Keytruda Plus Chemotherapy Significantly Improves Survival in Patients with High-Risk Early-Stage Triple-Negative Breast Cancer

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Findings from the Phase III KEYNOTE-522 trial (NCT03036488) demonstrated that Keytruda (pembrolizumab) plus chemotherapy produced a significant improvement in overall survival (OS) among patients with high-risk early-stage triple-negative breast cancer (TNBC). The data, published in The New England Journal of Medicine, show that at a median follow-up of 75.1 months (range, 65.9-84.0), the combination therapy lowered the risk of death by 34% (HR=0.66 [95% CI, 0.50-0.87]; p=0.0015) compared to chemotherapy alone.^1-3

“These impactful overall survival results add to the previously reported pathological complete response and event-free survival (EFS) data from the KEYNOTE-522 trial,” Peter Schmid, MD, PhD, FRCP, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, England, said in a press release. “In this study, [Keytruda] 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 [TNBC].”¹

Keytruda, an anti-PD-1 therapy, enhances the immune system's ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect the tumor and healthy cells. Keytruda has been approved by the FDA for two indications in TNBC. The agent has been approved for patients with high-risk early-stage TNBC combined with chemotherapy as neoadjuvant treatment followed by treatment as a single agent postsurgery; and combined with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.⁴

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.⁴

The randomized, double-blind KEYNOTE-522 trial compared Keytruda plus chemotherapy as neoadjuvant treatment and then continuing as an adjuvant monotherapy vs. placebo plus neoadjuvant chemotherapy followed by placebo as an adjuvant treatment in patients with high-risk early-stage TNBC. The trial’s dual primary endpoints were pCR rate, which investigators defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery; and EFS, which they defined as time from randomization to time of first occurrence of either disease progression that precluded definitive surgery, local or distant recurrence, occurrence of second primary cancer, or death from any cause. OS was one of the trial’s key secondary endpoints.

A total of 1,174 patients were randomly assigned at a 2:1 ratio to receive either Keytruda plus chemotherapy of paclitaxel and carboplatin, followed by Keytruda plus chemotherapy of cyclophosphamide and either doxorubicin or epirubicin as neoadjuvant treatment, followed by adjuvant Keytruda monotherapy (n=784); or placebo plus chemotherapy of paclitaxel and carboplatin, followed by placebo plus chemotherapy of cyclophosphamide and either doxorubicin or epirubicin as neoadjuvant treatment, followed by adjuvant placebo monotherapy (n=390).

Results from the trial show a five-year OS rate of 86.6% (95% CI, 84.0-88.8) in the Keytruda cohort compared to 81.7% (95% CI, 77.5-85.2) in the chemotherapy-placebo cohort, with median OS not reached in either group.

“After a median follow-up of 75.1 months, the 5-year overall survival was 4.9 percentage points higher with the addition of [Keytruda],” the study authors wrote. “The benefit of [Keytruda] treatment with respect to overall survival was seen in certain prespecified subgroups, including those defined according to PD-L1 expression, nodal status, and tumor size. The subgroup data are underpowered and require cautious interpretation.”³

Additional findings show the combination regimen lowered the risk of EFS events by 35% (HR=0.65 [95% CI, 0.51-0.83]) compared to the chemotherapy-placebo cohort. Five-year EFS was 81.2% (95% CI, 78.3-83.8) in the Keytruda combination cohort compared to 72.2% (95% CI, 67.4-76.4) in the chemotherapy-placebo cohort.

In terms of safety, treatment-related adverse events (TRAEs) were reported by 98.9% of patients in the Keytruda combination cohort (n=783) compared to 99.7% of patients in the chemotherapy-placebo cohort (n=389).

“Pembrolizumab–chemotherapy continued to be associated with improved event-free survival after a median follow-up of more than 6 years,” the study authors concluded. “These results provide further support for [Keytruda] plus neoadjuvant chemotherapy followed by adjuvant [Keytruda] as treatment for high-risk, early-stage triple-negative breast cancer.”³

References

1. KEYTRUDA® (pembrolizumab) Plus 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 (TNBC). News release. Merck. September 15, 2024. Accessed September 24, 2024. https://www.merck.com/news/keytruda-pembrolizumab-plus-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-ri/

2. Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/​KEYNOTE-522). ClinicalTrials.gov. Updated July 12, 2024. Accessed September 24, 2024. https://clinicaltrials.gov/study/NCT03036488

3. Schmid P, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med 2024. doi/full/10.1056/NEJMoa2409932.

4. Merck Announces Phase 3 KEYNOTE-522 Trial Met its Overall Survival (OS) Endpoint in Patients With High-Risk Early-Stage Triple Negative Breast Cancer (TNBC). News release. Merck. May 28, 2024. Accessed September 24, 2024. https://www.merck.com/news/merck-announces-phase-3-keynote-522-trial-met-its-overall-survival-os-endpoint-in-patients-with-high-risk-early-stage-triple-negative-breast-cancer-tnbc/