Phase IB/II study of alpelisib combined with paclitaxel in patients with PIK3CA-altered metastatic or recurrent gastric cancer.

This phase IB/II study assessed safety, pharmacokinetics, and efficacy of alpelisib, a selective PI3Kα inhibitor, plus weekly paclitaxel in patients with PIK3CA-altered metastatic or recurrent gastric cancer (GC). In phase IB, patients with advanced solid tumors received alpelisib 250 mg (dose level [DL] 0) or 300 mg (DL1) once daily plus paclitaxel 70 mg/m2 on Days 1, 8, and 15 every 4 weeks to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose (RP2D). In phase II, patients with PIK3CA-altered GC received RP2D, and the primary endpoint was 4-month progression-free survival (PFS). Subjects with diabetes or those with risk factors for diabetes who also had impaired glucose tolerance were excluded. Pharmacokinetic sampling was performed in phase IB at cycle 1, Days 1 (initial dose) and 8 (steady state). In phase IB, MTD was not reached; RP2D was established at DL1. Two patients developed DLTs at DL0 (grade 3 hyperglycemia, diarrhea, and fatigue) and DL1 (grade 3 hyponatremia). Toxicities were consistent with known PI3Kα inhibitor plus taxane combination profiles and were generally manageable. In phase II (n = 9), the 4-month PFS rate was 22.2%, and enrollment was discontinued early for futility; no objective responses were observed, and the median PFS was 2.6 months. Alpelisib exposure, assessed by Cmax and AUC0-24, was within expected ranges, and prior gastrectomy was associated with lower exposure. Alpelisib plus paclitaxel was tolerable and pharmacologically feasible with a defined RP2D but showed limited efficacy in PIK3CA-altered GC.