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Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS , and PTEN We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2 , and MET Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. Cancer Res; 77(13); 3666-71. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Immune checkpoint inhibitor treatment represents a promising approach toward treating cancer and has been shown to be effective in a subset of melanoma, non-small cell lung cancer (NSCLC), and kidney cancers. Recent studies have suggested that the number of nonsynonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment. It is hypothesized that a higher burden of NsM generates novel epitopes and gene products, detected by the immune system as foreign. We conducted an assessment of NsM across 7,757 tumor samples drawn from 26 cancers sequenced in the Cancer Genome Atlas (TCGA) Project to estimate the subset of cancers (both types and fractions thereof) that fit the profile suggested for melanoma and NSCLC. An additional independent set of 613 tumors drawn from 5 cancers were analyzed for replication. An analysis of the receiver operating characteristic curves of published data on checkpoint inhibitor response in melanoma and NSCLC data estimates a cutoff of 192 NsM with 74% sensitivity and 59.3% specificity to discriminate potential clinical benefit. Across the 7,757 samples of TCGA, 16.2% displayed an NsM count that exceeded the threshold of 192. It is notable that more than 30% of bladder, colon, gastric, and endometrial cancers have NsM counts above 192, which was also confirmed in melanoma and NSCLC. Our data could inform the prioritization of tumor types (and subtypes) for possible clinical trials to investigate further indications for effective use of immune checkpoint inhibitors, particularly in adult cancers. Cancer Res; 76(13); 3767-72. ©2016 AACR., (©2016 American Association for Cancer Research.)