KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC

LBA100Background: In patients (pts) with NSCLC, pembrolizumab (pembro) has shown efficacy as monotherapy in the adjuvant (adj) and advanced settings and in combination with chemotherapy(chemo) in metastatic disease. KEYNOTE-671 (NCT03425643), evaluated the addition of pembro to platinum-based chemo as neoadjuvant therapy followed by resection and pembro vs placebo as adj therapy in patients with early stage NSCLC. Methods: Eligible pts with stage II, IIIA, or IIIB (N2) resectable NSCLC per AJCC v8 and ECOG PS 0-1 were randomized 1:1 to 4 cycles of pembro 200 mg or placebo + cisplatin based chemo followed by surgery and adj pembro or placebo for up to an additional 13 cycles. Stratification factors were stage (II vs III), PD-L1 TPS (<50% vs <greater than or equal to>50%), histology (squamous vs nonsquamous), and region (east Asia vs not east Asia). Dual primary end points were EFS (time from randomization to local progression precluding planned surgery, unresectable tumor, progression or recurrence per RECIST 1.1 by investigator assessement, or death) and OS (time from randomization to all-cause death) in the ITT population. Secondary end points included mPR (<= 10% viable tumor cells in resected primary tumor and lymph nodes) and pCR (ypT0/Tis ypN0) by blinded independent pathology review, and safety. Results: 797 pts were randomized to pembro (n=397) or placebo (n=400). As of July 29, 2022, data cutoff, median follow-up was 25.2 month (range, 7.5-50.6). Baseline characteristics were balanced between arms. EFS was significantly improved with pembro + chemo followed by resection and adj pembro over placebo + chemo followed by resection and adj placebo (HR 0.58 (95% CI, 0.46-0.72); P<0.00001). Median EFS was not reached (NR) (95% CI, 34.1-NR) with pembro and was 17 mo (95% CI, 14.3-22) with placebo (2-year EFS rate, 62.4% vs 40.6%). With only 177 events, the significance boundary for OS was not crossed (HR 0.73 (95% CI, 0.54-0.99); P=0.02124). In the pembro arm 80.6% underwent definitive surgery compared to 75.5% in the placebo arm, of these 92% and 84% had an R0 resection, respectively. The mPR and pCR rates were 30.2% vs 11% (difference: 19.2% (95% CI: 13.9, 24.7); p<0.00001) and 18.1% vs 4% (difference: 14.2% (95% CI: 10.1, 18.7); P<0.00001) in the pembro vs placebo arms, respectively. Treatment-related (TR) Grade <greater than or equal to>3 AEs occurred in 44.9% of pts in the pembro arm vs 37.3% in the placebo arm; TRAEs led to discontinuation of all treatment in 12.6% vs 5.3% and death in 1% vs. 0.8%; immune-mediated AEs of any grade occurred in 25.3% vs 10.5%. Conclusions: Pembro + chemo followed by resection and adjuvant pembro provided a statistically significant and clinically meaningful improvement in EFS, pCR and mPR in pts with resectable stage II, IIIA, and IIIB (N2) NSCLC. The safety profile of pembro was as expected. OS will be tested at future analyses according to the statistical plan. Clinical trial information: NCT03425643.