Results of a phase I study of alpelisib and sacituzumab govitecan (SG) in patients with HER2-negative metastatic breast cancer (MBC).

Abstract

1094 Background: Sacituzumab govitecan (TROP2-directed antibody drug conjugate, ADC) is effective in treatment of pretreated HER2-negative MBC. PI3K is the most frequently altered pathway in breast cancer. This phase I trial investigated the combination of SG plus alpelisib (oral α-specific PI3K inhibitor) in HER2-negative MBC. Methods: Eligible patients had HER2-negative MBC and had received ≥1 prior line of chemotherapy in the advanced or neo/adjuvant setting and had not received prior PI3K/AKT inhibitor. The study was 3+3 dose escalation design: dose level 1: alpelisib 250 mg+SG 8 mg/kg; dose level 2: alpelisib 250 mg+SG 10 mg/kg; dose level 3: alpelisib 300 mg+SG 10 mg/kg. Alpelisib was dosed PO daily and SG IV, D1 and 8 every 21 days. Antidiarrheal prophylaxis was utilized for the first two cycles. Primary endpoint was recommended phase 2 dose (RP2D). Additional endpoints included adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and pharmacokinetics. Results: 12 patients were enrolled between 2022-2024 (dose level 1: N = 3, dose level 2: N = 6, dose level 3: N = 3). 7/12 (58%) had triple-negative breast cancer (TNBC), and 5/12 (42%) had hormone receptor (HR)-positive disease. All patients had visceral disease. 8/12 (67%) had ≥1 prior metastatic chemotherapy; 4/12 (33%) had prior immunotherapy; 3/12 (25%) had prior ADC. One dose-limiting toxicity (hyperbilirubinemia) was observed at dose level 2. RP2D was alpelisib 300 mg + SG 10 mg/kg. The most frequent grade ≥3 treatment-related AEs were electrolyte imbalance (G3 17%, G4 17%), neutropenia (G3 33%, G4 0%), diarrhea (G3 17%, G4 0%), and hyperglycemia (G3 8%, G4 8%). There were no G5 AEs. Pharmacokinetics of SG and its metabolites were consistent with previous reports. Among 11 patients evaluable for response, ORR was 36% (4/11) (complete response [CR] = 1, partial response [PR] = 3) and clinical benefit rate (CR + PR + stable disease > 24 weeks) was 64% (7/11). ORR in TNBC was 50% and in HR-positive disease was 20%. Among patients with prior ADC, ORR was 33% and clinical benefit rate was 67%. Three of four patients with ORR had response lasting > 6 months, with median duration of response of 14.9 (range 3.2 to 28.1) months. Median PFS was 5.7 months. Tumor and serial ctDNA analysis are ongoing. Conclusions: Combination of SG + alpelisib was feasible, with manageable side effects. The toxicity profile of the combination was consistent with the known safety profiles of the two agents. This combination demonstrated encouraging efficacy in HER2-negative MBC, with prolonged duration of responses, and warrants further evaluation in larger studies. Clinical trial information: NCT05143229 .