FDA Grants Traditional Approval to Selpercatinib for RET Fusion-Positive Solid Tumors Across Multiple Cancer Types

The FDA granted traditional approval to selpercatinib (Retevmo; Eli Lilly and Company) for the treatment of adult and pediatric patients aged 2 years and older with locally advanced or metastatic RET fusion-positive solid tumors that have progressed following prior systemic therapy or for whom no satisfactory alternative treatment options exist.

The decision converts the accelerated approval initially granted for adults in 2022 and expanded to pediatric patients in 2024 into full approval, reinforcing the role of precision oncology for patients with RET-driven malignancies across multiple tumor types.¹

Traditional Approval Expands Tissue-Agnostic Treatment Option

The approval is supported primarily by findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128), an open-label, multicenter study evaluating selpercatinib in patients with advanced RET-altered malignancies.^1,2 Unlike approvals limited to a single tumor type, this indication is tissue agnostic, meaning eligibility is determined by the presence of a RET gene fusion identified using an FDA-approved diagnostic test rather than the cancer's site of origin.¹

Among 75 patients with RET fusion-positive solid tumors other than non–small cell lung cancer (NSCLC) and thyroid cancer who had progressed after prior systemic therapy or lacked satisfactory treatment options, selpercatinib demonstrated an overall response rate (ORR) of 47% (95% CI, 35%-59%). The median duration of response (DOR) reached 24.5 months (95% CI, 11.2-49.1), highlighting the durability of responses observed across diverse malignancies.¹

Responses were reported in multiple tumor types, including colorectal cancer, pancreatic adenocarcinoma, cholangiocarcinoma, breast cancer, ovarian cancer, salivary gland tumors, soft tissue sarcoma, neuroendocrine tumors, bronchial carcinoid, carcinoma of unknown primary, skin carcinoma, and small intestine cancers.¹

Pediatric Data Further Support Approval

Additional evidence came from the phase 1/2 LIBRETTO-121 trial (NCT03899792), which evaluated selpercatinib in pediatric and young adult patients with advanced RET fusion-positive solid tumors that were refractory to available therapies or lacked curative treatment options.¹

Objective responses were observed in patients with congenital infantile fibrosarcoma, spindle cell sarcoma, and RET fusion-positive thyroid cancer, supporting the expansion of this precision therapy to pediatric patients aged 2 years and older.¹

The FDA noted that the application was reviewed using its voluntary Assessment Aid program and was approved approximately 2 months ahead of its target action date. Selpercatinib also retains orphan drug designation for its tissue-agnostic indication.¹

Clinical Evidence Demonstrates Durable RET Inhibition

Selpercatinib is a highly selective RET kinase inhibitor developed to target oncogenic RET alterations while minimizing off-target kinase inhibition.² Earlier findings from LIBRETTO-001 established its clinical benefit in RET fusion-positive NSCLC, where previously treated patients achieved an ORR of 64% and treatment-naïve patients achieved an ORR of 85%.

Durable responses and meaningful intracranial activity were also observed, supporting the drug's broader development across RET-driven cancers.³ These findings helped establish RET fusions as actionable therapeutic targets across multiple solid tumors.

Safety Profile and Dosing Considerations

The prescribing information includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity reactions, tumor lysis syndrome, impaired wound healing, hypothyroidism, embryo-fetal toxicity, and slipped capital femoral epiphysis/slipped upper femoral epiphysis in pediatric patients.¹

For adults and adolescents aged 12 years and older, the recommended dosage is weight based: patients weighing less than 50 kg should receive 120 mg orally twice daily, while those weighing at least 50 kg should receive 160 mg orally twice daily. Separate dosing recommendations are provided for children aged 2 to younger than 12 years in the full prescribing information.¹

The conversion from accelerated to traditional approval further solidifies selpercatinib's role as an important precision medicine option for patients with RET fusion-positive solid tumors, emphasizing the continued importance of comprehensive molecular testing to identify patients who may benefit from targeted therapy.

REFERENCES

1. FDA grants traditional approval to selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. Published July 14, 2026. Accessed July 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive

2. A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001). ClinicalTrials.gov. Updated April 4, 2026. Accessed July 14, 2026. https://clinicaltrials.gov/study/NCT03157128

3. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653