Selpercatinib Improves Outcomes in RET Mutation–Positive Medullary Thyroid Cancer

Madrid, Spain—Treatment with selpercatinib (Retevmo), a highly selective and potent RET inhibitor, resulted in a statistically significant improvement in progression-free survival (PFS) compared with the multikinase inhibitors cabozantinib (Cabometyx) or vandetanib (Caprelsa) in the first-line treatment of patients with advanced or metastatic RET mutation–positive medullary thyroid cancer (MTC). In addition to prolonged PFS, patients in the selpercatinib arm experienced prolonged treatment failure-free survival (TFFS) and a favorable safety profile compared with those in the control arm. The findings, which were collected from a prespecified interim efficacy analysis of the phase 3 LIBRETTO-531 clinical trial, were presented during the European Society for Medical Oncology Congress 2023,¹ and also published in the New England Journal of Medicine.²

“These results, therefore, support selpercatinib as the first-line standard of care for patients with advanced RET-mutant [MTC],” said Julien Hadoux, MD, PhD, Medical Oncologist and Attending Physician, Institut de Cancérologie Gustave Roussy, Villejuif, France, and lead investigator of LIBRETTO-531.

The study also highlighted the importance of implementation of early biomarker testing for patients with metastatic MTC.

“RET mutations are found in nearly all hereditary MTC and in up to 90% of sporadic cases, especially at the metastatic stage,” Dr Hadoux said. Cabozantinib and vandetanib, 2 multikinase inhibitors, have already been approved for use in patients with advanced MTC, irrespective of RET mutational status. The efficacy of these agents, however, has been limited by incomplete RET inhibition, off-target toxicity, and poor pharmacokinetics, he added.

Study Details

In the phase 3, international, multicenter, open-label, LIBRETTO-531 trial, 291 patients with advanced RET mutation–positive MTC were randomized in a 2:1 ratio to receive selpercatinib 160 mg twice daily (n=193), or physician’s choice (n=98) of cabozantinib 140 mg/day (n=71) or vandetanib 300 mg/day (n=27). Eligible patients had a documented history of disease progression without prior exposure to a kinase inhibitor within 14 months of enrollment, measurable disease by RECIST version 1.1 criteria, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and acceptable organ function.

The median age between both arms was 54.6 years, and approximately one-fourth of patients were aged ≥65 years. Most patients were male (64.5%), White (68.7%), and had an ECOG performance status of 0 (59.7%). Almost two-thirds (62.5%) had a RET M918T mutation, the most common mutation found in sporadic MTC, noted Dr Hadoux. The median time from diagnosis to study enrollment was 42.7 months in the selpercatinib arm and 61.6 months in the control arm.

Crossover to selpercatinib was permitted after disease progression for patients in the control arm. The primary end point of the study was PFS on blinded independent central review (BICR). Secondary end points included TFFS by BICR and investigator, investigator-assessed PFS, overall survival (OS) by BICR and investigator assessment, and safety.

Results

At a median follow-up of 12 months, median PFS was not reached with selpercatinib and was 16.8 months with physician’s choice of cabozantinib or vandetanib (hazard ratio [HR], 0.280; 95% confidence interval [CI], 0.165-0.475; P<.0001). TFFS was defined as the time from randomization to the first occurrence of progressive disease assessed, discontinuation due to treatment-related adverse event (AE), both assessed by BICR, or death. The median TFFS by BICR was not reached with selpercatinib (95% CI, not estimable-not estimable) compared with 13.9 months (95% CI, 11.3-25.1) with cabozantinib or vandetanib (HR, 0.254; P<.0001). When assessed by investigator, the TFFS advantage with selpercatinib was similarly robust (HR, 0.157; P<.0001).

These results, therefore, support selpercatinib as the first-line standard of care for patients with advanced RET-mutant [MTC].

—Julien Hadoux, MD, PhD

At a median follow-up of 15 months, there were 8 deaths in the selpercatinib arm versus 10 in the control arm, and 94.8% and 85.7% of patients, respectively, were still alive. Although OS data are immature due to a censoring rate of 90%, OS favored selpercatinib (HR, 0.374; P=.0312). Of the 24 patients who crossed over to selpercatinib, 19 remained on treatment as of data cutoff.

Grade ≥3 treatment-emergent AEs occurred in 52.8% and 76.3% of patients assigned to selpercatinib and cabozantinib or vandetanib, respectively. The most common grade ≥3 treatment-emergent AEs in patients on selpercatinib were hypertension (19%), an increase in the level of alanine aminotransferase (10%), an increase in the level of aspartate aminotransferase (5%), fatigue (4%), and diarrhea (3%). In the control arms, the most common grade ≥3 treatment-emergent AEs were hypertension (18%), mucosal inflammation (13%), palmar-plantar erythrodysesthesia syndrome (9%), and diarrhea (8%).

Permanent treatment discontinuation due to AEs occurred in 4.7% of patients in the selpercatinib arm compared with 26.8% in the control arm. Fatal AEs occurred in 2.1% of patients in each arm.

In May 2020, the FDA granted accelerated approval to selpercatinib for the treatment of patients with metastatic RET fusion–positive non–small cell lung cancer, MTC, and other thyroid cancers.³

References

1. Hadoux J, Elisei R, Brose MS, et al. Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer. Ann Oncol. 2023;34(suppl 2):S1338. Abstract book of the ESMO Congress 2023. doi:10.1016/j.annonc.2023.10.103
2. Hadoux J, Elisei R, Brose MS, et al; for the LIBRETTO-531 Trial Investigators. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389:1851-1861.
3. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. U.S. Food and Drug Administration. May 8, 2020. Accessed November 15, 2023. www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-patients-lung-and-thyroid-cancers-certain-genetic-mutation-or-fusion