A post hoc analysis of the phase 3 KEYNOTE-671 trial indicates that neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy results in greater pathologic regression compared to chemotherapy alone in patients with early-stage non-small cell lung cancer (NSCLC). The data, presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer, provides a more granular understanding of the relationship between pathologic response and event-free survival (EFS).
The KEYNOTE-671 trial initially randomized 797 patients with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC to either neoadjuvant chemotherapy plus pembrolizumab (n = 397) or placebo (n = 400), followed by adjuvant pembrolizumab or placebo, respectively. The overall study demonstrated statistically significant improvements in overall survival (OS) and EFS in the pembrolizumab arm.
Evaluating Pathologic Response
An exploratory analysis of KEYNOTE-671 suggested an EFS benefit with pembrolizumab compared to placebo in patients achieving a pathological complete response (pCR) or major pathological response (mPR). However, Dr. David R. Jones from Memorial Sloan Kettering Cancer Center noted that using only pCR or mPR for stratification might oversimplify the pathologic response's relationship to EFS.
To address this, Jones et al. assessed the efficacy of perioperative pembrolizumab across different residual volume tumor (RVT) cut points beyond pCR and mPR. In patients with pathologically evaluable tumors, the median %RVT was 29.5% (IQR, 1%-56%) in the pembrolizumab arm versus 52% (IQR, 29%-68%) in the placebo arm. Patients were stratified into four categories based on %RVT in the primary lung tumor and sampled lymph nodes.
The %RVT for the pembrolizumab versus 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), and 17.5% vs 35.0% (>60% RVT). As expected, lower %RVT was associated with more favorable EFS, regardless of treatment arm.
Impact on Event-Free Survival
Within the %RVT categories, EFS was consistently higher in the pembrolizumab arm compared to the placebo arm: 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 every 3 weeks.
At the first interim analysis, the 24-month EFS rate was 62.4% versus 40.6% in the pembrolizumab versus control arms, respectively (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). The mPR and pCR rates were 30.2% versus 11% (P < .00001) and 18.1% versus 4% (P < .00001), respectively.
The second interim analysis showed that at 36 months, the EFS rates were 54.3% versus 35.4%, respectively (HR, 0.59; 95% CI, 0.48-0.72). 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 versus 52.4 months (95% CI, 45.7-NE) in the placebo arm (HR, 0.72; 95% CI, 0.56-0.93; P = .00517). The 36-month OS rates were 71.3% in the pembrolizumab arm versus 64% in the control arm.
Regulatory Approval and Clinical Implications
Based on the KEYNOTE-671 trial data, the FDA approved pembrolizumab in October 2023 for neoadjuvant treatment in combination with platinum-containing chemotherapy, followed by postsurgical adjuvant pembrolizumab monotherapy for patients with resectable NSCLC. This approval underscores the clinical significance of pembrolizumab in improving outcomes for patients with early-stage NSCLC.
