Hope Rugo, MD of the University of California San Francisco speaks about the SABCS abstract – FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Chemotherapy for Patients With Locally Recurrent Unresectable or Metastatic Triple‑Negative Breast Cancer Whose Tumors Express PD-L1 (CPS ≥10).
KENILWORTH, N.J.—(BUSINESS WIRE)—Outside of the United States and Canada, Merck (NYSE: MRK), known as MSD, today reported that the U.S. KEYTRUDA, Merck’s anti-PD-1 therapy in conjunction with chemotherapy, has been approved by the Food and Drug Administration (FDA 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) as determined by an FDA-approved test. The approval is based on findings from the Phase 3 KEYNOTE-355 trial in which KEYTRUDA significantly decreased the risk of cancer progression or death by 35% for patients whose tumors express PD-L1 (CPS ⇠10) against the same chemotherapy in combination with chemotherapy-paclitaxel (pac), paclitaxel protein-bound (commonly known as nab-paclitaxel) or gemcitabine (gem) and carboplatin (carbo)- Events were observed in 62% (n=136/220) of these patients who received KEYTRUDA in conjunction with pac, nab-paclitaxel or gem/carbo versus 77% (n=79/103) of those who received KEYTRUDA alone under the same chemotherapy regimens. In the study, 38 percent of patients had PD-L1 expressing tumors with CPS ⇠10. This indication is approved under the Progression-Free Survival (PFS) Accelerated Approval; continued approval for this indication may be subject to confirmatory trial verification and explanation of clinical benefit.
Immune-mediated, serious, or fatal adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathy, nephritis, severe skin reactions, rejection of solid organ transplants, and complications of allogeneic hematopoietic stem cell transplantation, can occur with KEYTRUDA. KEYTRUDA should be withheld or withdrawn depending on the nature of the adverse reaction, and corticosteroids should be administered if necessary. KEYTRUDA can also trigger serious or life-threatening reactions associated with the infusion. Based on its mechanism of action, when given to a pregnant woman, KEYTRUDA can cause fetal damage. See “Selected Important Safety Information” below for more information.
Information Supporting the Approval
Accelerated approval was focused on evidence from a multicenter, double-blind, randomized placebo-controlled study of KEYNOTE-355 (ClinicalTrials.gov, NCT02819518), performed in 847 patients with locally recurrent unresectable or metastatic TNBC, irrespective of tumor PD-L1 expression, who were not previously treated with metastatic chemotherapy. Patients were randomized to receive either KEYTRUDA (200 mg on Day 1 every 3 weeks) or placebo (on Day 1 every 3 weeks) in conjunction with the following chemotherapy (2:1); both drugs were given by intravenous infusion:
Pac (90 mg/m2 every 28 days on Days 1, 8 and 15); or Nab-paclitaxel (100 mg/m2 every 28 days on Days 1, 8 and 15); or Gem/carbo (1,000 mg/m2 and AUC 2 mg/mL/min, respectively, every 21 days on Days 1 and 8).
Randomization was stratified by chemotherapy treatment (pac or nab-paclitaxel vs. gem and carbo), PD-L1 tumor expression (CPS ⇠1 vs. CPS <1) in conjunction with the PD-L1 IHC 22C3 pharmDx kit and previous treatment in the neoadjuvant setting with the same chemotherapy class (yes vs. no). Tumor status was measured at 8, 16, and 24 weeks, then every nine weeks for the first year and every 12 weeks thereafter. As measured by the Blinded Independent Central Review (BICR) according to RECIST v1.1, PFS was the key efficacy outcome factor, updated to meet a maximum of 10 target lesions and a maximum of five target lesions per organ evaluated in the subgroup of patients with CPS ⇠10.1. Overall survival, as well as objective response rate (ORR) and length of response (DOR) as measured by BICR, were additional efficacy outcome indicators.
The characteristics of the sample population were: the median age of 53 years (range, 22 to 85), 21 percentage of 65 or older; 100 percent female; 68 percent white, 21 percent asian and 4 percent black; 60 percent 0 ECOG PS and 40 percent 1 ECOG PS; and 68 percent postmenopausal. Seventy-five percent of patients had CPS expression of tumor PD-L1 by 1 and 38 percent had CPS expression of tumor PD-L1 by 10.
In KEYNOTE-355, efficacy findings were randomized to obtain KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo in patients who were PD-L1 positive with a CPS of ⇠10 (n=323) relative to the same chemotherapy regimens alone. KEYTRUDA decreased the risk of disease progression or death by 35 percent (HR=0.65 [95 percent CI, 0.49, 0.86]; p=0.0012) in conjunction with pac, nab-paclitaxel or gem/carbo (n=220) with a median PFS of 9.7 months (95 percent CI, 7.6, 11.3) versus 5.6 months (95 percent CI, 5.3, 7.5) with the same chemotherapy protocol alone (n=103). For PFS, 62% (n=136) of patients had a KEYTRUDA case in conjunction with pac, nab-paclitaxel, or gem/carbo versus 77% (n=79) of patients with the same chemotherapy regimens alone. The ORR was 53 percent (95 percent CI, 46, 60) for patients who received KEYTRUDA in combination with pac, nab-paclitaxel, or gem/carbo, with a 17 percent full response rate and a 36 percent partial response rate. The ORR was 40 percent (95 percent CI, 30, 50) for patients treated with the same chemotherapy regimens alone with a 13 percent full response rate and a 27 percent partial response rate. The median DOR with KEYTRUDA in conjunction with pac, nab-paclitaxel, or gem/carbo was 19.3 months (95 percent CI, 9.9, 29.8) versus 7.3 months (95 percent CI, 5.3, 15.8) with the same chemotherapy regimens alone.
The median period of KEYTRUDA exposure in the sample was 5.7 months (range, 1 day to 33.0 months). 2.5 percent of patients (n=596) undergoing KEYTRUDA in conjunction with chemotherapy, including cardio-respiratory arrest (0.7 percent) and septic shock, suffered fatal adverse reactions (0.3 percent ). In 30 percent of patients who received KEYTRUDA in combination with pac, nab-paclitaxel, or gem/carbo, severe adverse reactions occurred. Pneumonia (2.9 percent), anemia (2.2 percent), and thrombocytopenia were severe adverse reactions found in about 2 percent of patients (2 percent ). In 11 percent of patients, KEYTRUDA was discontinued because of adverse reactions. Increased alanine aminotransferase (ALT) (2.2 percent), increased aspartate aminotransferase (AST) (1.5 percent), and pneumonitis were the most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (~1 percent) (1.2 percent ). In 50 percent of patients, adverse reactions leading to the cessation of KEYTRUDA occurred. Neutropenia (22 percent), thrombocytopenia (14 percent), anemia (7 percent), increased ALT (6 percent), leukopenia (5 percent), decreased white blood cell count (3.9 percent), and diarrhea were the most common adverse reactions leading to KEYTRUDA interruption (~2 percent) (2 percent ). Fatigue (48 percent), nausea (44 percent), alopecia (34 percent), diarrhea and constipation (28 percent each), vomiting and rash (26 percent each), cough (23 percent), reduced appetite (21 percent), and headache were the most common adverse reactions (all grades ~20 percent) for KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo (20 percent ).
Triple-Negative Breast Cancer Around (TNBC)
Triple-negative breast cancer is an aggressive form of breast cancer that in the first five years after diagnosis has a characteristically high rate of recurrence. Although some breast cancers may test positive for estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER2) over-expression, for all three, TNBC tests are negative. Roughly 20 percent of breast cancer patients are diagnosed with TNBC.