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RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

ABSTRACT: The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world' studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting.

SUBMITTER: Novello S

PROVIDER: S-EPMC10166168 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

Novello Silvia S Califano Raffaele R Reinmuth Niels N Tamma Antonella A Puri Tarun T

The oncologist 20230501 5

The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET ...[more]

PMID: 36821595

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Project description:BackgroundPralsetinib is a selective RET inhibitor. The ARROW trial revealed that RET fusion-positive non-small-cell lung cancer (NSCLC) can benefit from pralsetinib with tolerable adverse events (AEs). However, the efficacy and safety of pralsetinib in real world has rarely been reported.Materials and methodsThis study reviewed the efficacy and safety of pralsetinib in RET fusion-positive NSCLC patients between March 2021 and December 2021. Progression-free survival (PFS) and overall survival (OS) were evaluated by a Kaplan-Meier analysis and log-rank test. A Cox regression model was performed to identify independent prognostic factors.ResultsA total of 28 patients were enrolled, and the median follow-up time was 18.1 months. The objective response rate and disease control rate of the whole cohort were 57.2% and 71.4%, respectively, and the median PFS and OS were 8.1 months [95% confidence interval (CI), 3.1-13.2] and 13.8 months (95% CI, 2.8-24.8), respectively. Baseline characteristics of the treatment naive group and pre-treated group were listed. The median PFS tended to be better in treatment naive group (18.3 vs. 8.0 months, P = 0.067), while the median OS were similar between the two groups (28.4 vs. 11.6 months, P = 0.308). Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2 had worse median PFS comparing with those with ECOG PS score of 0-1 (3.8 vs. 12.6 months, P = 0.004). Besides, patients previously treated with platinum-based chemotherapy (PBC) also revealed worse median PFS comparing with those without previous PBC (8.0 vs. 18.6 months, P = 0.023). Furthermore, patients previously treated with anti-programmed death-1 (PD-1) antibody or multikinase inhibitors (MKIs) showed worse median OS compared with those without previous anti-PD-1 antibody (5.0 vs. 22.0 months, P = 0.002) or MKIs (6.2 vs. 28.4 months, P = 0.015). The most common AEs was increased aspartate aminotransferase (39.3%).ConclusionPralsetinib was effective in RET fusion-positive NSCLC with tolerable AEs in real-world practice. Efficacy of pralsetinib was decreased in patients previously treated with PBC, immunotherapy, or MKIs.

Project description:BackgroundRET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.ConclusionsSelpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

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.

Dataset Information

RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

Publications

RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

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