My Take On KEYNOTE-671: ASCO23 June 3, 2023

Author: 

Lei Deng, MD

PGY-6 Fellow of Hematology/Oncology – Roswell Park Comprehensive Cancer Center, Buffalo, NY. 

Incoming Assistant Professor at UW/Fred Hutch, Seattle, WA

Live report from ASCO23, Chicago, IL

June 3, 2023  8am – 9:30am Hall D1

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.

Key points

• In phase 3 KEYNOTE-671, resectable stage II, III, and IIIB (T3-4N2) NSCLC received four cycles of neoadjuvant pembrolizumab (or placebo) + chemotherapy followed by adjuvant pembrolizumab (or placebo) for up to 13 cycles. 
• The interim analysis reported at ASCO 2023 showed statistically improved event-free survival (1-year EFS: 73.2 % vs. 59.9 %, HR 0.58), pCR (18.1% vs. 4.0%) and mPR (30.2% vs. 11.0%)
• 17.9% of patients did not proceed to in-study surgery
• Questions remain are 1) the added benefit of an extra one cycle before surgery; and 2) who is the population to benefit from extra adjuvant anti-PD(L)1

For early-stage resectable non-small cell lung cancer without EGFR/ALK alterations, current FDA-approved options are adjuvant pembrolizumab (PEARLS/KEYNOTE-091) and atezolizumab (Impower010) in the adjuvant setting and neoadjuvant nivolumab plus chemotherapy (CheckMate-816) in the neoadjuvant setting1-3. In the neoadjuvant space, several registrational trials (AEGEAN, KEYNOTE-671, CheckMate-77T, IMpower-030) compare neoadjuvant four cycles of chemotherapy plus PD-(L)1 blockade followed by adjuvant PD-(L)1 blockade to 4 cycles of chemotherapy alone.

Results of KEYNOTE-671 were presented at the 2023 ASCO annual meeting in Chicago (ASCO23). This randomized, double-blinded trial enrolled 797 patients with resectable stage II, IIIA, and IIIB (T3-4N2). Patients were randomized to neoadjuvant pembrolizumab plus chemotherapy for four cycles followed by adjuvant pembrolizumab for up to 13 cycles versus neoadjuvant placebo plus chemotherapy for four cycles followed by placebo treatment. The trial’s dual primary endpoints are event-free survival (EFS) and overall survival (OS).

In this prespecified interim analysis, 82.1% went on to in-study surgery. EFS was statistically improved in the pembrolizumab arm (1-year EFS: 73.2 % vs. 59.9 %, HR 0.58, 95% CI 0.46 – 0.72, p < 0.00001). Higher PD-L1 expression appears to be associated with larger EFS benefits. The pathological complete response (pCR) and major pathological response (mPR) were also statistically better in pembrolizumab arm (pCR 18.1% vs. 4.0%; mPR 30.2% vs. 11.0%). 

Early in April at AACR 2023, the AEGEAN trial of durvalumab was presented with a similar design to KEYNOTE-6715. The pCR rate was 17.2%, and the 1-year EFS rate was 74.3% in the durvalumab arm. The pCR rate was 24.0% in CheckMate-816 with only three cycles of neoadjuvant treatment. Of note, the proportion of patients who did not proceed to surgery was 16.8% in CheckMate-816 and 19.4% in AEGEAN, respectively. Questions that remain are: 1) the added benefit of extra one cycle neoadjuvant; and 2) who is the population to benefit from extra adjuvant anti-PD(L)1.

1. O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomized, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-1286.
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-1985.
3. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomized, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-1357.
4. Wakelee et al., 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. Presented at 2023 ASCO, Chicago, June 2-6, 2023.
5. Heymach et al. AEGEAN: A Phase 3 Trial of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab in Patients with Resectable NSCLC. Presented at AACR, April 14-19, 2023.