On May 8, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to selpercatinib (Retevmo™) for adult patients with metastatic, RET fusion–positive non-small cell lung cancer (NSCLC); adult and pediatric patients aged 12 or older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and adult and pediatric patients aged 12 or older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are refractory to radioactive iodine (if radioactive iodine is appropriate). This is the first drug approval for RET genetic alterations.
Efficacy was investigated in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001) in patients whose tumors had RET alterations. The alterations were prospectively identified 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 response evaluation criteria in solid tumors 1.1.
Efficacy for RET fusion–positive NSCLC was evaluated in 105 adult patients previously treated with platinum chemotherapy. ORR was 64% (95% CI = 54%, 73%) and 81% of patients had responses lasting six months or longer. Efficacy was also evaluated in 39 patients who had never received systemic treatment, where ORR was 85% (95% CI = 70%, 94%) and 58% of responding patients had responses lasting six months or longer.
Efficacy for advanced or metastatic RET-mutant MTC was investigated in adult and pediatric patients. The trial enrolled patients previously treated with cabozantinib, vandetanib, or both and patients who had not received either of the drugs. ORR for the 55 previously treated patients was 69% (95% CI = 55%, 81%), and 76% of the cohort had responses lasting six months or longer. Efficacy was also evaluated in 88 patients not previously treated with an approved therapy for MTC, where ORR was 73% (95% CI = 62%, 82%) and 61% had responses lasting six months or longer.
Efficacy for RET fusion–positive thyroid cancer was evaluated in adult and pediatric patients. The trial enrolled 19 patients who were refractory to radioactive iodine (if the therapy was appropriate) and had received another prior systemic treatment and eight patients who were refractory to radioactive iodine and had not received any additional therapy. ORR for the 19 previously treated patients was 79% (95% CI = 54%, 94%), and 87% of responding patients had responses lasting six months or longer. Efficacy was also evaluated in eight patients who received radioactive iodine and no other subsequent therapy, where all patients responded (95% CI = 63%, 100%) and 75% had responses lasting six months or longer.
The most common adverse reactions (≥ 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 coadministered with a proton pump inhibitor.
The review used Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The agency approved the application three months ahead of its goal date.
Selpercatinib was granted accelerated approval based on ORR and response duration. Continued approval may be contingent on verification of clinical benefit in confirmatory trials.
The application was also 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 800-FDA-1088.
For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.