Targeting EGFR mutations needs to be more precise with co-mutations

Paul R. Walker, Nitika Sharma, Praveen Namireddy

Abstract

Treatment decisions in epidermal growth factor receptor (EGFR) mutated lung cancers are continuing to evolve. There are now five FDA approved EGFR tyrosine kinase inhibitors (TKI) commercially available. Treatment options can be an EGFR TKI alone or in combination with chemotherapy or anti-VEGFA/VEGFR-2 monoclonal antibodies. With next-generation sequencing (NGS), additional non-driver co-occurring mutations are being identified in association with the actionable and targetable driver mutations. The impact of co-occurring mutations in EGFR mutated lung cancer can be adversely prognostic yet are not therapeutically fully or prospectively studied. kinase insert domain receptor (KDR) mutations through the VEGF pathway are associated with EGFR TKI resistance. Uniquely KDR mutations could plausibly indicate a predictive benefit of combination EGFR TKI with either bevacizumab or ramucirumab. This has yet to be fully clinically studied but there is a strong preclinical rationale. The prognostic and predictive utility of non-driver co-occurring mutations has an important role in the optimal treatment of patients with EGFR mutated lung cancer.