The US FDA has granted traditional approval to Retevmo (selpercatinib) for adult and pediatric patients aged two and older with locally advanced or metastatic solid tumors harboring a RET gene fusion — converting an accelerated approval first granted in 2022 into a full regulatory endorsement backed by confirmatory efficacy data. For Eli Lilly and Company, the conversion completes a regulatory arc that began with selpercatinib’s initial 2020 approval in RET-altered lung and thyroid cancers and extends the drug’s reach across a molecularly defined, histology-agnostic patient population spanning more than a dozen tumor types.
The indication requires RET gene fusion detection by an FDA-approved test, and covers patients who have progressed on prior systemic therapy or for whom no satisfactory alternative treatment exists. Dosing is weight-based and oral: patients under 50 kg receive 120 mg twice daily, while those 50 kg or above receive 160 mg twice daily, with separate pediatric dosing for children aged two to under 12. Selpercatinib carries orphan drug designation for the tissue-agnostic indication. The FDA approved the application two months ahead of its goal date.
Selpercatinib is a selective, ATP-competitive small molecule inhibitor of the RET receptor tyrosine kinase, designed to suppress oncogenic signaling driven by RET gene fusions and activating RET point mutations. Unlike earlier multikinase inhibitors such as cabozantinib and vandetanib, which incidentally inhibit RET among numerous other kinase targets, selpercatinib was engineered for high RET selectivity, reducing off-target toxicity while retaining activity against resistance mutations including RET V804L and V804M.
Efficacy supporting the traditional approval was evaluated in LIBRETTO-001 (NCT03157128), a multicenter, open-label, multi-cohort Phase I/II trial. The confirmatory analysis focused on 75 patients with RET fusion-positive tumors other than non-small cell lung cancer (NSCLC) and thyroid cancer with the overall evidence package supported by established efficacy in RET fusion-positive NSCLC and thyroid cancer. The primary efficacy measures were overall response rate (ORR) and duration of response (DOR). ORR was 47% (95% CI: 35, 59), with a median DOR of 24.5 months (95% CI: 11.2, 49.1). Tumor types demonstrating responses included colorectal, pancreatic adenocarcinoma, salivary gland, soft tissue sarcoma, cholangiocarcinoma, skin carcinoma, breast, ovarian, bronchial carcinoid, small intestine, and neuroendocrine tumors, among others. Pediatric efficacy was evaluated separately in LIBRETTO-121 (NCT03899792), with responses observed in patients with congenital infantile fibrosarcoma, spindle cell sarcoma, and RET fusion-positive thyroid cancer.