Regardless of Tumor Origin, Targeting RET Fusions: Selpercatinib Converts to Traditional Approval in the US

The way cancer treatment is classified is gradually expanding from “which organ the tumor grows in” to “which molecular abnormality drives it.” The US Food and Drug Administration (FDA) has converted the indication for selpercatinib (brand name Retevmo) in RET gene fusion-positive solid tumors from accelerated approval to traditional approval, providing more complete evidence of clinical benefit for this tumor-agnostic treatment pathway.

The approval covers adults and children aged two years and older. Patients must have locally advanced or metastatic RET fusion-positive solid tumors whose disease has progressed following systemic treatment, or have no satisfactory alternative treatment options; the RET fusion must also be confirmed by an FDA-approved test. The adult indication received accelerated approval in 2022, and children aged two years and older were added in 2024. Both have now been converted to traditional approval.

The primary evidence of tumor-agnostic efficacy came from the multicenter, open-label, phase 1/2 LIBRETTO-001 trial. The analysis included 75 patients with RET fusion-positive tumors other than lung and thyroid cancers. The objective response rate was 47%, with a 95% confidence interval of 35% to 59%. The median duration of response reached 24.5 months, but its confidence interval ranged from 11.2 to 49.1 months, indicating that the estimate still carries considerable uncertainty.

Treatment responses were not concentrated in a single organ but were observed across multiple tumor types, including colorectal cancer, pancreatic adenocarcinoma, salivary gland cancer, cholangiocarcinoma, breast cancer, ovarian cancer, small intestinal cancer, skin cancer, soft tissue sarcoma, bronchial carcinoid, neuroendocrine tumors, and cancers of unknown primary origin. This dispersed yet directionally consistent signal lies at the heart of “tumor-agnostic” approval: eligibility for treatment is determined by a shared driver alteration rather than the organ in which the cancer originated.

Supporting data for pediatric and young patients came from the open-label LIBRETTO-121 trial. The FDA noted that responses had been observed in patients with congenital infantile fibrosarcoma, spindle cell sarcoma, and RET fusion-positive thyroid cancer. However, the tumor-agnostic and pediatric populations were each limited in size, and the primary evidence also came from trials without randomized control groups. Therefore, the 47% response rate cannot be directly interpreted as a survival advantage over other treatments, and the effects in different rare cancer types are also difficult to estimate precisely on an individual basis.

Traditional approval does not mean that the risks have disappeared. Warnings in the drug labeling cover hepatotoxicity, interstitial lung disease or pneumonitis, hypertension, QT interval prolongation, hemorrhage, hypersensitivity reactions, tumor lysis syndrome, impaired wound healing, hypothyroidism, and embryo-fetal toxicity; slipped capital femoral epiphysis also requires attention in children. This regulatory conversion reinforces the clinical value of RET fusion testing while also highlighting the reality facing precision treatment for rare molecular subgroups: evidence can be accumulated across organ-based classifications, but long-term follow-up and more granular data by cancer type are still needed to define who truly benefits.