The FDA accepted a supplemental Biologics License Application for and granted Priority Review to pembrolizumab in combination with chemotherapy, which is intended for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1.
The FDA accepted a supplemental Biologics License Application (sBLA) for and granted Priority Review to pembrolizumab (Keytruda) in combination with chemotherapy, which is intended for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score [CPS] ≥10), Merck announced in a press release.1
“There is a real need to advance new treatment options for triple-negative breast cancer, an aggressive form of the disease. The FDA’s acceptance of these Keytruda applications for review is an important step toward helping patients with both early-stage and metastatic disease,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement about two applications for FDA approval. “These acceptances mark the first US applications for Keytruda in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible.”
The FDA has set a target action date of November 28, 2020 under the Prescription Drug User Fee Act for a final decision on the application.
Data from the phase 3 KEYNOTE-355 trial support the sBLA. The results, which were presented by Javier Cortes, MD, PhD, during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, showed that pembrolizumab in combination with different chemotherapy partners led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when compared with chemotherapy alone.1,2
In the study, 847 patients were randomized 2:1 to receive either intravenous (IV) pembrolizumab administered at 200 mg every 3 weeks plus chemotherapy (n = 556) or chemotherapy alone (n = 281). Chemotherapy regimens consisted of IV nab-paclitaxel (Abraxane) at 100 mg/m2 on days 1, 8, and 15 every 4 weeks; IV paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 4 weeks; or gemcitabine 1000 mg/m2 and carboplatin AUC 2 on days 1 and 8 every 3 weeks. Patients in each arm were divided into cohorts comprised of individuals with PD-L1 expression of CPS ≥10, CPS ≥1, and the intention-to-treat (ITT) population.
The CPS ≥10 cohort had 215 PFS events across both study arms. The median PFS was 9.7 months in the pembrolizumab/chemotherapy arm compared with 5.6 months in the chemotherapy-alone arm (HR, 0.65; 95% CI, 0.49-0.86; one-sided P = .0012).
The cohort with CPS ≥1 had 450 PFS events with a median PFS of 7.6 months in the pembrolizumab-plus-chemotherapy arm versus 5.6 months in the chemotherapy arm (HR, 0.74; 95% CI, 0.61-0.90; one-sided P = .0014). The PFS results did not meet the prespecified criteria for statistical significance.
Finally, in the ITT cohort, 602 PFS events occurred. The median PFS observed with the pembrolizumab combination was 7.5 months versus 5.6 months with chemotherapy alone (HR, 0.82; 95% CI, 0.69-0.97).
Overall, the pembrolizumab arm was favored in terms of PFS. This was observed across the subgroup population, with some variances in the CPS <1 group and the CPS <10 groups.
In terms of safety, treatment-related adverse events (AEs) occurred in 96.3% of patients in the combination arm versus 95% in the chemotherapy-alone arm. Grade 3-5 treatment-related AEs were seen in 68.1% of patients treated with pembrolizumab plus chemotherapy versus 66.9% of those who received chemotherapy alone. Few treatment-related AEs led to death in the pembrolizumab arm and there were none in the chemotherapy arm. For any study drug, 18.1% of treatment-related AEs led to discontinuation in the pembrolizumab arm, as did 11.0% in the chemotherapy arm.
The most common any-grade AEs in the combination and chemotherapy arms included anemia (48.9% vs 45.9%), neutropenia (41.1% vs 38.1%), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), neutrophil count decrease (22.2% vs 26.3%), and alanine aminotransferase increase (20.5% vs 16.4%).
Immune-mediated AEs occurred in 25.6% of patients in the pembrolizumab group compared with 6.0% in the chemotherapy group. Grade 3 to 5 immune-mediated AEs were seen in 5.2% of patients in the combination arm but in no percentage of the chemotherapy arm. There were no deaths caused by immune-mediated AEs, but 3.9% of the patients in the pembrolizumab arm and 1.1% in the chemotherapy arm did discontinue treatment of any drug due to these AEs.
Based on these findings, Cortes et al noted that there may be a role for the combination of pembrolizumab and chemotherapy as frontline treatment of patients with metastatic TNBC.
KEYNOTE-355 is an ongoing, randomized, double-blind, placebo-controlled study assessing the coprimary end points of PFS and overall survival in patients with metastatic TNBC. The secondary end points of the study include objective response rate, duration of response, disease control rate, and safety.
Prior to the submission and acceptance of the sBLA for this agent as treatment of metastatic TNBC, the FDA granted a Breakthrough Therapy designation to pembrolizumab plus chemotherapy as neoadjuvant treatment of patients with high-risk, early-stage TNBC based on data from KEYNOTE-522 (NCT03036488), the first randomized trial of an anti–PD-L1 agent in the neoadjuvant and adjuvant setting of TNBC.
1. Merck announces two us regulatory milestones for keytruda® (pembrolizumab) in triple-negative breast cancer (tnbc). News release. Merck. July 30, 2020. Accessed July 30, 2020.
2. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020: 38 (suppl; abstr 1000). doi: 10.1200/JCO.2020.38.15_suppl.1000