FDA Grants Full Approval to Selpercatinib for RET+ Thyroid Cancer

FDA

The FDA has granted full approval to selpercatinib (Retevmo) for the treatment of adult and pediatric patients at least 2 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI) refractory, if RAI is appropriate.¹

Selpercatinib received accelerated approval in the same indication in May 2020.²

The FDA's full approval was supported by data from the phase 1/2 LIBRETTO-001 trial (NCT03157128), which showed that patients who received prior treatment (n = 41) achieved an overall response rate (ORR) of 85% (95% CI, 71%-94%), and patients who were naive to systemic therapy (n = 24) experienced an ORR of 96% (95% CI, 79%-100%). Previously treated patients had a median duration of response (DOR) of 26.7 months (95% CI, 12.1–not evaluable [NE]), and systemic therapy–naive patients had a median DOR that was NE (95% CI, 42.8-NE).¹

The full approval was also supported by efficacy data from 10 pediatric and young adult patients with thyroid cancer harboring RET fusions who were treated with selpercatinib during the phase 1/2 LIBRETTO-121 trial (NCT03899792), which evaluated the agent in pediatric and young adult patients with advanced RET-altered solid tumors. These 10 patients experienced an ORR of 60% (95% CI, 26%-88%), and 83% of responders experienced a DOR of at least 12 months.

The most common adverse effects reported in at least 25% of patients treated with selpercatinib included edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common grade 3/4 laboratory abnormalities that occurred in at least 5% of patients consisted of decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, decreased sodium, and decreased calcium.

The recommended dose of selpercatinib is based on body surface area for pediatric patients at least years 2 and less than 12 years of age. For patients 12 years of age and older, the recommended dosage is based on body weight.

LIBRETTO-001

The ongoing, single-group, open-label basket trial is enrolling patients at least 18 years of age (or at least 12 years of age where permitted by regulatory authorities) with RET-altered cancers.³ The study included patients with RET-mutant medullary thyroid cancer with or without previous treatment with vandetanib (Caprelsa) or cabozantinib (Cabometyx), as well as patients with previously treated RET fusion–positive thyroid cancer.⁴

Patients with thyroid cancer had to be in need of systemic therapy, and a prospectively identified RET fusion or mutation was required, per local testing. Other key inclusion criteria included an ECOG performance status of 0 to 2; adequate organ function; and a corrected QT interval of no more than 470 msec.

During the phase 1 dose-escalation portion of the study, selpercatinib was administered at doses ranging from 20 mg once per day to 240 mg twice per day. In phase 2, the recommended dose of 160 mg twice per day was given. Notably, patients were allowed to continue treatment with selpercatinib after documented disease progression if they were receiving clinical benefit.

ORR per RECIST 1.1 criteria as assessed by blinded independent central review served as the trial's primary end point. Secondary end points included progression-free survival (PFS), DOR, and safety.

Additional data showed patients with RET fusion–positive thyroid cancer experienced a 1-year PFS rate of 64% (95% CI, 37%-82%).

LIBRETTO-121

The open-label, multicenter study evaluated selpercatinib in pediatric patients 6 months to 21 years of age with advanced or metastatic solid or primary central nervous system (CNS) tumors harboring activating RET alterations that progressed following standard-of-care therapies.

Other key inclusion criteria consisted of a Karnofsky performance status of at least 50 for patients 16 years of age or older, or a Lansky performance status of at least 50 in those under 16 years of age; and adequate hematologic, hepatic, and renal function. Notably, patients with with primary CNS tumors or cerebral metastases were required to be neurologically stable for 7 days prior to first study treatment, and they must not have required increasing doses of steroids within 7 days of enrollment.

Patients received escalating doses of selpercatinib during phase 1 to help determine the maximum tolerated dose (MTD), and patients treated in phase 2 were given selpercatinib at the MTD or recommended dose.

Safety was the primary end point of phase 1, and ORR was phase 2's primary end point. Secondary end points included pharmacokinetics and preliminary antitumor activity in phase 1. In phase 2, secondary end points were DOR, PFS, overall survival, clinical benefit rate, and safety.

References

1. FDA approves selpercatinib for RET fusion-positive thyroid cancer. FDA. June 12, 2024. Accessed June 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-ret-fusion-positive-thyroid-cancer
2. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. May 8, 2020. Accessed June 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions
3. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1
4. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651
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 March 7, 2024. Accessed June 12, 2024. https://clinicaltrials.gov/study/NCT03899792