First-Ever Phase 3 Clinical Trial in Treatment Naïve RET Fusion-Positive NSCLC

Dec 28, 2019 | Cancer, Eli Lilly, Melbourne, Oncology, Peter MacCallum Cancer Centre, RET Altered Cancers, Selpercatinib

First-Ever Phase 3 Clinical Trial in Treatment Naïve RET Fusion-Positive NSCLC

Eli Lilly recently reported that the commencement of its LIBRETTO-431 clinical trial [NCT04194944] for selpercatinib (LOXO-292) for treatment-naïve RET fusion-positive Non-Small Cell Lung Cancer (NSCLC) patients conducted in up to 158 clinical investigator sites including the Peter MacCallum Cancer Centre in Melbourne Australia.

The launch of this clinical trial was based on the positive results of the LIBRETTO-001 trial that demonstrated sustained responses with a well-tolerated safety profile. LIBRETTO-001 is a Phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with solid tumors; including RET-fusion positive solid tumors, Medullary Thyroid Cancer (MTC) and other tumors with RET activation.

What is RET Altered Cancers?

Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2 percent of non-small cell lung cancer, 10-20 percent of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60 percent of MTC. RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as “oncogene addiction,” renders such tumors highly susceptible to small molecule inhibitors targeting RET.

The Study

This most recent trial determines if the study drug selpercatinib (LOXO-292) compared to standard treatment is effective and safe in participants with rearranged during transfection (RET), fusion-positive, non-squamous, non-small cell lung cancer (NSCLC) that has spread to other parts of the body. Enrolled trial participants will be randomized 1:1 to receive either selpercatinib or platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without pembrolizumab as initial treatment of their advanced or metastatic RET fusion-positive NSCLC. RET fusions may be identified using local testing. The trial’s endpoint is Progression-Free Survival (PFS), and secondary endpoints include Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DoR), and Intracranial ORR. For patients randomized to the control arm, a crossover is allowed at progression. With up to 400 patients enrolled, it commenced this month and runs until April 2026.

What is Selpercatinib (LOXO-292)?

It is a highly selective and potent oral investigational new medicine in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms. Selpercatinib has received breakthrough designations in RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer (MTC), and RET fusion-positive thyroid cancers.

Clinical Investigator Comment

Professor Ben Solomon, the principal investigator at the Peter MacCallum Cancer Centre in Melbourne Australia, commented: “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 response with a well-tolerated safety profile.” He continued, “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.”

Lead Research/Investigator

Professor Ben Solomon, principal investigator at the Peter MacCallum Cancer Centre in Melbourne Australia

Call to Action: This study is being sponsored by Eli Lilly (Lilly Oncology). For more information, click here.

Source: Lilly

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