Publication | Closed Access
Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature.
198
Citations
0
References
2015
Year
3001 Background: Immunotherapy with anti–PD-1 monoclonal antibodies such as pembrolizumab shows robust, durable antitumor activity in patients with advanced melanoma. Examining gene expression related to the immune response within the tumor may provide new insights into the molecular features associated with clinical response to these agents. We evaluated immune-related gene expression patterns in patients with melanoma enrolled in the phase Ib KEYNOTE-001 study. Methods: Baseline tumor biopsy samples from 19 patients with melanoma enrolled in KEYNOTE-001 were used as a discovery set. Results were validated using samples from 62 additional patients from KEYNOTE-001, of whom 51 were evaluable for response per RECIST v1.1 by central review. RNA was extracted from formalin-fixed paraffin-embedded tissue sections and analyzed using the NanoString nCounter. Two signatures, the “Interferon-gamma [IFNγ] 10-gene” and the “Expanded-immune 28-gene,” were pre-specified prior to linking NanoString data to clinical outcomes. Results: The overall response rate (ORR) was 47% in the validation cohort. Both the IFNγ and the expanded-immune signatures showed statistically significant associations with ORR (P = 0.047 and 0.027, respectively) and progression-free survival (P = 0.016 and 0.015). Analysis of top-ranked genes on the platform led to the discovery of two new signatures, “TCR-signaling” and “Denovo” that were enriched in T-cell markers and MHC Class I and II genes. Conclusions: Measuring immune-related biomarkers, including T-cell specific, antigen presentation–related, and IFNγ signaling–related genes, may allow for improved selection of patients likely to respond to anti–PD-1 therapy with pembrolizumab. Results are consistent with the hypothesis that clinical responses to PD-1 blockade occur in patients with a preexisting interferon-mediated adaptive immune response. Further confirmation of these new signatures in melanoma is required. Clinical trial information: NCT01295827.