In a prospective, randomised, placebo-controlled, phase III KEYNOTE-522 study, neoadjuvant pembrolizumab combined with chemotherapy followed by adjuvant pembrolizumab (pembrolizumab–chemotherapy group) resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone (placebo–chemotherapy group), in overall survival (OS) among patients with previously untreated, high-risk, early-stage triple-negative breast cancer (TNBC). The benefit with respect to OS was observed in certain patient subgroups defined according to prognostic risk factors, including lymph-node involvement and tumour size, and was observed regardless of PD-L1 expression status and the outcome with respect to pathological complete response (pCR).
Pembrolizumab–chemotherapy continued to be associated with improved event-free survival (EFS) after a median follow-up of more than 6 years. The findings are presented at the ESMO Congress 2024 along with a simultaneous publication by Prof. Peter Schmid of the Centre for Experimental Cancer Medicine, Barts Cancer Institute and Queen Mary University of London in London, UK, and colleagues on 15 September 2024 in The New England Journal of Medicine.
At the first interim analysis of the KEYNOTE-522 study, the addition of pembrolizumab to platinum-containing neoadjuvant chemotherapy resulted in a significant increase in pCR, defined as pathological stage ypT0–Tis ypN0 (indicating no residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes) at the time of definitive surgery, of 13.6% (p < 0.001).
At the fourth interim analysis after a median follow-up of 39.1 months, the addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement in EFS (hazard ratio for event or death 0.63; p < 0.001). The study team now reports the final OS results from the KEYNOTE-522 trial.
The study team randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III TNBC to receive neoadjuvant therapy with four cycles of pembrolizumab at a dose of 200 mg or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab–chemotherapy group) or placebo (placebo–chemotherapy group) every 3 weeks for up to nine cycles. The primary endpoints were pCR and EFS; OS was a secondary endpoint.
Of the 1174 patients who underwent randomisation, 784 were assigned to the pembrolizumab–chemotherapy group and 390 to the placebo–chemotherapy group. At the data-cutoff on 22 March 2024, the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated OS at 60 months was 86.6% (95% confidence interval [CI] 84.0 to 88.8) in the pembrolizumab–chemotherapy group, as compared with 81.7% (95% CI 77.5 to 85.2) in the placebo–chemotherapy group (p = 0.002).
Pembrolizumab–chemotherapy continued to be associated with improved EFS after a median follow-up of more than 6 years. The sustained benefit of pembrolizumab treatment with respect to EFS is notable given that recurrences in TNBC tend to occur earlier than in other breast cancer subtypes, with up to 90% occurring in the first 5 years.
Furthermore, the addition of pembrolizumab to chemotherapy resulted in a reduction in distant recurrences (9.8% in the pembrolizumab–chemotherapy group versus 14.4% in the placebo–chemotherapy group), an established predictor of favourable long-term outcomes in line with the present results regarding OS.
The benefit of pembrolizumab plus chemotherapy with respect to OS and EFS was seen regardless of PD-L1 expression, nodal status, and tumour size. However, analyses in patient subgroups were exploratory, and the subgroup data are underpowered and warrant cautious interpretation.
Adverse events were consistent with the established safety profiles of pembrolizumab and platinum-, taxane-, and anthracycline-containing chemotherapy, and the addition of pembrolizumab did not substantially exacerbate common chemotherapy-related side-effects. As expected, immune-mediated adverse events occurred more frequently in the pembrolizumab–chemotherapy group, which were driven primarily by endocrinopathies. These events were generally low grade and successfully managed with treatment interruption, glucocorticoid administration, or hormone replacement.
The study was not designed to discern the relative efficacy contributions of the neoadjuvant and adjuvant treatment phases. Furthermore, adjuvant capecitabine was not included in the treatment protocol because the results of the Capecitabine for Residual Cancer as Adjuvant Therapy trial showing a survival benefit in patients with TNBC were reported after the study was designed.
Analyses of molecular biomarkers that might predict clinical response to pembrolizumab are ongoing.
The study was supported by Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ).
References
- Schmid P, Cortes J, Dent R, et al. for the KEYNOTE-522 Investigators. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. NEJM; Published 15 September 2024; DOI: 10.1056/NEJMoa2409932.
- LBA4 – Schmid P, Cortés J, Dent RA, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase III KEYNOTE-522 study. Annals of Oncology 2024;35(Suppl 2):S1204-S1205.