Introduction: KEYNOTE-001 (NCT01295827) was a phase 1 study of pembro in pts with locally advanced or metastatic melanoma (parts B and D). KEYNOTE-006 (NCT01866319) was a randomized phase 3 study of pembro vs ipilimumab in pts with advanced melanoma. We explored potential relationships between key tumor microenvironment canonical signatures beyond T cell-inflamed gene expression profile (GEP) and response/resistance to pembro monotherapy in pts with melanoma.
Methods: In pembro-treated, ipilimumab-naive pts from KEYNOTE-001 and KEYNOTE-006 with available RNA-sequencing and clinical data (n = 476), we analyzed association of 9 non-T cell-inflamed GEP canonical signatures (angiogenesis, gMDSC, glycolysis, hypoxia, Myc, proliferation, RAS, stromal/EMT/TGFβ, WNT) with clinical outcomes. Signatures were defined with TCGA and Moffitt databases (independent of any pembro trial) using a correlation algorithm to select individual genes for membership in the canonical signature based on correlation with reference signatures identified in literature or internal work. Relationships between RNA signatures and clinical outcomes were assessed using 2 models: 1 adjusted for ECOG PS and batch effect and 1 adjusted for T cell-inflamed GEP to understand the additional explanatory value of a non-T cell-inflamed GEP signature for clinical outcomes. P values were adjusted for multiplicity; significance was predefined at α = 0.05. Database cutoffs for clinical data: 11/27/2017 (KEYNOTE-001), 12/4/2017 (KEYNOTE-006).
Results: T cell-inflamed GEP was statistically significantly associated with response to pembro (P < 0.0001). No canonical signatures showed statistically significant association with response/resistance to pembro after multiplicity adjustment when adjusting for T cell-inflamed GEP, ECOG PS, and batch effect. Without adjusting for T cell-inflamed GEP, Myc signature was the only signature identified as statistically significantly associated with response to pembro in the postulated direction of negative association. Prolonged OS, but not PFS, was observed in pts with a lower Myc signature. Myc signature did not show independent predictive value beyond T cell-inflamed GEP, indicating that interferon γ-related T-cell inflammation has a more dominant impact on immunotherapy efficacy than the Myc signature and other gene sets in immune-suppressive axes.
Conclusions: In this exploratory analysis, no canonical signatures showed statistical significance after adjusting for T cell-inflamed GEP. Although observed only without adjusting for T cell-inflamed GEP, Myc signature was negatively associated with response in ipilimumab-naive pts with melanoma receiving pembro monotherapy.
Citation Format: Adil Daud, Matteo S. Carlino, Antoni Ribas, Ana Arance, Jean-Jacques Grob, James Larkin, Georgina V. Long, Jacob Schachter, Andrea L. Webber, Clemens Krepler, Chunsheng Zhang, Jared Lunceford, Razvan Cristescu, Qing Zhao, Junshui Ma, Caroline Robert. Evaluation of RNA-sequencing signatures with response to pembrolizumab (pembro) monotherapy in ipilimumab-naive patients (pts) with melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2009.