Alpelisib in combination with trastuzumab and pertuzumab as maintenance therapy in patients with HER2+, PIK3CA-mutant advanced breast cancer: EPIK-B2 Study Part 1 safety and efficacy results

Abstract Introduction: Current standard first-line (1L) treatment (tx) for patients (pts) with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) includes taxanes plus trastuzumab (T) and pertuzumab (P). Mutations (mut) in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene encoding PI3Kα have been reported in 12%-39% of HER2+ BCs and associated with worse prognoses and lower pathological complete response to anti-HER2 tx in the neoadjuvant setting. Alpelisib (ALP) is an oral, α-specific PI3K inhibitor approved at 300 mg per day (QD) in combination with fulvestrant in hormone receptor (HR)-positive, HER2−, PIK3CA-mut ABC following progression on/after endocrine therapy. EPIK-B2 is a 2-part Phase 3 study to evaluate ALP plus T+P as 1L maintenance tx in pts with HER2+, PIK3CA-mut ABC, without progressive disease at study entry. Here, we report results of Part 1, the safety run-in of EPIK-B2. Methods: Part 1 of EPIK-B2 was open label and assessed safety of ALP plus T+P in pts with HER2+ ABC and confirmed the recommended Phase 3 dose of ALP for the randomized Part 2. Pts with HER2+ ABC, with or without a PIK3CA mut, who had completed induction taxane chemotherapy plus T+P were eligible for Part 1. Part 2, currently enrolling, allows only PIK3CA-mut pts. Pts in Part 1 received 300 mg (Cohort A) or 250 mg (Cohort B) ALP QD plus 6 mg/kg T and 420 mg P, on Day 1 of each 21-day cycle. The primary endpoint of Part 1 was incidence of dose-limiting toxicities (DLTs) in the first 6 wk of tx; secondary endpoints included safety/tolerability and ALP exposure by dose level. Preliminary confirmed overall response rate (ORR; best overall response [BOR] of CR/PR) and clinical benefit rate (CBR; BOR of CR/PR/SD lasting ≥24 wk) were evaluated per RECIST v1.1 during the on-treatment period. Results: Three pts in Cohort A and 12 in Cohort B received 300 mg and 250 mg ALP, respectively. DLTs, 1 event each of hyperglycemia and dermatitis acneiform, were seen in Cohort A, none were reported in Cohort B pts given 250 mg ALP; however, Part 2 of EPIK-B2 will be initiated with 200 mg ALP with the option of intrapatient dose escalation to 250 mg QD, the maximum tolerated dose, per FDA feedback to consider a lower toxicity threshold in 1L maintenance setting. No unexpected AEs were reported; most common AEs were diarrhea, decreased appetite, and hyperglycemia. Six of 15 pts (40%; 2 in Cohort A, 4 in Cohort B) had PIK3CA-mut disease. Among these, ORR was 50% (n/N=3/6) and CBR was 100% (n/N=6/6). Tumor response was maintained in 5 of 6 pts with PIK3CA mutations (83%) after ≥21 cycles of tx (range, 21-31). Conclusions: ALP plus T+P combination is safe; reported AEs align with those in previous ALP studies. Preliminary efficacy data suggest promising clinical benefit with ALP plus T+P for pts with HER2+ PIK3CA-mut disease. Citation Format: Sara A. Hurvitz, François-Clement Bidard, Wei Li, Xichun Hu, Sonia Pernas, Joseph Thaddeus Beck, Mario Campone, Kevin Punie, Michelle Miller, Mathilde Kaper, Yu Han, Farhat Ghaznawi, Guy Jerusalem. Alpelisib in combination with trastuzumab and pertuzumab as maintenance therapy in patients with HER2+, PIK3CA-mutant advanced breast cancer: EPIK-B2 Study Part 1 safety and efficacy results. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4926.