At the time of analysis, the median duration of response had not been reached with three of five responders on therapy for 11 months or more (range, 15 to 40+ weeks).
These early findings, from the ongoing Phase 1b KEYNOTE-012 study, were shared today for the first time as part of the official press program at the 2014 San Antonio Breast Cancer Symposium (SABCS) (ABSTRACT #S1-09) and will be presented in an oral session at 10:45 a.m. CST by Dr. Rita Nanda, the University of Chicago.
"Metastatic, triple-negative breast cancer is an aggressive and often difficult to treat disease," said Dr. Rita Nanda, associate director, breast medical oncology, the University of Chicago and principal investigator for the KEYTRUDA triple-negative breast cancer Phase 1b study cohort.
"The results presented at this year’s SABCS, while early, show encouraging anti-tumor activity in these patients, most of whom had received multiple prior chemotherapies."
"This year, Merck has significantly advanced our immuno-oncology development program and new data for KEYTRUDA have been presented in seven different cancers, including these first findings in triple-negative breast cancer," said Dr. Alise Reicin, vice president, global clinical development, oncology, Merck Research Laboratories.
"These early data with KEYTRUDA show responses in patients with one of the most aggressive forms of breast cancer and further our understanding of the PD-1 pathway’s role in this disease. Our Phase 2 study planned for the first half of 2015 will be an important next step for our breast cancer clinical program."
Data presented were from a cohort of the ongoing Phase 1b KEYNOTE-012 study which evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with advanced TNBC whose tumors were determined to be positive for PD-L1 expression (n=32).
As measured by Merck’s proprietary PD-L1 immunohistochemistry (IHC) clinical trial assay, tumors were considered to be PD-L1 positive if staining was present in the stroma or in greater than or equal to one percent of tumor cells. In the study, 58 percent of patients screened had tumors determined to be positive for PD-L1 expression. Most patients enrolled in this study had received two or more prior chemotherapies for metastatic disease and 87.5 percent had received prior neo-adjuvant or adjuvant therapy.
The median time to response was 18 weeks (range, 7-32 weeks). In the study, 33 percent of patients with KEYTRUDA achieved tumor shrinkage. At six months, the progression-free survival rate with KEYTRUDA was 23.3 percent.
Adverse events were consistent with previously reported safety data for KEYTRUDA. The most common treatment-related adverse events (occurring in greater than or equal to five percent of patients) included arthralgia (n=6), fatigue (n=6), myalgia (n=5), nausea (n=5), ALT increased (n=2), AST increased (n=2), diarrhea (n=2), erythema (n=2) and headache (n=2).
Grade 3-5 treatment-related adverse events occurred in a total of five patients and included anemia, disseminated intravascular coagulation (DIC), headache, meningitis aseptic, decreased blood fibrinogen, and pyrexia. Two patients discontinued KEYTRUDA due to adverse events. One treatment-related death was reported in a patient with rapidly progressive disease and was due to DIC with thrombocytopenia and decreased blood fibrinogen.
KEYNOTE-012 is an ongoing multi-center, non-randomized Phase 1b trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy in patients with advanced triple-negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial (bladder) cancer, or advanced gastric cancer.
The primary endpoints of the study include overall safety, tolerability and anti-tumor activity (as measured by RECIST v1.1 assessed by independent radiology review) in PD-L1 positive tumors; secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response. In 2014, early findings were presented for all four cohorts of the Phase 1b KEYNOTE-012 study.
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.