–0.70).

In additional subgroup analyses, hazard ratios were 0.78 (95% CI = 0.38–1.62) among 91 patients from North America, 0.80 (95% CI = 0.361.77) among 66 patients from Europe, and 0.45 (95% CI = 0.29–0.71) among 177 patients from Asia; 0.87 (95% CI = 0.48–1.56) among patients with stage IB to II disease and 0.54 (95% CI = 0.37–0.80) among those with stage IIIA disease; 0.77 (95% CI = 0.49–1.22) among 182 patients with squamous histology and 0.50 (95% CI = 0.32–0.79) among 176 with nonsquamous histology; 0.86 (95% CI = 0.47–1.57) among 102 patients with tumor mutation burden < 12.3 mutations/megabase and 0.69 (95% CI = 0.33–1.46) among 76 with ≥ 12.3 mutations/megabase; and 0.71 (95% CI = 0.49–1.03) among patients receiving cisplatin-based chemotherapy and 0.31 (95% CI = 0.14–0.67) among those receiving carboplatin-based chemotherapy.

At the first prespecified interim analysis, median overall survival was not reached in either group. The hazard ratio was 0.57 (99.67% CI = 0.30–1.07, P = .008), which did not meet the prespecified criterion for significance (P = .0033).

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the group given nivolumab plus chemotherapy vs 36.9% of the group given chemotherapy alone. Serious treatment-related adverse events occurred in 11.9% vs 10.2% of patients, and treatment-related adverse events led to discontinuation of treatment in 10.2% vs 9.7%. Death due to treatment-related adverse events occurred in none of the patients in the nivolumab group and in three (1.7%) in the control group. The most common immune-mediated adverse event in the nivolumab group was rash (8.5%); two patients (1.1%) had grade 1 to 2 pneumonitis. Adverse events led to delay of surgery in 3.4% vs 5.1% of patients and to surgery cancellation in 1.1% vs 0.6%. Among patients who underwent surgery, surgery-related adverse events of any grade occurred in 41.6% vs 46.7% of patients.

The investigators concluded: “In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Forde has served as a consultant to Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, F-Star, G1 Therapeutics, Genentech, iTeos, Janssen Global Services, Merck, Novartis, Sanofi Pasteur, and Surface Oncology; has received institutional research grants or philanthropic gifts to fund research from AstraZeneca, BioNTech, Bloomberg Philanthropies, Bristol Myers Squibb, Corvus, Earl and Darielle Linehan, Kyowa Hakko Kirin, LUNGevity Foundation, Mark Foundation, Martha Furman, NCI Cancer Center, Novartis, Regeneron Pharmaceuticals, Stand Up To Cancer, and Susan Troll; and has served on data and safety monitoring boards or scientific advisory boards for Flame Biosciences, LUNGevity Foundation, and Polaris.

REFERENCE

1. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 386:1973-1985, 2022.