Assessment of gedatolisib (geda) pharmacokinetics (PK), drug-drug interactions (DDI), and exposure-safety and exposure-efficacy relationships.

Abstract

e13069 Background: Gedatolisib is a highly potent, multitarget PI3K/AKT/mTOR (PAM) inhibitor that targets all class I PI3K isoforms and both mTOR complexes, mTORC1 and mTORC2. Safety and efficacy have been demonstrated in adults with HR+/HER2- advanced breast cancer (ABC) after progression on/after CDK4/6 and aromatase inhibition. Because i n vitro studies demonstrate that geda inhibits CYP2C8, BCRP, and MATE1/2-K and is a substrate for P-gp, we conducted a two-part DDI study in healthy volunteers. We also performed exposure-response analyses using pooled PK, safety, and efficacy data from clinical trials, including the phase 3 VIKTORIA-1 study. Methods: Adults aged 18-55 years were eligible for PK/DDI study. In Part 1, single oral doses of repaglinide (0.5 mg; CYP2C8), rosuvastatin (5 mg; BCRP) and metformin (500 mg; MATE1/2-K) without geda, and after washout, with geda (180 mg) were administered. In Part 2, two single doses of geda (45 mg), without itraconazole (P-gp inhibitor), and after washout, with multiple itraconazole doses (200 mg/daily) were given. Serial PK samples were collected. Safety and tolerability were assessed based on AEs and clinical findings. For exposure analyses, geda concentrations from phase 3 (180 mg 3w on/1w off), FiH dose-escalation (10 to 319 mg qw) and Phase 1b (180 mg qw or 3w on/1w off) were pooled & analyzed by population PK methods to derive predicted estimates of C max , C min and cumulative Cycle 1 AUC. Clinical data from Phase 1b & Phase 3 were used for exposure-efficacy analysis. Safety endpoints were Gr ≥3 stomatitis/mucositis, any grade AE and Gr ≥3 AE causing dose reduction/withdrawal, and hyperglycemia, myelosuppression, GI AEs, rash and infusion reactions. Results: With concomitant geda + repaglinide, C max and AUC inf were 43.7% and 4.7% lower, respectively); geda + rosuvastatin, C max and AUC inf were 36.4% and 44.4% higher; geda + metformin, C max and AUC inf were 45.5% and 67.7% higher. With concomitant geda + itraconazole, C max and AUC inf were 17.3% and 1.4% lower. Geda was generally well tolerated, with TEAEs of mild-to-moderate severity. In exposure analyses, tumor size change and PFS stratified by quartiles of Cycle 1 geda PK parameters did not show clear or consistent relationship to exposure. In pts with stable or progressive disease or partial response, best overall response did not appear related to exposure. Logistic regression analysis of geda PK parameters did not show statistically significant and/or clinically relevant relationships between exposure and safety endpoints. Conclusions: Dose modification of CYP2C8, BCRP and MATE1/2-K substrates is not required when co-administered with geda, and geda dose modification is not required with P-gp inhibitors. Exposure-efficacy and exposure-safety assessments support the currently recommended geda dose of 180 mg administered in a 3w on/1w off regimen. Clinical trial information: NCT05501886 ; NCT00940498 ; NCT02684032 .