Abstract
(1) Background: Phenotypic and genotypic heterogeneity are characteristic features of cancer patients. To tackle patients' heterogeneity, immune checkpoint inhibitors (ICIs) represent some the most promising therapeutic approaches. However, approximately 50% of cancer patients that are eligible for treatment with ICIs do not respond well, especially patients with no targetable mutations. Over the years, multiple patient stratification techniques have been developed to identify homogenous patient subgroups, although matching a patient subgroup to a treatment option that can improve patients' health outcomes remains a challenging task. (2) Methods: We extended our Subgroup Discovery algorithm to identify patient subpopulations that could potentially benefit from immuno-targeted combination therapies in four cancer types: head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), and skin cutaneous melanoma (SKCM). We employed the proportional odds model to identify significant drug targets and the corresponding compounds that increased the likelihood of stable disease versus progressive disease in cancer patients with the EGFR wild-type (WT) gene. (3) Results: Our pipeline identified six significant drug targets and thirteen specific compounds for cancer patients with the EGFR WT gene. Three out of six drug targets-FCGR2B, IGF1R, and KIT-substantially increased the odds of having stable disease versus progressive disease. Progression-free survival (PFS) of more than 6 months was a common feature among the investigated subgroups. (4) Conclusions: Our approach could help to better select responders for immuno-targeted combination therapies and improve health outcomes for cancer patients with no targetable mutations.