Systemic and CNS Activity of Selective RET Inhibition With Selpercatinib (LOXO-292) in a Patient With RET-Mutant Medullary Thyroid Cancer With Extensive CNS Metastases.
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SUBMITTER: Andreev-Drakhlin A
PROVIDER: S-EPMC7608524 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Systemic and CNS Activity of Selective RET Inhibition With Selpercatinib (LOXO-292) in a Patient With RET-Mutant Medullary Thyroid Cancer With Extensive CNS Metastases.
Andreev-Drakhlin Alexander A Cabanillas Maria M Amini Behrang B Subbiah Vivek V
JCO precision oncology 20201030
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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.
| S-EPMC7208240 | biostudies-literature
Project description: Not available
| S-EPMC8140803 | biostudies-literature
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| S-EPMC7450975 | biostudies-literature
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| S-EPMC6724540 | biostudies-literature
Project description: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.
| S-EPMC10652291 | biostudies-literature
Project description:BackgroundMedullary thyroid cancer (MTC) standard of care includes multikinase inhibitors (MKIs), which can exacerbate disease-related diarrhea, primarily because of non-RET kinase inhibition. We report diarrhea and other patient-reported outcomes (PROs) with selpercatinib, a highly selective RET inhibitor, among patients with RET-mutant MTC in the ongoing, phase I/II LIBRETTO-001 trial.Materials and methodsInstrument completion time points were baseline (cycle 1, day 1) and approximately every other 28-day cycle until cycle 13 (every 12 weeks thereafter) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and baseline, weekly during cycle 1, and day 1 of every cycle for the modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). A ≥10-point change from baseline in domain score was considered clinically meaningful. PROs were summarized through cycle 13 in all patients and by subgroups with or without prior exposure to MKIs vandetanib and/or cabozantinib (V/C).ResultsAmong the overall MTC population (n = 226), 88 (39%) and 124 (55%) patients comprised the V/C-naïve and previous V/C subgroups, respectively. Compliance was >85% for both instruments at each time point. Most patients maintained/improved in all health-related quality of life (HRQoL) subscales throughout treatment. Improvements in diarrhea were clinically meaningful in 43.5% of patients overall and in 36.8% and 51.3% of V/C-naïve and previous V/C subgroups, respectively. At baseline, 80.4% of all patients reported diarrhea on mSTIDAT. The percentage of patients who reported diarrhea was reduced to less than half of all patients (range: 33.3%-48.3%) after cycle 2.ConclusionThese interim results demonstrate that patients with RET-mutant MTC improved/remained stable on all domains of HRQoL during treatment with selpercatinib. Future analyses will be conducted as the data mature.
| S-EPMC9714586 | biostudies-literature
Project description:Genetic alternation of REarranged during Transfection (RET) that leads to constitutive RET activation is a crucial etiological factor for thyroid cancer. RET is known to regulate mitochondrial processes, although the underlying molecular mechanisms remain unclear. We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells. In this study, we hypothesized that the RET-selective inhibitor, selpercatinib, can increase Δψm and, subsequently, tumor cell uptake of the mitochondria-targeted ubiquinone (MitoQ) to the level to break the mitochondrial homeostasis and induce lethal responses in RET-mutated thyroid tumor cells. We show that selpercatinib significantly increased Δψm, and its combination with MitoQ synergistically suppressed RET-mutated human thyroid tumor cells, which we validated using RET-targeted genetic approaches. Selpercatinib and MitoQ, in combination, also suppressed CCDC6-RET fusion cell line xenografts in mice and prolonged animal survival more effectively than single treatments of each agent. Moreover, we treated two patients with CCDC6-RET or RETM918T thyroid cancer, who could not take selpercatinib at regular doses due to adverse effects, with a dose-reduced selpercatinib and MitoQ combination. In response to this combination therapy, both patients showed tumor reduction. The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.
| S-EPMC10879150 | biostudies-literature
Project description: Not available
| S-EPMC10660185 | biostudies-literature
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.).
| S-EPMC10777663 | biostudies-literature
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.
| S-EPMC10467255 | biostudies-literature