Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring <i>RET</i> Gene Alterations

Ortiz, Michael V.; Gerdemann, Ulrike; Raju, Sandya Govinda; Henry, Dahlia; Smith, Steve; Rothenberg, S. Michael; Cox, Michael C.; Proust, Stéphanie; Bender, Julia Glade; Frazier, A. Lindsay; Anderson, Peter M.; Pappo, Alberto S.

doi:10.1200/po.19.00401

Cited by 34 publications

(38 citation statements)

References 31 publications

(36 reference statements)

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“…The second report detailed five cases aged between 2 months and 15 years with tumours harbouring RET alterations, two with MTC, and one each with neuroblastoma, mesoblastic nephroma/ infantile fibrosarcoma or lipofibromatosis. As of 1 October 2019 four patients had partial response and one had stable disease [13].…”

Section: Ret-altered Cancers In Paediatric Patientsmentioning

confidence: 98%

Selpercatinib: First Approval

Markham

2020

Drugs

107

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Selpercatinib (RETEVMO™) is a receptor tyrosine kinase RET (rearranged during transfection) inhibitor being developed by Loxo Oncology for the treatment of cancers harbouring RET alterations. Based on results from the phase I/II LIBRETTO-001 trial, selpercatinib was recently approved by the US FDA for the treatment of RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer. This article summarizes the milestones in the development of selpercatinib leading to this first approval. Selpercatinib (RETEVMO™): Key PointsA receptor tyrosine kinase RET (rearranged during transfection) inhibitor is being developed by Loxo Oncology for the treatment of various cancers harbouring RET alterations Received its first approval on 8th May 2020 in the US Approved for use in adult patients with metastatic RET fusion-positive NSCLC, adult and paediatric patients ≥ 12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy and adult and paediatric patients ≥ 12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

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Section: Ret-altered Cancers In Paediatric Patientsmentioning

confidence: 98%

Selpercatinib: First Approval

Markham

2020

Drugs

107

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“…Selpercatinib has been shown to be active against intracranial metastases in a patient with RET fusion-positive thyroid cancer, 19 a patient with RET-mutant medullary thyroid cancer, 20 and a pediatric patient with RET fusion-positive congenital mesoblastic nephroma. 21 LIBRETTO-001 continues to enroll patients with non-lung/non-thyroid cancers that harbor RET fusions or mutations. Additional confirmation of the drug's activity in this setting will help establish the overall impact of selpercatinib on intracranial disease in patients with RET-dependent cancers of any histology in both adult and pediatric populations.…”

Section: Selpercatinib Safetymentioning

confidence: 99%

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial

Subbiah

Gainor

Oxnard

et al. 2021

Clinical Cancer Research

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We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the US for RET fusion-positive non-small cell lung cancers (NSCLCs). Methods:In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RETaltered solid tumors, selpercatinib was dosed orally (160mg twice/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 RET fusion-positive NSCLC patients 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.Results: Eighty NSCLC patients 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%CI=60-95), including 23% with complete responses. Among all intracranial responders (measurable and non-measurable, 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 to the full NSCLC trial population. Conclusion:Selpercatinib has robust and durable intracranial efficacy in RET fusion-positive NSCLC patients.Research.

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“…However, the addition of two FDA-approved treatments may provide value to select patients whose tumors harbor some actionable mutations. In patients harboring RET fusions, selective RET inhibition has already shown clinical benefit in case reports and the basket cohorts of the selective RET trials (65,66).…”

Section: Discussionmentioning

confidence: 99%

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

Adashek

Desai

Andreev-Drakhlin³

et al. 2021

Molecular Cancer Therapeutics

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Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers.Herein, we review the registrational data from the selective RETinhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRAS G12C inhibition.

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Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring RET Gene Alterations

Cited by 34 publications

References 31 publications

Selpercatinib: First Approval

Selpercatinib: First Approval

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

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