samotolisib (LY3023414)

Strategies under investigation include pro-oxidant therapies, ROS-sensitive drug delivery systems, ROS-activated agents, and targeted PAM inhibitors such as everolimus and dual-targeting compounds like samotolisib. ROS-mediated PAM signaling modulation provides a promising, mechanism-based therapeutic pathway for pLGG. Combinations of redox-targeted approaches with molecular characterization and current therapies have the potential to increase precision, efficacy, and safety, eventually leading to better survival and quality of life for the involved children.

P1, N=94, Terminated, Eli Lilly and Company | Phase classification: P1b --> P1 | Completed --> Terminated; The study was terminated due to business considerations

P2, N=180, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting | N=130 --> 180 | Trial completion date: Aug 2030 --> Aug 2031 | Trial primary completion date: Aug 2027 --> Aug 2028

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | N=2316 --> 1376 | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Jun 2025 --> Mar 2025

P1, N=198, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2024 --> Dec 2025

Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E-H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F. Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC.

P2, N=18, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Dec 2024

P2, N=2316, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2027 --> Jun 2025 | Trial primary completion date: Sep 2027 --> Jun 2025

P2, N=18, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P2, N=2316, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027

This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.