Selpercatinib Elicits Notable PFS Benefit in RET+ Medullary Thyroid Cancer

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Positive data from a prespecified interim efficacy analysis of the phase 3 LIBRETTO-531 trial support selpercatinib as a potential treatment in advanced, RET-mutant medullary thyroid cancer.

The open label, randomized phase 3 LIBRETTO-531 study (NCT04211337) is the first trial to assess the safety and efficacy of treating patients with RET-mutated medullary thyroid cancer with a highly selective RET kinase inhibitor compared with a multikinase inhibitor.

The open label, randomized phase 3 LIBRETTO-531 study (NCT04211337) is the first trial to assess the safety and efficacy of treating patients with RET-mutated medullary thyroid cancer with a highly selective RET kinase inhibitor compared with a multikinase inhibitor.

Initial treatment with selpercatinib (Retevmo) resulted in a statistically significant and clinically meaningful progression-free survival (PFS) benefit over physician’s choice of multikinase inhibitor—cabozantinib or vandetanib (Caprelsa)—in a population of patients with advanced or metastatic RET-mutated medullary thyroid cancer, according to a press release on topline data from the phase 3 LIBRETTO-531 study (NCT04211337).

These findings, which met the trial’s primary end point of PFS, came from a prespecified interim efficacy analysis that was performed via an independent data monitoring committee. In terms of safety, investigators reported that adverse effects aligned with those reported in prior studies, including the phase 1/2 LIBRETTO-001 (NCT03157128), phase 1/2 LIBRETTO-121 (NCT03899792), and phase 2 LIBRETTO-321 (NCT04280081) studies.

The agent’s warning label details the possibility of hepatotoxicity, interstitial lung disease, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, chance of impaired wound healing, hypothyroidism, and embryo-fetal toxicity following treatment.

Full trial results are set to read out at an upcoming medical meeting, and investigators will submit them to a peer-reviewed journal and health authorities.

“These data from the LIBRETTO-531 trial confirm the importance of selectivity in 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@Lilly, said in the press release. “Taken together with the recent positive [selpercatinib] phase 3 LIBRETTO-431 trial [NCT04194944] 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. We look forward to sharing detailed data with the oncology community.”

The open label, randomized LIBRETTO-531 study is the first trial to assess the safety and efficacy of treating patients within this indication with a highly selective RET kinase inhibitor compared with a multikinase inhibitor. Patients who enrolled on the trial (n = 291) were randomly assigned 2:1 to either the selpercatinib arm or the physician’s choice arm.

Secondary end points for the study include treatment failure–free survival, overall response rate, duration of response, overall survival, PFS2, and comparative tolerability.

To be included in the study, patients needed to be 18 years or older with histologically or cytologically confirmed unresectable, locally advanced and/or metastatic medullary thyroid cancer, and had undergone no prior treatment with a kinase inhibitor for advanced/metastatic disease. At screening, patients also needed to have evidence of radiographic disease progression via RECIST 1.1 criteria that could be compared with imaging from 14 months prior.

Additional inclusion criteria included having a RET gene alteration, an ECOG performance status of 0 to 2, an ability to swallow capsules, as well as adequate hematologic, hepatic, and renal function.

Patients who had an additional validated oncogenic driver in MTC were excluded from the trial, as this could have resulted in resistance to selpercatinib. Those with symptomatic central nervous system metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression were also unable to enroll. Other exclusion criteria included active or uncontrolled bacterial, viral, or fungal infections; active or significant risk of hemorrhage; or any other malignancy with the exception of inactive nonmelanoma skin cancer in-situ that was diagnosed 2 years or more prior to study enrollment.

Reference

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://bit.ly/3KRVgKd

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