Javier Salvador Bofill

Supplementary Table S2 | Criteria for defining DLT. AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicities; GI, gastrointestinal; LLN, lower limit of normal; SOC, standard of care; ULN, upper limit of normal.

Supplementary Data S1. Detailed description of the experimental and analytical methods used in this study

Supplementary Table S1 | Representativeness of Study Participants

Supplementary Table S3 | Treatment-Emergent Adverse Events (TEAE) and serious TEAE in the study safety population (N = 17)

Purpose:The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut).Patients and Methods:This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP.Results:Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months.Conclusions:These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut.

Supplementary data S3. Analysis outputs

Supplementary Figure S1 | IPATHER trial design. aPatients could be pre-screened before or during induction treatment with chemotherapy and dual anti-HER2 blockade regimen. Patients who were HER2-positive and harbored a PIK3CA mutation, identified in archival or fresh tumor tissue samples (from primary breast, local recurrence, or metastatic lesions) or in ctDNA, qualified for the study. ctDNA, circulating tumor DNA; EOT, end of treatment; ER, estrogen receptor; HR, hormone receptor; MBC, metastatic breast cancer; PO, oral administration; PR, progesterone receptor; SC, subcutaneous.

Supplementary Table S4 | Drug-related dose interruptions, dose reductions, and treatment discontinuations (N = 17)

Supplementary Figure S4 | Progression-free survival in the efficacy cohort since the initiation of first-line treatment for advanced disease (N = 16). Kaplan-Meier curve from the first-line treatment for metastatic breast cancer with trastuzumab plus pertuzumab plus chemotherapy. CI, confidence interval; NR; not reported; PFS, progression-free survival.

Supplementary Figure S3 | Translational genomic analysis of screened patients (N = 116). Oncoplot depicting the genomic landscape of all screened patients. ER, estrogen receptor; IHC, immunohistochemistry; ISH, in situ hybridization; NA, not available; PR, progesterone receptor.