Background: Despite advances in the treatment of advanced GEP NETs, long‐term disease control remains a challenge. Overexpression and altered regulation of cyclin-dependent kinases (CDK) 4 and 6 have been observed in multiple subtypes of GEP NETs. Preclinical studies have demonstrated that the CDK 4/6 inhibitor palbociclib reduces growth of pancreatic NET cell lines and levels of phosphorylated retinoblastoma protein in vitro. Moreover, the drug significantly inhibited tumor growth in vivo in pancreatic NET xenograft models. Abemaciclib is a selective small molecule CDK 4/6 inhibitor, approved for the treatment of HR+ HER2– metastatic breast cancer. Clinical activity and central nervous system penetration of the drug have been observed in several tumor types in clinical trials, including partial response in one pt with metastatic small intestinal NET. We have developed a Phase 2 trial of abemaciclib in GEP NETs to evaluate its efficacy and safety in these rare cancers. Methods: This is an investigator-initiated non-randomized phase 2 trial using a two-stage design. Eligible pts have metastatic or locally advanced unresectable well-differentiated grade 1-2 GEP NETs, ECOG PS 0-2, and must have progressed on at least one line of systemic therapy. Prior or concurrent treatment with somatostatin analogs is allowed,. Abemaciclib is administered at a dose of 200 mg orally every 12 hours continuously in 28-day cycles. Dose reductions for toxicities are allowed to level -1 (150 mg) and -2 (100 mg). Primary endpoint is objective response rate (ORR) by RECIST v1.1. Secondary endpoints include progression free survival (PFS), overall survival (OS), and toxicity. A two‐stage design with 88% power to detect an increase in ORR to 20% with abemaciclib at the 1‐sided 0.05 level would require a total of 37 patients. Stage 1 will include 20 patients, and if one response is seen among these patients, the study will continue to enroll another 17 patients. The trial was activated in January 2020, and 3 patients have been enrolled to date. Available archival tumor tissue and molecular profiling data are collected for future correlative studies including assessment of response biomarkers.

Eli Lilly.