Selpercatinib Extends PFS in Advanced/Metastatic, RET-Mutant MTC


According to Marcia Brose, MD, PhD, FASCO, interim findings from the phase 3 LIBRETTO-531 trial confirms the benefit of selpercatinib in patients with advanced, RET-mutant medullary thyroid cancer.

Marcia S. Brose, MD, PhD, FASCO

Marcia S. Brose, MD, PhD, FASCO

Frontline treatment with selpercatinib (Retevmo) achieved a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when compared with physician’s choice of a multikinase inhibitor, in patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC).1

With this dimension of PFS benefit, the primary end point of the phase 3 LIBRETTO-531 study (NCT04211337) has been met per the prespecified interim efficacy analysis conducted by an independent data monitoring committee. Interim safety findings were consistent with prior data from the LIBRETTO-001 (NCT03157128), and other studies in the LIBRETTO program.

“This study is very important as it not only confirms that selpercatinib is active for patients with RET-mutant medullary thyroid cancer but shows that this treatment provides improved disease control compared to our prior therapies. This is very important data, and we look forward to the presentation of the full study results from this important trial in the near future, Marcia S. Brose, MD, PhD, FASCO, vice chair of Medical Oncology at The Sidney Kimmel Cancer Center (SKCC) and SKCC Regional Chief of Cancer Services at Jefferson Torresdale Hospital and lead United States investigator of LIBRETTO-531 told Targeted Oncology™.

LIBRETTO-531 is a multicenter, open-label, randomized, controlled, phase 3 study of selpercatinib vs cabozantinib (Cabometyx) or vandetanib (Caprelsa) in patients with advanced or metastatic MTC and RET mutations. The overarching goal of the study is to improve on efficacy and safety of treatment for advanced or metastatic, RET-mutant MTC. With the agents FDA approved for treatment of this patient population, cabozantinib and vandetanib, response rates range from 28% to 45%, and these agents showed a PFS of 7.2 months and 11.2 months, respectively. But the drugs also came with significant toxicity.1,2

Among patients treated with vandetanib and cabozantinib, the dose interruption rates were 35% and 79%, respectively. Further, discontinuation of treatment occurred in 12% of those treated with vandetanib and 16% of those who received cabozantinib. Experts, therefore, saw a need to develop RET-specific inhibitors and selpercatinib is 1 of the FDA-approved RET inhibitors for the treatment of advanced or metastatic RET fusion-positive solid tumors.

Image Credit: © SciePro - |  3D Rendered Medical Illustration of Male Anatomy - Thyroid Cancer.

3D Rendered Medical Illustration of Male Anatomy - Thyroid Cancer. | Image Credit: © SciePro - www.stock.adobe.con

The target enrollment for this study is 400 patients who will be evaluated for up to 30 months to determine the PFS benefit and the secondary end points of treatment-free survival, overall response rate, and duration of response. Overall survival, another secondary end point, will be evaluated for up to 60 months and PFS2 will be assessed for up to 48 months. Comparative tolerability and the concordance or local laboratory and the central laboratory RET results will also be evaluated during the study.3

Those eligible for enrollment are patients aged 12 years or older with histologically or cytologically confirmed disease, radiographic progression per RECIST v1.1 at screening, a RET gene alteration, ECOG performance status of 0 to 2 and adequate hematologic, hepatic, and renal function and electrolytes. The study excludes patients with any additional oncogenic drivers in MTC, and symptomatic central nervous system metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. The study also excludes patients with clinically significant active cardiovascular disease or history of myocardial infarction within 6 months, active uncontrolled systemic bacterial, viral, or fungal infection or another serious condition, and those with active hemorrhage or risk of serious hemorrhage or another malignancy.

LIBRETTO-531 is the largest clinical trial including patients with RET-driven cancers undergoing RET inhibitor treatment, according to Loxo Oncology, Inc. The positive interim analysis results were from 291 patients who received either 120 mg or 160 mg of selpercatinib twice daily until disease progression, or unacceptable toxicity.1

"These data from the LIBRETTO-531 trial confirm the importance of selectivity in targeting RET-driven cancers and suggest Retevmo should be considered the preferred first-line treatment for people with advanced RET-mutant medullary thyroid cancer," said David Hyman, MD, chief medical officer, Loxo Oncology at Eli Lilly and Company, in a press release. "Taken together with the recent positive Retevmo phase 3 LIBRETTO-431 [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."


1. Lilly's Retevmo® (selpercatinib) demonstrates superior progression-free survival compared to approved multikinase inhibitors in RET-mutant medullary thyroid cancer. News release. August 22, 2023. Accessed August 23, 2023.

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. A study of selpercatinib (LY3527723) in participants with RET-mutant medullary thyroid cancer (LIBRETTO-531). Updated July 17, 2023. Accessed August 22, 2023.

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