Selected Articles from This Issue

Abstract

Patients with EGFR-mutant NSCLC initially respond to EGFR-targeted therapy, although drug resistance often develops. Bertino and colleagues conducted a Phase Ib trial assessing the combination of navitoclax, an oral BCL-2/BCL-xL inhibitor, with osimertinib, a third-generation EGFR TKI, in patients with EGFR-mutant NSCLC. This combination was well tolerated and showed evidence of clinical efficacy, with 100% of patients in an escalation study showing an objective response. Reduction in plasma EGFR mutations were observed in the majority of patients. This work supports the further clinical investigation of this combination in NSCLC.Radiation therap. is thought to enhance antitumor immune responses and may affect the efficacy of immunotherapy, such as sipleucel-T. Marshall and colleagues performed a randomized phase II trial evaluating sipuleucel-T with or without radium-223 for men with metastatic castration resistant prostate cancer. Unexpectedly, combination treatment led to lower peripheral T-cell immune responses to the target antigen, PA2024, than treatment with sipuleucel-T alone. Regardless, patients receiving the combination showed PSA decline and had improved PFS and OS. Additional study of this combination in a larger cohort is warranted.Tumor mutational burden (TMB) is a predictive biomarker for efficacy of immune checkpoint blockade in NSCLC. Blood TMB (bTMB) assessments offer several advantages over tissue TMB (tTMB). Si and colleagues evaluated the accuracy and reproducibility of the GuardantOMNI ctDNA platform for quantifying bTMB. Patients received first-line darvalumab with or without tremelimumab versus chemotherapy alone in metastatic non-small cell lung cancer as part of the MYSTIC study. The success rate for obtaining valid TMB scores was higher for bTMB than tTMB. Cross-validation analysis confirmed the selection of bTMB ≥20 mut/Mb as the optimal cut-off for clinical benefit with durvalumab plus tremelimumab versus chemotherapy. Such analytical validation studies improve the reliability of TMB estimates to aid in clinical decision making.Fusions in receptor tyrosine kinases (RTKs) occur rarely in colorectal cancer (CRC) but represent potential actionable targets. Singh and colleagues characterized CRC harboring RTK fusions. RTK fusions were enriched in right-sided tumors with wild-type BRAF and RAS. One-third of the CRC cases with RTK fusions were microsatellite stable (MSS). Two patients with MSS CRC and RTK fusions derived clinical benefit from targeted therapy. One patient with an ALK fusion was treated with two sequential ALK targeted agents, crizotinib and alectinib, whereas the second patient with a ROS1 fusion was treated with entrectinib for 10 months, with treatment ongoing. These results confirm that RTK fusions are targetable in CRC, although a clinical trial is warranted to further assess targeted therapies in these patients.