New data from KEYNOTE-001, a phase 1b study evaluating Pembrolizumab ( Keytruda ), an anti-PD-1 therapy, in naïve and previously-treated patients with advanced non-small cell lung cancer ( NSCLC ) were presented at the American Association for Cancer Research (AACR) Annual Meeting.
In an analysis of 313 patients from a validation data set for tumor PD-L1 expression, overall-response rate ( ORR ) was 45.2% ( 95% CI, 33.5-57.3 ) in patients with greater than or equal to 50% of tumor cells positive for PD-L1 expression ( n=73 ).
In the other PD-L1 subgroups, ORR was 16.5% ( 95% CI, 9.9-25.1 ) in patients with 1-49% tumor cells positive ( n=103 ) and 10.7% ( 95% CI, 2.3-28.2 ) in patients with less than 1% tumor cells positive ( n=28 ) for PD-L1 expression.
In the total study population, ORR was 19.4% ( 95% CI, 16.0-23.2 ) ( n=495 ), which was consistent with data previously presented from this study.
The efficacy findings demonstrated that tumor PD-L1 expression may be a relevant biomarker for the identification of NSCLC patients with an enhanced likelihood of experiencing improved efficacy with an anti-PD-1 therapy. PD-L1 is a protein that may be overexpressed in the tumor and may contribute mechanistically to an inhibited immune response.
Data for progression-free survival ( PFS ) and overall survival ( OS ) based on tumor PD-L1 expression was also presented in 356 naïve and previously-treated patients with advanced NSCLC ( total evaluable for PD-L1 staining ).
In the greater than or equal to 50% PD-L1 sub-group, median PFS was 6.3 months ( 95% CI 2.9-12.5 ) ( n=119 ); within this group, PFS was 6.1 months ( 95% CI 2.1-12.5 ) for previously-treated patients ( n=294 ) and 12.5 months ( 95% CI 2.4-12.5 ) for naive patients ( n=62 ). Progression-free survival was 3.3 months ( 95% CI, 2.1-4.1 ) in the 1-49% PD-L1 sub-group ( n=161 ), and 2.3 months ( 95% CI, 2.1-4.0 ) in less than 1% PD-L1 sub-group ( n=76 ).
Median overall survival had not yet been reached in the greater than or equal to 50% PD-L1 sub-group, regardless of prior treatment. Median overall survival was 8.8 months for the other PD-L1 subgroups ( 95% CI, 6.8-12.4 for 1-49% sub-group and 5.5-12 for less than 1% sub-group, respectively ), and was similar regardless of prior treatment.
Median duration of response was similar across tumor PD-L1 expression subgroups; 12.5 months ( 2.1+ to 23.3 ) for the greater than or equal to 50% sub-group, 7.2 months ( 1.4+ to 8.3+ ) for the 1-49% sub-group, and not reached ( 1.0+ to 10.8+ ) in the less than 1% sub-group.
At the time of analysis, median follow-up duration was 10.9 months ( range, 5.2–27.5 ).
Adverse events evaluated in the total study population were consistent with previously reported safety data for Keytruda. The most common treatment-related adverse events were fatigue, pruritus, and decreased appetite. Grade 3-5 treatment-related adverse events occurred in 9.5% of patients ( n=47 ). Treatment-related adverse events of an inflammatory or immune-mediated nature that occurred in more than 2% of patients were infusion-related reactions ( n=15; 3.0% ), hypothyroidism ( n=34; 6.9% ), and pneumonitis ( n=18; 3.6% ).
One infusion reaction led to treatment discontinuation and all hypothyroidism cases were successfully managed with medical therapy.
There was one treatment-related death ( pneumonitis ) and grade 3-5 pneumonitis was observed in 1.8% of patients ( n=9 ). At the time of analysis, two pneumonitis cases were ongoing ( both grade 1-2 ).
KEYNOTE-001 is an ongoing multi-center, single-arm, open-label phase 1b study evaluating Pembolizumab in more than 1,000 patients with diverse late-stage cancers, predominantly lung and melanoma.
Three dosing regimens were evaluated; 10mg/kg every two weeks, 10mg/kg every three weeks or 2mg/kg every three weeks.
The primary endpoints include ORR and safety; the secondary endpoints include progression-free survival, overall survival and duration of response.
Tumor response was assessed every 9 weeks per RECIST 1.1 by independent, central, blinded radiographic review.
For the tumor PD-L1 expression validation data set, tumor samples were contemporaneously collected within six months of staining and tumor PD-L1 expression was measured by Dako’s immunohistochemistry companion diagnostic test PD-L1 IHC 22C3 PharmDx.
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.
PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells.
Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 ( PD-1 ), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present.
When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells, a type of cancer-killing immune cell, allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung and bladder cancer. High levels of PD-L1 expression, called overexpression, are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches. ( Xagena )
Source: Merck, 2015