FDA Awards Traditional Approval to Selpercatinib for RET+ Advanced Solid Tumors

The FDA has granted traditional approval to selpercatinib (Retevmo) for the treatment of adult and pediatric patients 2 years and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.¹

The full approval follows accelerated approval for selpercatinib in the same indication in September 2022.²

Regular approval was supported by data from the phase 1/2 LIBRETTO-001 (NCT03157128) and LIBRETTO-121 (NCT03899792) trials, along with data from the agent’s use in patients with RET fusion–positive non–small cell lung cancer (NSCLC) and thyroid cancer.¹

In LIBRETTO-001, patients with RET fusion–positive tumors other than NSCLC and thyroid cancer (n = 75) achieved an overall response rate (ORR) of 47% (95% CI, 35%-59%) and a median duration of response (DOR) of 24.5 months (95% CI, 11.2-49.1).

Data from LIBRETTO-121 demonstrated that selpercatinib generated responses in 1 patient with congenital infantile fibrosarcoma, 1 patient with a spindle cell sarcoma, and patients with RET fusion–positive thyroid cancer.

Notably, selpercatinib previously received full approval in the following indications³:

• Adult patients with locally advanced or metastatic NSCLC with a RET fusion, as detected by an FDA-approved test
• Adult and pediatric patients 2 years and older with advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, who require systemic therapy
• Adult and pediatric patients 2 years and older with advanced or metastatic thyroid cancer with a RET fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate)

What was the design of the LIBRETTO-001 trial?

During phase 1 of the open-label, first-in-human study, investigators enrolled patients 12 years and older with locally advanced or metastatic solid tumors who experienced disease progression on or intolerance to standard therapy; did not have a standard therapy available; were not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, in the opinion of the investigator; or declined standard therapy.⁵ Notably, a RET alteration was not initially required, but once adequate pharmacokinetic exposure was achieved, evidence of a RET alteration in the tumor and/or blood was needed. Other key inclusion criteria for phase 1 included measurable or nonmeasurable disease per RECIST 1.1 or RANO criteria, based on tumor type; an ECOG performance status of 0 to 2 or a Lansky performance status of at least 40% for those younger than 16 years; and a life expectancy of at least 3 months.

In phase 2, patients in cohorts 1 and 2 were required ot have a RET alteration and at least 1 measurable lesion per RECIST 1.1 or RANO criteria. Patients in cohort 5 were not required to have measurable disease. Patients in cohort 6 were eligible if they received a prior RET inhibitor and met the criteria for cohorts 1, 2, and 5. Cohort 7 included patients with stage IB to IIIA NSCLC harboring a RET fusion. Notably, cohorts 3 and 4 were closed for enrollment.

After varying dose levels and schedules were evaluated in phase 1, patients in phase 2 received selpercatinib 160 mg twice per day in continuous 28-day cycles.

Determining the recommended phase 2 dose and maximum tolerated dose was the primary end point in phase 1. ORR was the primary end point in phase 2.

How was LIBRETTO-121 conducted?

LIBRETTO-121 was an open-label, multicenter study that evaluated selpercatinib in pediatric patients aged 6 months to 21 years with locally advanced or metastatic solid or primary central nervous system (CNS) tumors that progressed on standard-of-care therapies; evidence of an activating RET alteration in the tumor and/or blood was required.⁵

Measurable or nonmeasurable disease was permitted. Other key inclusion criteria comprised a Karnofsky (patients ≥ 16 years) or Lansky (patients < 16 years) performance score of at least 50, and adequate hematologic, hepatic, and renal function. Patients with primary CNS tumors or cerebral metastases needed to be neurologically stable for 7 days prior to enrollment and must not have required increasing doses of steroids within the past 7 days.

Patients were assigned based on tumor type, with cohort 1 including patients with medullary thyroid cancer, cohort 2 featuring patients with papillary thyroid cancer, and cohort 3 including those with other tumor types. Selpercatinib was administered at 160 mg twice per day in 28-day cycles in all cohorts, with treatment continuing until disease progression or unacceptable toxicity.

Dose-limiting toxicities marked the primary end point in phase 1, and ORR was the primary end point in phase 2.

What is the safety profile and recommended dosing for selpercatinib?

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

For patients 12 years of age or older, selpercatinib is recommended at 120 mg twice daily for patients weighing less than 50 kg and at 160 mg twice daily for patients weighing 50 kg or more.

For patients aged 2 to 11 years, the recommended dosages based on body surface area include³:

• 0.33-0.65 m²: 40 mg orally 3 times per day
• 0.66-1.08 m²: 80 mg orally 2 times per day
• 1.09-1.52 m²: 120 mg orally 2 times per day
• at least 1.53 m²: 160 mg orally 2 times per day

References

1. FDA grants traditional approval to selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. 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. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. September 21, 2022. Accessed July 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors
3. Retevemo. Prescribing information. Eli Lilly and Company; 2025. Accessed July 14, 2026. https://uspl.lilly.com/retevmo/retevmo.html#pi
4. A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). ClinicalTrials.gov. Updated April 16, 2026. Accessed July 14, 2026. https://clinicaltrials.gov/study/NCT03157128
5. A study of oral LOXO-292 (selpercatinib) in pediatric participants with advanced solid or primary central nervous system (CNS) tumors (LIBRETTO-121). ClinicalTrials.gov. Updated January 6, 2026. Accessed July 14, 2026. https://clinicaltrials.gov/study/NCT03899792