Dual CDKN2A/MTAP loss compared to CDKN2A loss alone and response to immune-checkpoint inhibitors (ICI) in advanced solid tumors.
Authors: Adib Elio , Nassar Amin , El Zarif Talal , Kale Neil , Rakaee Mehrdad , Mouhieddine Tarek H. , Abou Alaiwi Sarah , Freeman Dory , Labban Muhieddine , Akl Eli , Haddad Robert I. , Hodi F. Stephen , Sonpavde Guru P. , Giannakis Marios , Braun David A. , Gusev Alexander , Choueiri Toni K. , Overstreet Erin , Stone Everett , Kwiatkowski David J. 
Published: June 2022

2622 Background: We previously showed that CDKN2A genomic alterations (GAs) are associated with resistance to ICI (Adib E, Clinical Cancer Research, 2021). The majority of such GAs are homozygous deletions, which commonly (̃50-80%) include MTAP, located 100kb telomeric of CDKN2A. MTAP loss leads to 5′-deoxy-5′-methylthioadenosine (MTA) accumulation and immunosuppressive effects in tumors. We examined combined CDKN2A/MTAP deletion vs. CDKN2A deletion/mutation alone as predictors of poor ICI response. Methods: We curated clinical data for cancer patients (pts) treated with ICI at Dana-Farber Cancer Institute through 6/2021, who had targeted panel sequencing. Inclusion criteria were: ICI in metastatic setting, ≥2 cycles, no concurrent systemic therapy, cancer type with > 50 pts treated. CDKN2A/ MTAP GAs were defined as a deep deletion affecting both genes; CDKN2A only GAs included both homozygous deletions and truncating mutations. Hazard ratios (HR) for overall survival (OS) and time-to-treatment failure (TTF) were derived using multivariable Cox regression, adjusted for prior lines of therapy, treatment type (single vs. combination ICI), tumor mutational burden and ECOG PS. We also used a machine learning approach to quantify the density of tumor-infiltrating lymphocytes (TILs) in digital whole-slide H&E images of 144 melanoma pts with available genomic data. Results: 921 pts with 6 cancer types were studied: non-small cell lung cancer (NSCLC, n = 366), melanoma (mel, n = 228), urothelial carcinoma (UC, n = 120), esophagogastric carcinoma (EGC,n = 90), head and neck squamous cell carcinoma (HNSCC, n = 58), and renal cell carcinoma (RCC, n = 59). UC pts with MTAP/ CDKN2A GAs had shorter OS and TTF than pts without GA in either gene (OS HR = 1.9[1.1-3.4], p = 0.005; TTF HR = 1.8[1.0-3.1], p = 0.0016) after adjusting for covariates. Similar results were seen for melanoma (OS HR = 2.5[1.4-2.6],p = 0.00065; TTF HR = 1.9[1.1-3.2],p = 0.018). There was no significant difference between pts with CDKN2A GA only and those without GA in either gene for OS or TTF in either UC or melanoma. CDKN2A/MTAP status was not associated with significantly shorter survival for NSCLC and EGC; while the analysis was confounded by HPV events for HNSCC, and underpowered for RCC. ML-based analysis of digital slides for melanoma, showed that tumors with CDKN2A GAs only (n = 42) had similar median density of TILs compared to tumors without GAs in either gene (n = 84; 920 vs. 943 TILs/mm2; p = 0.42). In contrast, tumors with co-occurring CDKN2A/ MTAP GAs had lower TIL density (529 TIL/mm2, n = 17 vs. 925 TIL/mm2, n = 126 (pooled); p = 0.018, Wilcoxon rank sum). Conclusions: In this study, we showed that co-occurrence of MTAP/CDKN2A GAs, but not CDKN2A GA only, was associated with worse outcomes in pts with UC and melanoma treated with ICI. Lower TIL density was also seen in melanoma tissue samples with combined MTAP/CDKN2A GA.