Abstract 965: Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma

Abstract Background: Despite significant advances, only a subset of patients with advanced melanoma treated with immune checkpoint blockade (ICB) experience durable responses, and biomarkers to predict response are limited. Further, while combination ICB has higher response rates and improved progression-free survival compared to single-agent therapy in the front-line setting, there is significantly increased toxicity with combination ICB, and biomarkers to identify patients who would disproportionately benefit from combination therapy vs aPD-1 ICB are poorly characterized. Methods: To understand resistance mechanisms to ICB therapy, we analyzed whole-exome-sequencing (WES) of pre-treatment tumor and matched normal tissue from 4 cohorts of previously ICB-naïve, aPD-1 treated patients (n=140). The SKCM TCGA cohort (from a pre-immuno- and targeted-therapy time period) was used for comparison to understand the prognostic and predictive role of the features identified. We then developed a parsimonious predictive model to identify patients with intrinsic resistance (PD as BOR) on aPD1 treatment with high specificity. Finally, we analyzed two additional independent cohorts to validate the model and to test whether patients predicted to have intrinsic resistance to single-agent aPD-1 may respond to combination ICB. Results: We found that high intratumoral genomic heterogeneity and low ploidy robustly identified patients with intrinsic resistance to aPD-1 within and across each independent cohort. Compared to the TCGA SKCM (“untreated” cohort), genomic heterogeneity specifically predicted response (Mann-Whitney p=0.018) and survival (multivariate Cox log rank p=0.002) in the ICB treated cohorts, but not in the untreated cohort, while ploidy was prognostic of overall survival in the “untreated” (by targeted therapy or ICB) group. (log-rank p=0.01). To establish clinically actionable predictions, we optimized a simple decision tree using genomic ploidy and heterogeneity and identified with high confidence a subset of patients with intrinsic resistance (PPV=90%) and significantly worse survival on aPD1 treatment (optimized decision tree OS log-rank p<0.001; PFS log-rank p<0.001). We then validated this model in a set of independent cohorts, and further demonstrate that these features and predictions of the model are independent of known clinical features and previously reported molecular biomarkers associated with poor-risk disease or poor response to ICB. Finally, in an additional cohort, we found that a significant proportion of patients predicted to have intrinsic resistance to single agent aPD-1 responded to combination aPD1+aCTLA4. Conclusions: These findings nominate the clinical and biological importance of genomic heterogeneity and ploidy, and sets a concrete framework towards clinical actionability, broadly advancing precision medicine in oncology. Citation Format: Giuseppe Tarantino, Cora A. Ricker, Annette Wang, Will Ge, Amy Y. Huang, Shariq Madha, Jiajia Chen, Yingxiao Shi, Dennie T. Frederick, Samuel Freeman, Marta M. Holovatska, Michael P. Manos, Lisa Zimmer, Alexander Rösch, Anne Zaremba, Brendan Reardon, Jihye Park, Haitham Elmarakeby, Bastian Schilling, Anita Giobbie-Hurder, Natalie Vokes, Elizabeth I. Buchbinder, Keith Flaherty, Rizwan Haq, Catherine Wu, Genevieve Boland, F. Stephen Hodi, Eliezer Van Allen, Dirk Schadendorf, David Liu. Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 965.