Goals in the Phase 1 Study of a New RET Inhibitor for NSCLC and MTC

Nathan A. Pennell, MD, PhD, co-director of the Cleveland Clinic Lung Cancer Program, vice chair of clinical research at the Taussig Cancer Center, and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses the study design and goals of an ongoing phase 1 trial (NCT05241834) of a novel RET inhibitor for patients with non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).

The first-in-human phase 1 trial of the selective RET inhibitor LOXO-260 consists of phase 1a and phase 1b parts. In the phase 1a part, patients with any solid tumors with a RET fusion or RET mutation were enrolled, the most common being NSCLC and MTC. Patients must have received a prior selective RET inhibitor such as selpercatinib (Retevmo) or pralsetinib (Gavreto) since LOXO-260 is intended to overcome resistance to prior RET inhibition.

The primary end point of the phase 1a study is to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) within the first 28 days of treatment and secondary end points include pharmacokinetics and overall response rate (ORR). The phase 1b dose expansion part will evaluate efficacy end points including ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DOR) as well as adverse events (AEs) related to treatment.

Pennell says that since this drug has never been tested clinically, its AE profile and efficacy are not yet known, and it is important to learn from the outcome of this trial.

TRANSCRIPTION:

0:08 | There's 2 parts of the trial: phase 1a and phase 1b. The initial phase 1a, which is open now, is for essentially any cancer that has a RET mutation or a RET gene fusion. Most of those will end up being [patients with lung cancer] because that's the most common type of cancer with RET fusions, or MTC or other types of thyroid cancer with RET mutations. They have to have incurable stage IV disease and then they have to have progressed after prior treatment with a selective RET inhibitor like selpercatinib or pralsetinib. So they have to have already received the most appropriate standard treatment, and then have moved on to needing another option.

0:57 | The main goal of the phase 1 study is to determine the MTD and the RP2D. Secondary end points include: What is the response rate in resistant patients? What is the PFS, OS, DOR, etc? What are all the [AEs] of the drug since it's a brand-new drug and we don't yet know?