Association of distinct baseline tissue biomarkers with response to nivolumab (NIVO) and ipilimumab (IPI) in melanoma: CheckMate 064.

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9515 Background: CheckMate 064 (open label, phase 2) randomized advanced melanoma pts to NIVO 3 mg/kg Q2W for 6 doses then IPI 3 mg/kg Q3W for 4 doses (n = 70; cohort A), or the reverse (IPI then NIVO; n = 70; cohort B). More cohort A than cohort B pts had complete or partial response (54% and 31%, respectively). We sought to determine whether common or distinct baseline biomarkers were associated with response for each cohort. Methods: Protein expression of biomarkers identifying a broad array of cell lineages and immunoregulatory factors was determined by IHC and evaluated by 2 pathologists, with concordance. Global transcript expression was determined by RNAseq from frozen tissue. An elastic net predictor was trained on cohort A (α = 0.1, λ = 0.05) using leave-one-out cross-validation. RECIST v1.1 was used to assess tumor response. Results: Patients with tumors showing a pro-inflammatory transcriptional signature at baseline had superior overall response in cohort A, but not cohort B. Consistent with this observation, a parsimonious classifier of 10 immune/IFNγ-related genes predicted BOR (AUC 0.87) and OS (CPH log-likelihood P= 0.0003) for patients in cohort A, but not cohort B. In contrast, low baseline expression of MHC class I protein by malignant cells ( < 50% positive) was associated with disease progression (MHCI < 50% vs ≥50%: 12/13 vs 16/28 progressed) and inferior OS for patients in cohort B (MHCI < 50%: 6.42 mo [2.20, 9.66]; MHCI ≥50%: mOS 18.02 mo [7.98, not reached]: P= 0.0021, log-rank test), but not cohort A. Conclusions: Different pre-treatment biological characteristics of melanoma are associated with clinical response to NIVO followed by a planned switch to IPI (cohort A) and clinical response to IPI followed by NIVO (cohort B). Improved outcome with initial NIVO is strongly associated with a pro-inflammatory signature enriched for IFNγ targets. Inferior outcome with initial IPI is associated with reduction/loss of MHC I antigen presentation machinery. These data imply that NIVO broadly activates innate and adaptive immunity, whereas IPI is reliant upon CD8/MHC class I mediated adaptive immunity to effect clinical response. Clinical trial information: NCT01783938.