Abstract CT037: Genomic analyses and immunotherapy in advanced melanoma

Background: Increased tumor mutational burden (TMB) and inflammation are associated with improved clinical outcomes to immuno-oncology (I-O) therapy in many tumor types. Genomic correlates of response to nivolumab (N) vs dacarbazine (D) (CheckMate [CM] 066; NCT01721772) and N+ipilimumab (I) combination therapy or N vs I (CM 067; NCT01844505) were evaluated for association of TMB and an inflammatory gene signature with clinical outcomes. Methods: In pretreatment tumor samples from eligible patients (pts), TMB was analyzed by whole-exome sequencing using median number of total missense mutations to define high vs low TMB (TMB-H/TMB-L). Associations of TMB with progression-free survival (PFS) and overall survival (OS) were evaluated per protocol-defined exploratory analyses using 4-year follow-up data for both trials. PFS and OS associations with an inflammatory signature were assessed by RNAseq in CM 067 samples only and grouped into tertiles for analysis. HR and 95% CI were calculated using Cox modeling and P values were calculated using the Wald test. Results: In CM 066, TMB was evaluable in 122 of 411 pts. PFS and OS were significantly longer in pts treated with N, but not with D, for TMB-H vs TMB-L tumors. The benefit of PFS and OS for N vs D was greater in pts with TMB-H than TMB-L (Table). In CM 067, 583 of 937 pts were evaluable for TMB and 299 were evaluable using an inflammatory signature. PFS and OS were longer in each treatment (tx) arm in pts with TMB-H vs TMB-L (Table). Across tx arms, a numerical benefit was observed for PFS and OS in pts with high vs low inflammatory signature (Table). TMB-H and a high inflammatory signature score were independently associated with clinical outcomes to I-O. Conclusions: High TMB or high inflammatory signature was associated with benefit to I-O. TMB status did not differentiate between N+I and N, and higher inflammatory status increased the likelihood of benefit for N+I and N, suggesting further evaluation of these biomarkers to characterize the response to I-O regimens in melanoma. Citation Format: F. Stephen Hodi, Jedd D. Wolchok, Dirk Schadendorf, James Larkin, Max Qian, Abdel Saci, Tina C. Young, Sujaya Srinivasan, Han Chang, Megan Wind-Rotolo, Jasmine I. Rizzo, Donald G. Jackson, Paolo A. Ascierto. Genomic analyses and immunotherapy in advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT037.