Analysis Shows Perioperative Pembrolizumab Efficacy in NSCLC

A POST HOC ANALYSIS showed that neoadjuvant pembrolizumab (Keytruda) plus chemotherapy led to greater pathologic regression based on percent residual volume tumor (%RVT) vs placebo plus chemotherapy in patients with early-stage non–small cell lung cancer (NSCLC). Data from the analysis of the phase 3 KEYNOTE-671 trial (NCT03425643) were presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.¹

In the overall KEYNOTE-671 trial, 797 patients with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were randomly assigned in a 1:1 ratio to receive neoadjuvant chemotherapy plus either pembrolizumab (n = 397) or placebo (n = 400) followed by adjuvant pembrolizumab in the treatment arm or placebo in the control arm. Data from the overall study population showed statistically significant improvements in overall survival (OS) and event-free survival (EFS) in the pembrolizumab vs placebo arm.

An exploratory analysis from KEYNOTE-671 found there was an EFS benefit with pembrolizumab vs placebo among patients who reached a pCR or mPR. However, David R. Jones, MD, a thoracic surgeon at Memorial Sloan Kettering Cancer Center in New York, New York, explained at the IASLC conference that “stratification using only pCR or mPR does not address the pathologic response and its relationship to EFS in a more granular manner and may, in fact, be oversimplified.”

Accordingly, Jones et al sought to close this knowledge gap by assessing the “efficacy of perioperative pembrolizumab across different RVT cut points beyond pCR and mPR.”

Among this population of patients with pathologically evaluable tumors, the median %RVT was 29.5% (IQR, 1%-56%) in the pembrolizumab arm vs 52% (IQR, 29%-68%) in the placebo arm. Jones et al stratified patients into 4 categories based on %RVT in the primary lung tumor and sampled lymph nodes. Among the 4 stratified RVT groups, the %RVT for the pembrolizumab vs control groups was 31.9% vs 12.3% (0%-5% RVT), 19.1% vs 14.7% (> 5%-30% RVT), 31.6% vs 38% (> 30%-60% RVT), and17.5% vs 35.0% (>60% RVT). Jones said that as expected, lower %RVT was associated with more favorable EFS, regardless of treatment arm.

When assessing the relationship within the %RVT categories, the EFS was higher in the pembrolizumab arm vs the placebo arm across all groups: 0%-≤5% RVT (HR, 0.58); >5%-≤30% RVT (HR, 0.73); >30%-≤60% RVT (HR, 0.65); and >60% RVT (HR, 0.90). In the double-blind, multicenter KEYNOTE-671 trial, patients with early-stage NSCLC received neoadjuvant pembrolizumab 200 mg or placebo once every 3 weeks.^2,3

At the first interim analysis, the 24-month EFS rate was 62.4% vs 40.6% in the pembrolizumab vs control arms, respectively (HR, 0.58; 95% CI, 0.46-0.72; P < .00001).^2,3 The mPR and pCR rates were 30.2% vs 11% (P < .00001) and 18.1% vs 4% (P < .00001), respectively.^2,3

The second interim analysis showed that at 36 months, the EFS rates were 54.3% vs 35.4%, respectively (HR, 0.59; 95% CI, 0.48-0.72).⁴ The pembrolizumab regimen led to a statistically significant improvement in OS. The median OS was not yet reached (95% CI, not estimable [NE]-NE) in the pembrolizumab arm vs 52.4 months (95% CI, 45.7-NE) in the placebo arm (HR, 0.72; 95% CI, 0.56-0.93; P = .00517).⁴ The 36-month OS rates were 71.3% in the pembrolizumab arm vs 64% in the control arm.⁴

Based on data from KEYNOTE-671 trial, the FDA approved pembrolizumab in October 2023 for use in combination with platinum-containing chemotherapy as neoadjuvant treatment and with continuation of pembrolizumab monotherapy as postsurgical adjuvant treatment for patients with resectable NSCLC.⁵

References
1. Jones DR, Wakelee H, Spicer JD, et al. Association of pathologic regression with event-free survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage NSCLC. Abstract presented at: International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer; September 7-11, 2024; San Diego, CA. Abstract OA01.03.
2. Wakelee HA, Liberman M, Kato T, 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. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100
3. Wakelee H, Liberman M, Kato T, et al; KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983
4. Spicer JD, Gao S, Liberman M, et al. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Abstract presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain.
Abstract LBA56.
5. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed September 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer