As reported in The New England Journal of Medicine by Forde et al, 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).

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

Patient Outcomes

A 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). Event-free survival 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). 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).

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 nivolumab-plus-chemotherapy group vs 36.9% of the chemotherapy-alone group. 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 no patients in the nivolumab group and in 3 (1.7%) in the control group.

The most common immune-mediated adverse event in the nivolumab group was rash (8.5%); 2 patients (1.1%) had grade 1 or 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.”

Patrick M. Forde, MB, BCh, of Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Kimmel Cancer Center, is the corresponding author for The New England Journal of Medicine article.

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