Data on the investigational use of Pembrolizumab ( Keytruda ), an anti-PD-1 agent, in PD-L1 positive, advanced urothelial cancer ( also known as bladder cancer ) presented at ESMO ( European Society for Medical Oncology ) 2014 Congress.
The early findings presented showed a confirmed overall response rate of 24% with Pembrolizumab as monotherapy, as measured by RECIST v1.1, central review ( n= 7/29: 95% CI, 10.3-43.5 ) including a complete response rate of 10% ( 3/29 ).
At the time of analysis, response durations ranged from 16+ to 40+ weeks with six of the seven responders continuing on therapy.
In the ongoing study, 64% ( 61/95 ) of patients screened had tumors that were determined to be positive for PD-L1 expression.
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, Pembrolizumab 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 ( Yervoy ) 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.
Data from a cohort of the ongoing phase 1b KEYNOTE-012 study evaluated Pembrolizumab monotherapy at 10 mg/kg every two weeks in patients with advanced bladder cancer whose tumors were determined to be positive for PD-L1 expression ( n=29 ).
As measured by Merck’s proprietary immunohistochemistry ( IHC ) clinical trial assay, tumors were classified as PD-L1 positive based on greater than or equal to 1% of tumor cells demonstrating expression of the PD-L1 marker, or any positive staining with the same reagent in tumor stroma.
The majority of patients had received one or more prior lines of therapy.
At six months, 58% of patients were alive and median overall survival was 9.3 months ( 95% CI, 3.6-NR ). Additionally, tumor shrinkage was achieved in 64% of evaluable patients with one post-baseline treatment scan.
Adverse events were consistent with previously reported safety data for Pembrolizumab. The most common investigator-assessed, treatment-related adverse events ( occurring in greater than or equal to two patients ) included fatigue ( 18% ), peripheral edema ( 12% ), and nausea ( 9% ).
Grade 3-5 investigator-assessed, treatment-related adverse events occurred in a total of four patients. One infusion-related reaction was observed and one patient discontinued Pembrolizumab due to a treatment-related adverse reaction.
There were no treatment-related deaths.
KEYNOTE-012 is an ongoing multi-center, non-randomized phase 1b trial evaluating the safety, tolerability, and anti-tumor activity of Pembrolizumab monotherapy in patients with advanced triple negative breast cancer ( TNBC ), advanced head and neck cancer, advanced urothelial 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 ) in PD-L1 positive tumors; secondary endpoints include progression-free survival, overall survival and duration of response. ( Xagena )
Source: Merck, 2014