Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer

Abstract

Background: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

Methods: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.

Results: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.

Conclusions: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

Figure 1.. Event-Free Survival as Assessed According to Investigator Review (Intention-to-Treat Population).

Panel A shows Kaplan–Meier estimates of event-free survival. Event-free survival was defined as the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence (according to the Response Evaluation Criteria in Solid Tumors, version 1.1) by the investigator’s assessment, or death from any cause. The intention-to-treat population included all the participants who had undergone randomization. Tick marks indicate censored data. Panel B shows event-free survival in subgroups. The magnitude of the event-free survival treatment effect in subgroups was calculated with the use of an unstratified Cox regression model with trial group as a covariate and Efron’s method of handling ties. Race was reported by the participant. The subgroup of participants with ALK translocation (21 participants) was excluded from the forest plot because the statistical analysis plan specified that subgroups with less than 30 participants were to be excluded from the forest plot. PD-L1 denotes programmed death ligand 1, and TPS tumor proportion score.

Figure 2.. Overall Survival (Intention-to-Treat Population).

Tick marks indicate censored data.

Figure 3.. Exploratory Analysis of Event-Free Survival According to Major Pathological Response and Pathological Complete Response (Intention-to-Treat Population).

Event-free survival was assessed according to investigator review. The hazard ratios for disease progression, disease recurrence, or death, along with the 95% confidence intervals, were calculated with the use of an unstratified Cox regression model with treatment as a covariate and Efron’s method of handling ties. A major pathological response was defined as no more than 10% viable tumor cells in resected primary tumor and lymph nodes, and a pathological complete response as the absence of residual invasive cancer in resected primary tumor and lymph nodes (ypT0/Tis ypN0) as assessed on the basis of blinded, central examination by a pathologist. Tick marks indicate censored data.