Selpercatinib Significantly Improves PFS Over MKIs in RET-Mutant Medullary Thyroid Cancer

David Hyman, MD

Selpercatinib (Retevmo) demonstrated a statistically significant improvement in progression-free survival (PFS) vs physician’s choice of cabozantinib (Cabometyx) or vandetanib (Caprelsa) in patients with advanced or metastatic RET-mutant medullary thyroid cancer, meeting the primary end point of the phase 3 LIBRETTO-531 trial (NCT04211337).¹

The topline data were collected from a prespecified interim efficacy analysis that was performed by an independent data monitoring committee.

The safety profile observed with the agent proved to align with what has previously been reported. The labeling for selpercatinib includes warnings and precautions regarding hepatotoxicity, interstitial lung disease or pneumonitis, QT interval prolongation, hypersensitivity, tumor lysis syndrome, hemorrhagic events, risk of hindered wound healing, hypothyroidism, and embryo-fetal toxicity.

Full data from LIBRETTO-531 will be shared at an upcoming conference, submitted for publication in a peer-reviewed journal, and presented to health authorities, according to Eli Lilly and Company.

“These data from the LIBRETTO-531 trial confirm the importance of selectively targeting RET-driven cancers and suggest [selpercatinib] should be considered the preferred first-line treatment for people with advanced RET-mutant medullary thyroid cancer,” David Hyman, MD, chief medical officer at Loxo Oncology at Eli Lilly and Company, stated in a press release.

It is known that the clinical course of medullary thyroid cancer is very heterogeneous, and frontline management is dependent on clinical presentation.² Although for some patients who have localized disease can be cured with surgery, about half of patients will experience disease recurrence. Metastatic disease continues to be incurable.

The multikinase inhibitors (MKIs) cabozantinib and vandetanib have been approved for use in patients with advanced medullary thyroid cancer, irrespective of RET mutational status. However, the efficacy of these drugs has been limited by incomplete RET inhibition, off-target toxicity, and poor pharmacokinetics. To fill this need, selective RET inhibitors like selpercatinib and pralsetinib (Gavreto) have been developed.

A first-in-class, highly selective RET kinase inhibitor, selpercatinib has showcased nanomolar potency against RET alterations and wild-type RET, including certain mutations that have been linked with resistance to MKIs. In May 2020, selpercatinib was granted accelerated approval from the FDA for use in patients with RETalteration–positive non–small cell lung cancer, medullary thyroid cancer, and other thyroid cancers.³

Data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) showed that selpercatinib elicited an objective response rate (ORR) of 69% (95% CI, 61%-77%) by blinded independent central review (BICR) assessment in those who had prior exposure to cabozantinib and/or vandetanib (n = 143).2 In those who were not previously treated with the MKIs (n = 112), selpercatinib induced an ORR of 71% (95% CI, 62%-80%) by BICR.

The multicenter, open-label, controlled, phase 3 LIBRETTO-531 trial enrolled 291 patients with progressive, advanced MKI-naïve, RET-mutant medullary thyroid cancer. To be eligible for enrollment, patients needed to be at least 12 years of age, have documented disease progression within 14 months of study treatment, measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and acceptable organ function.

If patients had an additional validated oncogenic driver, symptomatic central nervous system metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression, they were excluded. They also could not have active cardiovascular disease or a history of myocardial infarction within 6 months before study treatment initiation. They could not have previously received kinase inhibitors, and they could not concomitantly receive an agent that is known to cause QTc prolongation.

Study participants were randomly assigned 2:1 to receive selpercatinib at 160 mg twice daily or physician’s choice of cabozantinib at 140 mg daily or vandetanib at 300 mg once daily as initial treatment for advanced disease. Treatment continued until progressive disease, intolerable toxicity, start of a new anticancer therapy, withdrawn consent, death, or study completion.

Key stratification factors included mutational status (M918T vs other), investigator’s choice of treatment if assigned to physician’s choice arm (cabozantinib vs vandetanib). Upon radiographic progression, patients could potentially crossover to receive selpercatinib if they meet select criteria.

In addition to the primary objective of the trial being PFS by RECIST v1.1 criteria, a key secondary end point is treatment failure-free survival, ORR, duration of response, overall survival, safety, and tolerability.

Recently, selpercatinib was found to improve PFS compared with platinum-based chemotherapy plus pemetrexed and pembrolizumab (Keytruda) in patients with advanced or metastatic RET-positive non–small cell lung cancer, meeting the primary end point of the phase 3 LIBRETTO-431 trial (NCT04194944).4 Full data will also be shared at an upcoming medical conference and be discussed with health authorities.

“Taken together with the recent positive [selpercatinib] phase 3 LIBRETTO-431 announcement in lung cancer, these results underscore the importance of timely and broad-based genomic testing to ensure patients who could potentially benefit receive targeted therapies,” Hyman added in the press release. “We look forward to sharing detailed data with the oncology community.”

References

1. Lilly’s Retevmo (selpercatinib) demonstrates superior progression-free survival compared to approved multikinase inhibitors in RET-mutant medullary thyroid cancer. News release. Eli Lilly and Company. August 22, 2023. Accessed August 22, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-retevmor-selpercatinib-demonstrates-superior-progression
2. Wirth LJ, Brose MS, Elisei R, et al. LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor–naïve RET-mutant medullary thyroid cancer. Future Oncol. 2022;18(28):3143-3150. doi:10.2217/fon-2022-0657
3. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. FDA. May 8, 2020. Accessed August 22, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-patients-lung-and-thyroid-cancers-certain-genetic-mutation-or-fusion
4. Lilly’s Retevmo (selpercatinib) is the first targeted therapy to demonstrate superior progression-free survival compared to a PD-1 inhibitor plus chemotherapy for adults with newly-diagnosed advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. Eli Lilly and Company. August 4, 2023. Accessed August 22, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-retevmor-selpercatinib-first-targeted-therapy-demonstrate