Background: Combination treatment of two recent trends in cancer therapy, namely immunotherapy with checkpoint inhibitors and drugs that target specific gene mutations, could improve cancer survivorship overall. Targeted drugs usually induce rapid tumor death leading to the release of neoantigens, and can affect immune development pathways, which could increase the efficacy of checkpoint inhibitor treatment. Assessment of somatic mutation profiles from large public databases provides an estimate of the prevalence of targetable somatic mutations and the burden of somatic nonsynonymous mutations (NsM), used as a surrogate for overall neoantigen load, which, in turn, correlates with clinical utility of checkpoint inhibitors for melanoma and lung adenocarcinoma. The rational design of these combinations based on somatic genomic profiles offers a prioritization scheme for new clinical trials. Methods: We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents and/or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a recently suggested threshold for response to checkpoint inhibitors. Results: Overall, 8.9% of cases have profiles that could benefit from combination therapy, which corresponds to approximately 11.2% of US annual incident cancer cases; the most commonly targetable mutations were observed in PIK3CA, BRAF, NF1, NRAS, and PTEN genes. Interestingly, cases with mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and/or MET appear to be enriched in those with high burdens of NsM, who have a higher likelihood of responding to immunotherapy. Of the 13,349 cases that could benefit from combination therapy, 50.9% had BRAF, NF1, GNAQ and/or GNA11 mutations which can be targeted by Trametinib; 26.1% by Taselisib (targets PIK3CA mutations); and 19.8% by Afatinib (EGFR and ERBB2 mutations). Conclusions: Our results indicate a significant proportion of solid tumor patients are eligible for combination therapy and suggest prioritizing specific cancers for combination trials using target drugs and checkpoint inhibitor therapy.