Vandetanib

On September 27, 2024, the Food and Drug Administration granted traditional approval to selpercatinib (Retevmo, Eli Lilly and Company) for adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy. Selpercatinib received accelerated approval for this indication for patients 12 years of age and older in 2020. On May 29, 2024, the FDA granted accelerated approval for this indication to pediatric patients 2 years of age and older. Efficacy was evaluated in LIBRETTO-531 (NCT04211337), a randomized, multicenter, open-label study in adults and adolescents with advanced or metastatic RET-mutant MTC. Patients were randomized (2:1) to receive either selpercatinib (160 mg twice daily) or physicians’ choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily). Patients were stratified based on RET mutation (M918T vs. other) and intended treatment if randomized to the control arm (cabozantinib vs. vandetanib). The main efficacy outcome measure was progression-free survival (PFS), as determined by a blinded independent review committee according to RECIST v1.1. Median PFS was not reached (NR) (95% CI: not evaluable [NE], NE) in the selpercatinib arm and 16.8 months (95% CI: 12.2, 25.1) in the cabozantinib/vandetanib arm (Hazard Ratio 0.280 [95% CI: 0.165, 0.475] p-value <0.0001). The clinical benefit of selpercatinib was supported by a pre-specified analysis of patient-reported comparative side effect impact; patients in the selpercatinib arm reported less time with severe side effect bother than those receiving cabozantinib or vandetanib. The most common adverse reactions (≥25%) were hypertension, edema, dry mouth, fatigue, and diarrhea. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased neutrophils, increased alkaline phosphatase (ALP), increased blood creatinine, decreased calcium, and increased aspartate aminotransferase (AST). The recommended selpercatinib dose for pediatric patients 2 to less than 12 years of age is based on body surface area and is based on weight for patients 12 years of age and older. See the prescribing information for specific dosing information. Expedited Programs This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted priority review, breakthrough designation, and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. Follow the Oncology Center of Excellence on X: @FDAOncologyExternal Link Disclaimer. Content current as of: 09/30/2024 Regulated Product(s) Drugs Content current as of: 09/30/2024 Regulated Product(s) Drugs Resources for Information | Approved Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description

On May 8, 2020, the Food and Drug Administration granted accelerated approval to selpercatinib (RETEVMO, Eli Lilly and Company) for the following indications: Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC); Adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; Adult and pediatric 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). Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001) in patients whose tumors had RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization. The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1. Efficacy for RET-fusion-positive NSCLC was evaluated in 105 adult patients, previously treated with platinum chemotherapy. The ORR was 64% (95% CI: 54%, 73%); 81% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 39 patients who never received systemic treatment. The ORR for these patients was 85% (95% CI: 70%, 94%); 58% of responding patients had responses lasting 6 months or longer. Efficacy for advanced or metastatic RET-mutant MTC was investigated in adults and pediatric patients (≥12 years of age). The trial enrolled patients previously treated with cabozantinib, vandetanib, or both, and patients who had not received these drugs. The ORR for the 55 previously treated patients was 69% (95% CI: 55%, 81%); 76% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 88 patients not previously treated with an approved therapy for MTC. The ORR for these patients was 73% (95% CI: 62%, 82%); 61% of responding patients had responses lasting 6 months or longer. Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients (≥12 years of age). The trial enrolled 19 patients who were radioactive iodine-refractory (if appropriate) and had received another prior systemic treatment, and 8 patients who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79% (95% CI: 54%, 94%); 87% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 8 patients who received RAI and no other subsequent therapy. All 8 patients responded (95% CI: 63%, 100%) and 75% had responses lasting 6 months or longer. The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase, increased alanine aminotransferase, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation. The recommended selpercatinib dose is weight based—120 mg for patients less than 50 kg, and 160 mg for those 50 kg or greater. Selpercatinib is taken orally twice daily with or without food; or with food when co-administered with a proton pump inhibitor. View full prescribing information for RETEVMO. This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was approved 3 months prior to the FDA goal date. This application was granted accelerated approval based on overall response rate and response duration. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials. This application was granted priority review, breakthrough therapy, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. For information on the COVID-19 pandemic, see the following resources: FDA: Coronavirus Disease 2019 (COVID-19) NCI: Coronavirus: What People With Cancer Should Know CDC: Coronavirus (COVID-19) Follow the Oncology Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer.