Keytruda (pembrolizumab) + chemotherapy before surgery and continued as single agent after surgery reduced risk of death by more than one-third (34%) versus neoadjuvant chemotherapy in high-risk early-stage triple-negative breast cancer

After a median follow-up of 75.1 months (range, 65.9-84.0), the Keytruda regimen significantly improved OS, a key secondary endpoint, reducing the risk of death by 34% (HR=0.66 [95% CI, 0.50-0.87]; p=0.0015) in patients with high-risk early-stage TNBC compared to the chemotherapy-placebo regimen (placebo plus chemotherapy followed by placebo after surgery). The five-year OS rate was 86.6% (95% CI, 84.0-88.8) for patients who received the Keytruda regimen versus 81.7% (95% CI, 77.5-85.2) for patients who received the chemotherapy-placebo regimen. Median OS was not reached in either group. The safety profile of Keytruda was consistent with that observed in previously reported studies with no new safety signals observed.

These late-breaking data are being presented for the first time  during a Presidential Symposium session at the European Society for Medical Oncology (ESMO) Congress 2024 (presentation #LBA4) and were selected for an official Press Briefing. These data are also being simultaneously published in the New England Journal of Medicine . Keytruda is the first and only immunotherapy-based regimen to show a statistically significant and clinically meaningful improvement in OS as neoadjuvant treatment with chemotherapy and then continued as a single agent as adjuvant treatment compared to placebo plus chemotherapy followed by placebo after surgery in patients with high-risk early-stage TNBC.

In pre-specified exploratory subgroup analyses of OS, the benefit of the Keytruda regimen was consistent across pre-specified subgroups, including those defined by PD-L1 expression, tumor size and nodal status.

“These impactful overall survival results add to the previously reported pathological complete response and event-free survival data from the KEYNOTE-522 trial,” said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England. “In this study, pembrolizumab plus chemotherapy as neoadjuvant treatment and continued as a single agent after surgery reduced the risk of death by more than one-third compared to neoadjuvant chemotherapy, reinforcing the important role this regimen plays in the treatment of high-risk early-stage triple-negative breast cancer.”

“Keytruda is the first and only immunotherapy-based regimen to show a statistically significant and clinically meaningful improvement in overall survival compared to chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “This is an important milestone and represents the fourth Keytruda study to demonstrate a significant overall survival benefit in an earlier stage of cancer, highlighting our efforts to help extend the lives of patients with certain cancers across different stages of disease.”

KEYNOTE-522 is one of four Phase III studies of a Keytruda-based regimen in an earlier stage of cancer to demonstrate an OS benefit, including KEYNOTE-A18 in newly diagnosed, high-risk locally advanced cervical cancer (as treatment with chemoradiotherapy, compared to chemoradiotherapy), KEYNOTE-671 in resectable stage II, IIIA or IIIB non-small cell lung cancer (as treatment with chemotherapy before surgery and then as a single agent after surgery, compared to pre-operative chemotherapy) and KEYNOTE-564 in renal cell carcinoma for patients at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (compared to placebo).

As previously announced, the KEYNOTE-522 trial met its dual primary endpoints of pCR and event-free survival (EFS) at earlier interim analyses. Based on these results, KEYTRUDA is approved in the U.S. in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery for the treatment of patients with high-risk early-stage TNBC. KEYNOTE-522 also supported regulatory approvals for certain patients with TNBC in Europe, Japan and other countries globally.

As announced , data spanning more than 20 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2024.

Study design and additional data from KEYNOTE-522

KEYNOTE-522 is a Phase III, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488 ) evaluating Keytruda in combination with chemotherapy as pre-operative (neoadjuvant) treatment and then continuing as a single agent after surgery (adjuvant) compared to placebo plus chemotherapy as neoadjuvant treatment followed by placebo as adjuvant treatment in patients with high-risk early-stage TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC). The dual primary endpoints were pCR rate, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the time of first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer or death from any cause. A key secondary endpoint was OS. The study enrolled 1,174 patients who were randomized 2:1 to receive either:  i. The Keytruda regimen: Keytruda  plus chemotherapy (paclitaxel and carboplatin), followed by Keytruda plus chemotherapy (cyclophosphamide and either doxorubicin or epirubicin) as neoadjuvant therapy prior to surgery, followed by Keytruda monotherapy as adjuvant therapy post-surgery (n=784), or; ii. The chemotherapy-placebo regimen: Placebo plus chemotherapy (paclitaxel and carboplatin), followed by placebo plus chemotherapy (cyclophosphamide and either doxorubicin or epirubicin) as neoadjuvant therapy prior to surgery, followed by placebo monotherapy as adjuvant therapy post-surgery (n=390).

After a median follow-up of 75.1 months (range, 65.9-84.0), the Keytruda regimen reduced the risk of EFS events by 35% (HR=0.65 [95% CI, 0.51-0.83]) in patients with high-risk early-stage TNBC compared to the chemotherapy-placebo regimen. The five-year EFS rate was 81.2% (95% CI, 78.3-83.8) for those treated with the Keytruda regimen compared to 72.2% (95% CI, 67.4-76.4) for those treated with the chemotherapy-placebo regimen.

At this analysis, treatment-related adverse events (TRAEs) were examined in the neoadjuvant phase, the adjuvant phase and the combined phases. TRAEs in the neoadjuvant phase have been previously reported. At the time of this data cutoff, no patients were still receiving protocol treatment. For the combined neoadjuvant and adjuvant phases, TRAEs occurred in 98.9% of patients receiving the Keytruda regimen (n=783) and 99.7% of patients receiving the chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in 82.4% versus 78.7%, respectively. TRAEs led to death in 0.5% of patients receiving the Keytruda regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified.

Immune-mediated adverse events (AEs) and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 44.8% of patients receiving the Keytruda regimen and 22.9% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in greater than10% of patients) were infusion reactions (18.0%) and hypothyroidism (15.1%) in patients receiving the Keytruda regimen and infusion reactions (11.6%) in patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the Keytruda regimen (n=2) and no patients receiving the chemotherapy-placebo regimen.

Citation: "Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer." Authors: Peter Schmid, M.D., Javier Cortes, M.D., Rebecca Dent, M.D., Heather McArthur, M.D., Lajos Pusztai, M.D., Sherko Kümmel, M.D., Carsten Denkert, M.D., +16, for the KEYNOTE-522 Investigators*.. NEJM. Published September 15, 2024