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Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update.

ABSTRACT: Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLC). Notably, new molecular profiling technologies have permitted dynamic growth in the identification of actionable driver oncogenes including RET rearrangements. RET oncogenes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction and next-generation sequencing are complementary diagnostic tools. In the clinical setting, the benefit of the most developed RET inhibitors, i.e., cabozantinb, vandetanib and lenvatinb, in terms of response and median progressionfree survival has been demonstrated. The absence of striking clinical results of RET inhibitors underscores the clear need for development of more selective and potent RET inhibitors. This paper reviews the clinical data available on RET inhibitors in RET-associated NSCLC.

SUBMITTER: Mendoza L

PROVIDER: S-EPMC6065052 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update.

Mendoza Luis L

Oncology reviews 20180710 2

Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLC). Notably, new molecular profiling technologies have permitted dynamic growth in the identification of actionable driver oncogenes including RET rearrangements. RET oncogenes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction and next-generation seq ...[more]

PMID: 30093982

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Project description:BackgroundRearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.Patients and methodsThis study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.ResultsWe analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.ConclusionsRET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

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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Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update.

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Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update.

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