Pembrolizumab monotherapy in patients with advanced gastric cancer: 31% overall response rate in patients with PD-L1 positive


Data on the investigational use of Pembrolizumab ( Keytruda ), an anti-PD-1 agent, in PD-L1 positive, advanced gastric cancer were presented during the ESMO ( European Society for Medical Oncology ) 2014 Congress. The early findings presented have shown an overall response rate ( confirmed and unconfirmed ) of 31% with Pembrolizumab as monotherapy, as measured by investigator assessed, RECIST v1.1 ( n= 12/39: 95% CI, 17-47 ).
Similar overall response rates were observed in Asian patients ( a population with a high incidence of gastric cancer ) and non-Asian patients.
At the time of analysis, response durations ranged from 8+ to 20+ weeks with 11 of 12 responders continuing on therapy.

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 was 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 gastric cancer whose tumors were determined to be positive for PD-L1 expression ( n=39 ).
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.
Enrollment was designed to include an equal number of Asian and non-Asian patients.
The majority of patients had received two or more prior lines of therapy.

In the study, tumor shrinkage was demonstrated in 41% of evaluable patients who had measurable disease with one post baseline scan, per RECIST v1.1 criteria.

Adverse events were consistent with previously reported safety data for Pembrolizumab. The most common investigator-assessed, treatment-related adverse events ( occurring in greater than 5% ) included hypothyroidism ( 12.8% ) and fatigue ( 12.8% ). Grade 3-5 investigator-assessed, treatment-related adverse events occurred in a total of three patients, with one patient each in peripheral sensory neuropathy ( grade 3 ), hypoxia ( grade 5 ) and pneumonitis ( grade 4 ).
No infusion-related reactions were observed and no patients discontinued Pembrolizumab due to a treatment-related adverse reaction. One treatment-related death due to hypoxia, as assessed by the investigator, was reported.

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 ( 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 ) in PD-L1 positive tumors; secondary endpoints include progression-free survival, overall survival and duration of response. ( Xagena )

Source: Merck, 2014

XagenaMedicine_2014



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