Tucatinib + Alpelisib (HER2 TKI + PI3Kα) Nets 60% Partial Responses in Heavily Pretreated HER2-Positive, PIK3CA-Mutated mBC

In the phase Ib P5-03-10 “Time-to-Event” dose-escalation study (NCT05230810) post-menopausal women with HER2-positive metastatic breast cancer harboring activating PIK3CA mutations (median 2 prior metastatic lines; all had trastuzumab ± pertuzumab, 50% prior T-DXd, 50% prior tucatinib) received twice-daily tucatinib with daily alpelisib plus fulvestrant when ER-positive. At DL1 (tucatinib 300 mg BID + alpelisib 250 mg QD; n = 5 in DLT window, n = 8 total), no dose-limiting toxicities were seen; common all-grade AEs were hyperglycemia 75%, diarrhea 50% (grade 3 = 25%), rash 38%, and weight loss 63%, all manageable with holds, reductions, and supportive care. DL2 (alpelisib 300 mg) produced grade 3 diarrhea or rash in all 3 pts and was abandoned. Among five RECIST-evaluable DL1 patients, three achieved confirmed partial responses (ORR = 60%; all carried the H1047R hotspot), two had durable stable disease, and four of eight remained on therapy >6 months (longest = 15 months). For comparison, the chemo-based HER2CLIMB regimen (tucatinib + trastuzumab + capecitabine) posts ~40% ORR and 7.6 mo median PFS after T-DM1.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/P5-03-10/753975/Abstract-P5-03-10-Safety-and-Preliminary-Efficacy