A large phase 3 randomized clinical trial has demonstrated significant overall survival and event-free survival benefits from adding perioperative pembrolizumab immunotherapy to neoadjuvant chemotherapy for patients with resectable early-stage non-small cell lung cancer (NSCLC). The KEYNOTE-671 study results were published in The Lancet on September 28, 2024.
This international, double-blind, placebo-controlled trial was conducted at 189 medical centers globally. It was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. The study aimed to evaluate the efficacy and safety of adding the PD-1 inhibitor pembrolizumab to standard neoadjuvant chemotherapy followed by surgery and adjuvant pembrolizumab, compared to neoadjuvant chemotherapy alone followed by surgery and placebo, in patients with resectable stage II-IIIB NSCLC.
A total of 797 patients were randomized 1:1 between May 2018 and December 2021 to receive either the pembrolizumab regimen (n=397) or placebo regimen (n=400). Eligible patients were adults (≥18 years) with previously untreated, pathologically confirmed stage II, IIIA, or IIIB (N2) NSCLC that was considered resectable after surgical consultation. Patients were required to have an ECOG performance status of 0-1 and provide a tumor sample for PD-L1 assessment.
The study population had a median age of 63-64 years, was predominantly male (71%), and included patients from East Asia (31%) and other regions (69%). Most patients had stage III disease (70%) and were current or former smokers (87%). Histology was balanced between non-squamous (57%) and squamous (43%) types.
The neoadjuvant phase comprised 4 cycles of pembrolizumab 200 mg or placebo given intravenously every 3 weeks plus cisplatin-based chemotherapy. Patients then underwent surgical resection followed by up to 13 cycles of adjuvant pembrolizumab or placebo. The primary endpoints were event-free survival and overall survival.
With a median follow-up of 36.6 months, the pembrolizumab regimen demonstrated a statistically significant improvement in overall survival compared to the placebo regimen. The 36-month overall survival rate was 71% with pembrolizumab versus 64% with placebo (hazard ratio 0.72, 95% CI 0.56-0.93, p=0.0052). Median overall survival was not reached in the pembrolizumab group and was 52.4 months in the placebo group.
Event-free survival was also significantly improved with pembrolizumab. Median event-free survival was 47.2 months in the pembrolizumab group versus 18.3 months in the placebo group (hazard ratio 0.59, 95% CI 0.48-0.72). The 36-month event-free survival rate was 54% with pembrolizumab compared to 35% with placebo.
The overall survival and event-free survival benefits were generally consistent across key subgroups, including disease stage, PD-L1 expression level, and histology. However, the relative benefit appeared less clear in some subgroups such as patients ≥65 years old, never smokers, and those with PD-L1 tumor proportion score <1%.
In terms of safety, treatment-related adverse events of any grade occurred in 97% of patients in the pembrolizumab group and 95% in the placebo group. Grade 3-5 treatment-related adverse events occurred in 45% and 38% of patients, respectively. The most common adverse events were nausea, decreased neutrophil count, and anemia. Immune-mediated adverse events were more frequent with pembrolizumab (26% vs 9%).
Importantly, the addition of pembrolizumab did not appear to negatively impact patients' health-related quality of life. There were no significant differences between groups in changes from baseline in global health status/quality of life scores during the neoadjuvant or adjuvant phases.
The authors concluded that the significant overall survival benefit, along with previously reported improvements in event-free survival and pathological response rates, coupled with a manageable safety profile, support perioperative pembrolizumab as a new standard of care option for patients with resectable stage II-IIIB NSCLC.
This study has several notable strengths, including its large sample size, randomized controlled design, and global patient population. The use of overall survival as a primary endpoint is particularly meaningful. The consistent benefit observed across multiple efficacy endpoints and key subgroups adds robustness to the findings.
However, there are some limitations to consider. The study design does not allow for direct analysis of the relative contributions of the neoadjuvant versus adjuvant components of the pembrolizumab regimen. The follow-up duration, while substantial, remains relatively short for early-stage disease. Additionally, the study population may not fully represent the general population of patients with resectable NSCLC, as it included younger patients on average and under-represented certain racial/ethnic groups.
The potential clinical impact of these results is significant. Perioperative immunotherapy added to neoadjuvant chemotherapy could become a new standard approach for resectable stage II-IIIB NSCLC, potentially improving long-term outcomes for many patients. The safety profile appears manageable, and quality of life does not seem to be negatively impacted.
However, several practical considerations will need to be addressed as this approach is integrated into clinical practice. These include patient selection, management of immune-related adverse events, and coordination of care between medical oncology, thoracic surgery, and other specialties involved in lung cancer treatment.
It will also be important to consider how these results fit into the evolving landscape of treatment options for early-stage NSCLC. Other recent trials have also shown benefits from perioperative immunotherapy regimens, and ongoing studies are evaluating various combinations and sequences of systemic therapy, surgery, and radiation therapy.
Cost-effectiveness analyses will be needed to evaluate the economic impact of adding expensive immunotherapy drugs to the perioperative setting. Additionally, biomarker studies to better predict which patients are most likely to benefit from this approach could help optimize patient selection.
Further follow-up from this trial will be important to assess the durability of survival benefit and to monitor for any late toxicities. Additional analyses of the rich biospecimen collection from this study may provide insights into mechanisms of response and resistance to perioperative immunotherapy.
In conclusion, the KEYNOTE-671 trial represents a significant advance in the treatment of early-stage NSCLC. It is the first phase 3 trial to demonstrate an overall survival benefit from perioperative PD-1 inhibition in this setting. While questions remain about optimal patient selection and sequencing of therapy, these results are likely to change clinical practice and improve outcomes for many patients with resectable lung cancer.
As with any major advancement in cancer therapy, the integration of these findings into clinical practice will require careful consideration of individual patient factors, multidisciplinary collaboration, and ongoing research to further refine treatment approaches. Nonetheless, the ability to significantly improve survival in early-stage lung cancer with a manageable toxicity profile represents an important step forward in the field of thoracic oncology.
References
Spicer JD, Garassino MC, Wakelee H, et al. 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. Lancet. 2024;404(10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
