Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer

Abstract

Background: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings.

Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients.

Results: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group.

Conclusions: 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. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Figure 1 (facing page).. Event-free Survival According to Blinded Independent Central Review.

Panel A shows event-free survival among the patients who underwent concurrent randomization, and Panel B shows event-free survival in prespecified patient subgroups. Event-free survival was defined as the length of time from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence of disease after surgery (on the basis of assessment by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1), progression of disease in the absence of surgery, or death from any cause; data on patients who received subsequent therapy were censored at the last tumor assessment that could be evaluated on or before the date of subsequent therapy. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores reflecting greater disability. NR denotes not reached, PD-L1 programmed death ligand 1, and TMB tumor mutational burden.

Figure 2 (facing page).. Pathological Complete Response According to Blinded Independent Pathological Review.

Panel A shows pathological complete response in the primary analysis population, and Panel B shows pathological complete response in prespecified patient subgroups. Pathological complete response was defined as 0% residual viable tumor cells in both primary tumor (lung) and sampled lymph nodes. According to the intention-to-treat principle, patients who did not undergo surgery were counted as not having had a response for the primary analysis. In Panel A, the between-group difference was calculated by means of a stratified Cochran–Mantel–Haenszel method.

Figure 3.. Overall Survival.

The 95% confidence interval of the hazard ratio was 0.38 to 0.87. At this first prespecified interim analysis, the P value for overall survival did not cross the boundary for statistical significance (0.0033).