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First Randomized Phase III Trial Opens for Treatment-Naive RET Fusion-Positive NSCLC

Dylann Cohn-Emery
Published Online:7:00 PM, Fri December 27, 2019
Selpercatinib (LOXO-292) will be compared with the standard of care in the first ever phase III clinical trial in patients with advanced or metastatic treatment-naïve RET fusion-positive non–small cell lung cancer (NSCLC), according to a press release from Eli Lilly and Company.1

In the LIBRETTO-431 trial (NCT04194944), 400 patients will be randomized 1:1 to either selpercatinib or a platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without pembrolizumab (Keytruda). The primary end point is progression-free survival (PFS) and secondary end points are overall survival, overall response rate (ORR), duration of response, and intracranial ORR. Crossover will be allowed at progression for patients randomized to the control arm.

"Given the remarkable results of the LIBRETTO-001 trial, I am excited to open this important phase III trial of selpercatinib, a highly selective and potent molecule that has previously demonstrated sustained responses with a well-tolerated safety profile," Ben Solomon, MBBS, PhD, the principal investigator at the Peter MacCallum Cancer Centre in Melbourne, Australia, said in a statement. "This trial endeavors to generate outcome data that place patients with RET fusions alongside those with EGFR mutations and ALK fusions, as driver-positive populations that should be treated with targeted therapies in the first-line setting, rather than chemoimmunotherapy."

When treating patients with RET fusions and mutations, which occur across multiple tumor types, selpercatinib inhibits native RET signaling and anticipated acquired resistance mechanisms. Genomic alterations like fusions and activating point mutations in RET kinase lead to overactive RET signaling and uncontrolled cell growth. In 2% of NSCLC, RETfusions have been identified. Additionally, RET fusions have been identified in 10% to 20% of patients with papillary and other thyroid cancers, as well as a subset of other cancers.

Breakthrough designations in RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer (MTC), and RETfusion-positive thyroid cancers have been granted to selpercatinib. About 60% of MTC have activating RET point mutations. Tumors that are primarily dependent on single activated kinase for their proliferation and survival, such as those in patients with RET fusion-positive cancers and RET-mutant MTC, are highly susceptible to small molecule inhibitors targeting RET.

"This is an important milestone in the journey to further demonstrate the benefit of selpercatinib and the potential for people living with advanced or metastatic RET fusion-positive [NSCLC] in the first-line setting against the current standard of care," Anne White, the president of Lilly Oncology, said in a statement. "Launching a trial of this size underscores the importance of now including RET fusions in the paradigm of genomic testing in lung cancer."
Lilly opens first ever randomized phase 3 clinical trial in treatment-naïve RET fusion-positive non–small cell lung cancer [press release]. Indianapolis, IN: Eli Lilly and Company; December 11, 2019. https://investor.lilly.com/news-releases/news-release-details/lilly-opens-first-ever-randomized-phase-3-clinical-trial. Accessed December 19, 2019.

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