Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoint inhibitor-based regimens have become standard treatments for advanced or metastatic non-small-cell lung cancer (NSCLC) without targetable molecular drivers. These drugs have shown significant benefits in improving progression-free survival and overall survival in patients with unresectable stage III NSCLC and have demonstrated promise in neoadjuvant and adjuvant therapy settings. However, despite the approval of various PD-1 and PD-L1 inhibitors, there remains a need to further enhance treatment outcomes for patients with resectable stage II or III NSCLC, as the risk of relapse and death from NSCLC still persists.
The eagerly anticipated results published in The New England Journal Of Medicine from the randomized, placebo-controlled, phase 3 KEYNOTE-671 trial have unveiled significant advancements in the treatment of resectable stage II or III non-small-cell lung cancer (NSCLC). This groundbreaking study investigated the effectiveness and safety of combining neoadjuvant pembrolizumab, a PD-1 immune checkpoint inhibitor, with cisplatin-based chemotherapy, followed by surgical resection and adjuvant pembrolizumab therapy, as compared to the standard neoadjuvant chemotherapy and surgery alone.
The interim analysis of the trial, reported today, has revealed highly promising findings that may revolutionize the management of resectable NSCLC. Participants who received the pembrolizumab-based regimen demonstrated substantial improvements in key outcome measures, including event-free survival, major pathological response, and pathological complete response, compared to those who received standard treatment.
One of the most significant findings was the substantial divergence in event-free survival curves, favoring the pembrolizumab group. The hazard ratio of 0.58 indicated a 42% reduction in the risk of disease progression, recurrence, or death in the pembrolizumab group. The difference in event-free survival between the two groups became apparent as early as 4 months into the treatment. The 24-month event-free survival estimates were 62.4% in the pembrolizumab group, a remarkable improvement compared to 40.6% in the placebo group.
The study also reported remarkable rates of major pathological response and pathological complete response in the pembrolizumab group. The percentage of participants achieving major pathological responses was nearly three times higher (30.2%) than in the placebo group (11.0%), while the percentage of participants with a pathological complete response was four times higher (18.1% vs. 4.0%). These outcomes underscore the potent anti-tumor activity of pembrolizumab when used in a neoadjuvant setting.
Interestingly, exploratory analyses suggested that the benefits of pembrolizumab extended beyond the neoadjuvant phase. Participants who achieved major pathological responses and those who achieved pathological complete responses, regardless of treatment group, demonstrated improved event-free survival. These findings indicate that the adjuvant component of the treatment regimen may provide additional benefits beyond neoadjuvant therapy and surgery alone.
The safety profile of the combined regimen of pembrolizumab plus chemotherapy, followed by surgery and adjuvant pembrolizumab, was consistent with the known safety profiles of the individual medications. No new safety signals emerged, and the incidence of treatment-related serious adverse events was similar to previously reported trials involving chemotherapy combined with checkpoint inhibitors. Most adverse events reported were associated with chemotherapy, such as anemia and nausea. The incidence and nature of immune-mediated adverse events in the pembrolizumab group were consistent with previous reports. Importantly, the trial did not observe a significant increase in treatment-related deaths.
While the trial demonstrated remarkable improvements in event-free survival, major pathological response, and pathological complete response, the overall survival benefit was not statistically significant in this interim analysis. Further follow-up and analysis are needed to determine the long-term survival impact of the pembrolizumab-based regimen.
Comparisons with other recent trials investigating perioperative checkpoint inhibition have also shown promising results. The AEGEAN trial and the Neotorch trial, conducted internationally and in China, respectively, demonstrated improved event-free survival, major pathological response, and pathological complete response when checkpoint inhibitors were combined with neoadjuvant chemotherapy and surgery. These findings, in conjunction with the KEYNOTE-671 trial, provide cumulative evidence supporting the potential benefits of perioperative immune checkpoint inhibition in the treatment of resectable stage II or III NSCLC.
It should be noted that the KEYNOTE-671 trial design does not allow for direct analysis of the specific contributions of the neoadjuvant and adjuvant components of the treatment regimen. A larger sample size would have been required to accommodate additional trial groups, such as neoadjuvant pembrolizumab plus chemotherapy with adjuvant placebo and neoadjuvant placebo plus chemotherapy with adjuvant pembrolizumab. Furthermore, the relatively short follow-up duration in this interim analysis limits the assessment of long-term outcomes. Future studies will be necessary to explore these aspects further.
In summary, the KEYNOTE-671 trial has demonstrated that the addition of pembrolizumab to neoadjuvant cisplatin-based chemotherapy, followed by surgical resection and adjuvant pembrolizumab therapy, significantly improves event-free survival, major pathological response, and pathological complete response in patients with resectable stage II or III NSCLC. These groundbreaking results hold tremendous promise for the field of lung cancer treatment, providing hope for improved outcomes and potentially reshaping the standard of care for patients with resectable NSCLC.