With a median follow-up of 3 years in a randomised, placebo-controlled phase III KEYNOTE-671 study, neoadjuvant pembrolizumab plus cisplatin-based chemotherapy followed by adjuvant pembrolizumab significantly improved overall survival (OS) compared with neoadjuvant chemotherapy alone in patients with molecularly unselected, resectable stage II, IIIA, or IIIB (N2) non-small cell lung cancer (NSCLC); OS curves began to diverge in favour of pembrolizumab at approximately month 16 and remained separated, with survival estimates favouring the pembrolizumab group by 7% at month 36.
Significant improvement in OS is consistent with the previously demonstrated improvements in event-free survival (EFS), major pathological response (MPR), and pathological complete response (pCR) compared with neoadjuvant chemotherapy alone. The efficacy benefits of perioperative pembrolizumab did not incur a long-term decrease in health-related quality-of-life (HRQoL). The findings were presented at ESMO Congress 2024 along with a simultaneous publication on 14 September 2024 by Dr. Jonathan D Spicer of the McGill University Health Centre, Montreal General Hospital in Montreal, QC, Canada and colleagues in The Lancet.
The authors wrote in the background that for patients with early-stage NSCLC without molecular alterations, neoadjuvant, perioperative, and adjuvant PD1 and PD-L1 inhibitor-based regimens have shown meaningful EFS and disease-free survival benefits. The ultimate objective for patients with resectable NSCLC is to prolong survival without compromising HRQoL. Despite representing important advances, none of the PD1-based or PD-L1-based regimens have demonstrated an OS benefit in the intention-to-treat (ITT) population, and limited HRQoL data have been published.
KEYNOTE-671 study is evaluating a perioperative approach of neoadjuvant pembrolizumab plus cisplatin-based chemotherapy followed by surgical resection and adjuvant pembrolizumab for patients with resectable stage II or III NSCLC. At the first interim analysis, perioperative pembrolizumab significantly improved EFS (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.46–0.72; one-sided p < 0.0001; one-sided threshold p = 0.0046), MPR (30% versus 11%; one-sided p < 0.0001), and pCR (18% versus 4%; one-sided p < 0.0001) compared with neoadjuvant chemotherapy alone and had a safety profile consistent with the known safety profiles of the individual medications. However, the OS benefit of perioperative pembrolizumab was not significant at the first interim analysis. The study team now reports efficacy, safety, and HRQoL outcomes from the second interim analysis.
KEYNOTE-671 is a global phase III study done at 189 medical centres. Eligible patients (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab 200 mg administered intravenously every 3 weeks plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab 200 mg administered intravenously every 3 weeks or to four cycles of neoadjuvant placebo administered intravenously every 3 weeks plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo administered intravenously every 3 weeks.
Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were OS and EFS evaluated in the ITT population. This study is ongoing, but closed to enrolment.
Between 11 May 2018 and 15 December 2021, 797 participants were randomly assigned in total, of whom 397 to the pembrolizumab group and 400 to the placebo group. Median study follow-up at the second interim analysis was 36.6 months (IQR 27.6–47.8); 36 month OS estimates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (95% CI 58–69) in the placebo group (HR 0.72, 95% CI 0.56–0.93; one-sided p = 0.0052; threshold one-sided p = 0.0054). Median OS was not reached in the pembrolizumab-treated patients compared with 52.4 months in the placebo group (95% CI 45.7 to not reached). Median EFS was 47.2 months (95% CI 32.9 to not reached) in the pembrolizumab group and 18.3 months (14.8–22.1) in the placebo group (HR 0.59, 95% CI 0.48–0.72).
At ESMO Congress 2024, the study team presented the EFS and OS results for key patients subgroups. Benefit in EFS for perioperative pembrolizumab was observed across all prespecified and exploratory subgroups assessed. Benefit in OS was observed regardless of sex, clinical disease and nodal stages, histology, EGFR mutation status, and ALK translocation status.
The authors commented that the relative benefit of pembrolizumab for OS was similar in patients with stage II (HR 0.67, 95% CI 0.41–1.10) and stage III N2 (HR 0.74, 95% CI 0.51–1.07) disease. Based on HR point estimates, the relative benefit of pembrolizumab for OS appeared to be less clear in the subgroups of age 65 years and older, non-White race, geographical region of east Asia, never smoker, and PD-L1 tumour proportion score less than 1%. OS data remain immature at this analysis, which might explain the different results for EFS and OS in subgroups.
In the as-treated population, grade 3–5 treatment-related adverse events occurred in 179 of 396 patients (45%) in the pembrolizumab group and in 151 of 399 patients (38%) in the placebo group. Treatment-related adverse events led to death in four patients (1%) in the pembrolizumab group and three patients (1%) in the placebo group.
The authors commented that in the past year, results of five phase III clinical trials (KEYNOTE-671, AEGEAN, CheckMate 77T, Neotorch, and RATIONALE-315) have shown that perioperative regimens of PD1 and PD-L1 inhibitors significantly improve MPR, pCR, and EFS in resectable early-stage NSCLC. Despite differences in the enrolled populations and design, a generally consistent benefit for perioperative immune checkpoint inhibition (ICI) was observed across these studies, supporting the validity of this treatment approach. KEYNOTE-671 is the first of these trials to show a statistically significant OS benefit.
In an accompanied comment, Drs. Carolyn J Presley and Dwight H Owen of The Ohio State University Comprehensive Cancer Center/The James Cancer Hospital & Solove Research Institute in Columbus, OH, USA wrote that although this was a large, global study, there are some considerations about generalisability, especially regarding the exclusive use of cisplatin in KEYNOTE-671. For older adults, or any adult with kidney or hearing impairment, cisplatin is not indicated. Also, the inclusion of patients with molecular driver alterations in this study, although a small number of patients, raises some concern. Furthermore, in KEYNOTE-671, subsequent therapy uptake after disease progression was high overall, 80% for pembrolizumab and 86% for placebo cohorts. However, subsequent ICI therapy was only used in 50% of patients in the placebo group.
Since adjuvant ICI therapy might be associated with higher rates of treatment-related deaths and grade 3–4 adverse events compared with neoadjuvant ICI therapy, it is still not clear which patients might benefit from the addition of adjuvant ICI after neoadjuvant chemoimmunotherapy or which patients might be harmed by it. Future studies must continue to include HRQoL according to the commenters to best inform patients of potential harms of treatment not captured by EFS or OS. In addition, some patients might benefit from chemotherapy-sparing immunotherapy-only approaches, although no phase III trial has evaluated this strategy.
This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
References
- Spicer JD, Garassino MC, Wakelee H, et al. on behalf of the KEYNOTE-671 investigators. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2024;404(10459):P1240-1252.
- Presley CJ, Owen DH. Improved survival for patients with lung cancer treated with perioperative immunotherapy. The Lancet 2024;404(10459):P1176-1178.
- 1210P - Garassino MC, Gao S, Liberman M, et al. Neoadjuvant pembrolizumab (pembro) or placebo (pbo) plus chemotherapy and adjuvant pembro or pbo for early-stage NSCLC: Subgroup analyses of the phase III KEYNOTE-671 study. Annals of Oncology 2024;35(Suppl 2):S778-S779.