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LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naive RET-mutant medullary thyroid cancer.

ABSTRACT: Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib.

SUBMITTER: Wirth LJ

PROVIDER: S-EPMC10652291 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naïve RET-mutant medullary thyroid cancer.

Wirth Lori J LJ Brose Marcia S MS Elisei Rossella R Capdevila Jaume J Hoff Ana O AO Hu Mimi I MI Tahara Makoto M Robinson Bruce B Gao Ming M Xia Meng M Maeda Patricia P Sherman Eric E

Future oncology (London, England) 20220815 28

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib i ...[more]

PMID: 35969032

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Project description:BackgroundPatient-reported outcomes (PROs) are increasingly becoming an important part of clinical trials as they are helpful in analyzing the safety and efficacy of treatment in chronic diseases like cancer.ObjectivesWe report PROs and health-related quality of life (HRQoL) with selpercatinib treatment among Chinese patients with rearranged in transfection (RET) fusion-positive non-small-cell lung cancer (NSCLC), RET fusion-positive thyroid cancer (TC), and RET-mutant medullary TC (MTC) as an exploratory analysis of the LIBRETTO-321 trial.DesignA total of 77 patients (47 RET fusion-positive NSCLC, 1 RET fusion-positive TC, and 29 RET-mutant MTC) were enrolled. Compliance for European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) was 100% at baseline and >90% at each time point.MethodsPROs were assessed using the EORTC QLQ-C30, and a bowel diary assessment for MTC patients with baseline diarrhea using the Systemic Therapy-Induced Diarrhea Assessment Tool. Data were collected at pre-dose; every 8 weeks from cycle 3; and every 12 weeks after cycle 13. A >10-point change from baseline was considered clinically meaningful. PRO changes were summarized through cycle 13.ResultsMost patients with NSCLC or MTC showed improvement or remained stable on the global health status and functional subscales. For global health status, 47.4% of NSCLC and MTC patients showed definite improvement with only 19.7% showing definite worsening. For functional subscales, less than 30% of the patients showed definite worsening. For symptom subscales, more than 64% of the patients either improved or remained stable for the symptoms. For MTC patients with bowel diary assessment (n = 5), there was no severity or worsening from baseline in the diarrheal episodes observed during treatment with selpercatinib.ConclusionThe study demonstrated favorable PROs in Chinese patients with RET fusion-positive NSCLC, TC, and RET-mutant MTC treated with selpercatinib. HRQoL was improved or stable as assessed by EORTC QLQ-30.Trail registrationThis study was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04280081) ClinicalTrials.gov Identifier: NCT04280081.

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: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:PurposeWe report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non-small cell lung cancers (NSCLC).Patients and methodsIn the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.ResultsEighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.ConclusionsSelpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.

Dataset Information

LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naive RET-mutant medullary thyroid cancer.

Publications

LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naïve <i>RET</i>-mutant medullary thyroid cancer.

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