Dataset Information

Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers.

ABSTRACT: Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10-20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET mutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selective RET inhibitors, selpercatinib and pralsetinib, have revolutionized the field of RET precision therapy. In this article, we review the current status on the use of the selective RET inhibitor, selpercatinib, in RET fusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.

SUBMITTER: Gouda MA

PROVIDER: S-EPMC10288430 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers.

Gouda Mohamed A MA Subbiah Vivek V

Therapeutic advances in medical oncology 20230621

Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10-20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET ...[more]

PMID: 37360768

Similar Datasets

Project description:BackgroundRET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, 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 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.ConclusionsIn this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Project description:Abstract The RET receptor tyrosine kinase proto-oncogene is activated by somatic or germline mutations in a majority of medullary thyroid cancers (MTC). However, treatment of MTC has been challenging due to the lack of effective and tolerable RET-specific therapy, thus testing tumors for the presence of somatic RET mutation has not been warranted. In a first-in-human, phase 1/2 clinical trial (LIBRETTO-001, NCT03157128), selpercatinib (LOXO-292), an investigational, highly selective, potent small molecule RET kinase inhibitor, demonstrated significant and durable anti-tumor activity in patients with advanced RET-mutant MTC or with diverse RET fusion-positive cancers (1). Among the primary analysis set of patients with RET-mutant MTC previously treated with cabozantinib and/or vandetanib (N=55), the investigator-assessed objective response rate (ORR) per RECIST 1.1 was 56% (95% CI 42.3-69.7, n=31/55). Duration of response was not reached with a 10.6-months median follow-up (data cutoff date 17-Jun-2019). Here, we evaluated investigator-assessed ORR per RECIST 1.1 and clinical benefit rate (CBR) in this previously treated patient population by RET alteration and by germline or somatic testing used for enrollment. The ORR remained consistent across subgroups with RET M918T (49%, 95% CI 30.8-66.5, n=16/33), V804M/L gatekeeper mutations (60%, 95% CI 14.7-94.7, n=3/5), extracellular cysteine mutations (43%, 95% CI 9.9-81.6, n=3/7), other mutations (90%, 95% CI 55.5-99.7, n=9/10), and germline (50%, 95% CI 6.8-93.2, n=2/4) or somatic (57%, 95% CI 42.2-70.7, n=29/51) testing. The CBR, defined as the proportion of patients with best overall response of confirmed complete response, confirmed or unconfirmed partial response, or stable disease lasting 16 weeks or more, in this patient set was 87% (95% CI 75.5-94.7, n=48/55). The CBR remained consistent across subgroups with RET M918T (88%, 95% CI 71.8-96.6, n=29/33), V804M/L gatekeeper mutations (80%, 95% CI 28.4-99.5, n=4/5), extracellular cysteine mutations (71%, 95% CI 29.0-96.3, n=5/7), other mutations (100%, 95% CI 69.2-100.0, n=10/10), and germline (75%, 95% CI 19.4-99.4, n=3/4) or somatic (88%, 95% CI 76.1-95.6, n=45/51) testing. The primary technologies used to identify RET alterations were tumor next-generation sequencing (n=43) and polymerase chain reaction (n=9). As previously reported, selpercatinib was well tolerated with an acceptable safety profile (1). These results indicate broad anti-tumor activity for selpercatinib in patients with RET-mutant MTC irrespective of the specific RET mutation, and support implementation of RET mutation testing for patients with advanced MTC, including somatic testing, to identify patients who may benefit from selpercatinib. Reference: (1) Wirth et al., Ann Oncol. 2019 Oct; 30(supplement 5): v933.

Project description:BackgroundAlterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.Patients and methodsPotent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.ResultsLOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.ConclusionsThese results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Dataset Information

Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers.

Publications

Precision oncology with selective RET inhibitor selpercatinib in <i>RET</i>-rearranged cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets