Identification of Immuno-Targeted Combination Therapies Using Explanatory Subgroup Discovery for Cancer Patients with EGFR Wild-Type Gene.

Abstract

Simple SummaryCancer immunotherapy is a form of cancer treatment that uses a person’s own immune system to prevent, control, and eliminate cancer. However, immunotherapy alone may not be effective, especially in patients with limited treatment options. Immuno-targeted combination therapies have a potential to create synergetic effects with improved health outcomes. Therefore, there is a growing interest in searching for therapeutic combinations that could extend the benefits of immunotherapy. In this study, we designed a computational method that facilitated the identification of effective combination therapies for cancer patients with few treatment options. We determined several specific drug targets that substantially increased the odds of stable disease versus progressive disease for head and neck cancer, lung cancer, and melanoma. The identified treatment combinations were targets in several clinical trials. Moreover, our approach has the potential to improve the selection of patients for immuno-targeted combination therapies and lead to an overall improvement in health outcomes for cancer patients with limited treatment options.(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.