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Decade in review: a new era for RET-rearranged lung cancers.

ABSTRACT: Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1-2% of NSCLCs and represent a substantial global burden of disease. Although these fusions were first identified more than thirty years ago, targeted therapy for RET fusion-positive lung cancers was only explored in the last decade. Whereas repurposed multikinase inhibitors were initially tested, selective inhibitors RET inhibitors have dramatically improved outcomes for patients whose tumors harbor these alterations. In 2020, the US Food and Drug Administration approved selpercatinib, a selective RET inhibitor, for adults with lung and thyroid cancers with RET rearrangements or mutations, making it the first targeted therapy to be approved for RET-altered cancers. While resistance to selective RET inhibition has been described, next-generation RET inhibitors are already being explored for patients who progress on prior RET kinase inhibitors.

SUBMITTER: Choudhury NJ

PROVIDER: S-EPMC7815364 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Decade in review: a new era for RET-rearranged lung cancers.

Choudhury Noura J NJ Drilon Alexander A

Translational lung cancer research 20201201 6

Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1-2% of NSCLCs and represent a substantial global burden of disease. Although these fusions were first identified more than thirty years ago, targeted therapy for RET fusion-positive lung cancers was only explored in the last decade. Whereas repurposed multikinase inhibitors were i ...[more]

PMID: 33489819

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Project description:BackgroundRET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored.Patients and methodsA retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers.ResultsWe evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers.ConclusionDurable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

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Decade in review: a new era for RET-rearranged lung cancers.

Publications

Decade in review: a new era for RET-rearranged lung cancers.

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