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Current management of RET rearranged non-small cell lung cancer.

ABSTRACT: The identification of oncogenic drivers, and the subsequent development of targeted therapies established biomarker-based care for metastatic non-small cell lung cancer (NSCLC). Biomarker testing is standard of care in NSCLC patients with adenocarcinoma because multiple targeted therapies are available. Rearranged during transfection (RET) rearrangements were identified as oncogenic drivers in NSCLC, and are more common among younger patients, adenocarcinoma histology, and patients with a history of never smoking. The prevalence is estimated to be 1-2% among patients with adenocarcinoma histology. The most common rearrangement is between intron 11 of the RET gene and intron 15 of the KIF5B gene, and the next most frequent rearrangement is with the CCDC6 gene. RET rearrangements lead to constitutive activation of the RET tyrosine kinase and increased cell proliferation, migration, and survival. Phase II studies investigated the activity of multi-targeted tyrosine kinase inhibitors in patients with NSCLC with a confirmed RET rearrangement. These agents have limited potency against RET, and activity against the epidermal growth factor receptor and vascular endothelial growth factor pathways. These agents revealed modest activity, and were poorly tolerated due to the off-target toxicities. These struggles contributed to the development of more potent and specific RET tyrosine kinase inhibitors. Preliminary results from early phase trials of selpercatinib (LOXO-292) and pralsetinib (BLU-667) revealed promising efficacy and improved tolerability. The availability of these agents will make routine testing for RET rearrangements a priority.

SUBMITTER: Stinchcombe TE

PROVIDER: S-EPMC7385825 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Current management of <i>RET</i> rearranged non-small cell lung cancer.

Stinchcombe Thomas E TE

Therapeutic advances in medical oncology 20200726

The identification of oncogenic drivers, and the subsequent development of targeted therapies established biomarker-based care for metastatic non-small cell lung cancer (NSCLC). Biomarker testing is standard of care in NSCLC patients with adenocarcinoma because multiple targeted therapies are available. Rearranged during transfection (<i>RET</i>) rearrangements were identified as oncogenic drivers in NSCLC, and are more common among younger patients, adenocarcinoma histology, and patients with a ...[more]

PMID: 32782485

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Project description:Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

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Current management of RET rearranged non-small cell lung cancer.

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Current management of <i>RET</i> rearranged non-small cell lung cancer.

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