ESMO 2023 Update – KEYNOTE-671

ESMO 2023 Update – KEYNOTE-671: The First Perioperative Immunotherapy Clinical Trial in Non-Small Cell Lung Cancer Improving Overall Survival

Author:

Lei Deng, MD

Assistant Professor/Medical Oncologist

Thoracic, Head & Neck Medical Oncology

University of Washington/Fred Hutchinson Cancer Center

Key Points:

• In phase 3 KEYNOTE-671, resectable stage II, IIIA and IIIB (T3-4N2) NSCLC received 4 cycles of neoadjuvant pembrolizumab (or placebo) + chemotherapy followed by adjuvant pembrolizumab (or placebo) for up to 13 cycles
• Updated analysis reported at ESMO 2023 showed statistically improved overall survival in the pembrolizumab arm (HR 0.72, median not reached [pembro]) vs. 52.4 months [placebo], 36-mo OS rates were 71.3% vs 64.0%)
• This is the first perioperative immunotherapy clinical trial in non-small cell lung cancer proving overall survival benefit
• Unresolved questions are 1) the added benefit of extra 1 cycle before surgery; and 2) who are 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 include 1) adjuvant pembrolizumab (PEARLS/KEYNOTE-091) and atezolizumab (Impower010) followed by adjuvant chemotherapy; 2) neoadjuvant nivolumab plus chemotherapy (CheckMate-816); and very recently perioperative pembrolizumab (KEYNOTE-671), which was just approved by US FDA on October 16, 2023^1-4. However, the details of the survival results remain unknown.

 

The updated overall survival of KEYNOTE-671 was presented at 2023 ESMO congress in Madrid, Spain (Abstract Number: LBA56). This randomized, double-blinded trial enrolled 797 patients with resectable stage II, IIIA and IIIB (T3-4N2, AJCC 8). Patients were randomized to neoadjuvant pembrolizumab plus chemotherapy for 4 cycles followed by adjuvant pembrolizumab for up to 13 cycles versus neoadjuvant placebo plus chemotherapy for 4 cycles followed by placebo treatment. Of note, the trial’s dual primary endpoints are event-free survival (EFS) and overall survival (OS).

 

In this updated analysis, the median time from randomization was 36.6 months. A total of 254 (31.9%) death events happened.  OS was statistically improved in the pembrolizumab arm (HR 0.72 [95% CI 0.56-0.93]. The 36-month OS rates were 71.3% vs 64.0%, respectively. Benefit seems to correlate with PD-L1 status, with higher PD-L1 expression associated with larger OS improvement. EGFR mutation was included, but with only 33 patients, no conclusions can be drawn.

 

The neoadjuvant only regimen of CheckMate-816 requires only 3 cycles of treatment before surgery, while KEYNOTE-671 regimen consists of 4 cycles preoperatively followed by adjuvant therapy for a year. With FDA approval, KEYNOTE-671 is a standard of care option for early-stage non-small cell lung cancer. It remains unclear which approach would be the best for patients or what biomarker can help identify the suitable population for each one. However, KEYNOTE-671 is the first trial reporting significant OS improvement among trials of chemoimmunotherapy administered before surgery for patients with non-small cell lung cancer.

 

 

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 randomised, 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 randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-1357.
4. USFDA. FDA approves neoadjuvant/ adjuvant pembrolizumab for resectable non-small cell lung cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer.