Phase III Randomized Double‑Blind Study of Alpelisib Plus Trastuzumab and Pertuzumab Maintenance Therapy in HER2‑Positive Advanced Breast Cancer with PIK3CA Mutation

The primary objective is twofold: (1) to confirm the Recommended Phase 3 Dose of alpelisib when given with trastuzumab and pertuzumab in a safety run‑in; and (2) to assess whether the combination prolongs progression‑free survival compared with placebo in adults with HER2‑positive advanced breast cancer harboring a PIK3CA mutation.

Secondary objectives include:

• Evaluation of safety and tolerability of alpelisib with trastuzumab and pertuzumab.
• Characterization of alpelisib exposure when co‑administered with trastuzumab and pertuzumab.
• Assessment of overall survival.
• Investigation of additional efficacy endpoints.
• Analysis of patient‑reported outcomes.
• Correlation of baseline circulating tumor DNA PIK3CA status with progression‑free survival.
• Measurement of time to deterioration of ECOG performance status.

The trial enrolled a total of 2 participants, as reported by the sponsor. Eligible individuals were adult patients of both sexes, including those classified as vulnerable, with an age range corresponding to the study’s predefined categories. All participants had histologically‑confirmed HER2‑positive advanced breast cancer and had previously received up to eight cycles of a taxane‑based induction regimen combined with trastuzumab and pertuzumab, with a minimum of four cycles permitted if taxane discontinuation resulted from toxicity. Inclusion required an ECOG performance status of 0 or 1 and adequate bone‑marrow and organ function. For the randomized portion of the study, enrollment was limited to subjects whose tumor tissue demonstrated a PIK3CA mutation as determined by a central laboratory. No specific lifestyle criteria such as diet or physical activity were detailed in the provided information.

The study (EPIK‑B2) is a two‑part, Phase III, multicenter trial employing a 1:1 randomization, double‑blind, placebo‑controlled design to evaluate alpelisib in combination with trastuzumab and pertuzumab as maintenance therapy for patients with HER2‑positive advanced breast cancer harboring a PIK3CA mutation. Part 1 is a safety run‑in in which alpelisib 300 mg orally daily together with trastuzumab 6 mg/kg IV and pertuzumab 420 mg IV are administered to confirm the recommended Phase 3 dose; dose‑limiting toxicities are assessed during the first six weeks. Part 2 randomizes eligible participants to receive either alpelisib or matching placebo, both continued with trastuzumab and pertuzumab, to determine progression‑free survival and overall survival. The trial enrolment began July 2020 and is projected to conclude February 2027. Study visits include a screening visit for eligibility verification, a baseline visit to initiate treatment, and subsequent visits every three weeks for IV infusions, safety monitoring, pharmacokinetic sampling, and imaging per RECIST 1.1 criteria; laboratory tests, vital signs, cardiac assessments, and patient‑reported outcomes are collected at predefined intervals. Participants remain on study until documented disease progression, unacceptable toxicity, withdrawal of consent, or study termination, with an end‑of‑study visit scheduled at discontinuation to capture final safety and efficacy data. Early termination criteria include occurrence of a dose‑limiting toxicity, investigator‑determined inability to continue therapy safely, or participant withdrawal.

The experimental oral agent alpelisib is supplied as a solid dosage form and administered at a dose of 300 mg per participant via the oral route.

The monoclonal antibody trastuzumab is administered by intravenous infusion at a dose of 6 mg/kg body weight.

The monoclonal antibody pertuzumab is administered by intravenous infusion at a fixed dose of 420 mg.

Participants assigned to the control arm receive a matching oral placebo in lieu of alpelisib and a matching intravenous placebo in lieu of trastuzumab and pertuzumab, preserving blinding of treatment allocation.

All study medications are given in accordance with the randomized schedule; oral doses are taken once daily, and intravenous infusions are performed on the designated study days. Compliance with oral therapy is monitored through pill count reconciliation and patient diary entries, while adherence to infusion protocols is documented by infusion records and administration logs.

Efficacy will be evaluated primarily by Progression‑free survival (PFS) as determined by investigator assessment using RECIST 1.1 criteria. Secondary efficacy endpoints include Overall survival (OS), Objective response rate (ORR) with confirmed response, Clinical benefit rate (CBR) with confirmed response, Duration of response (DOR), Time to response (TTR), PFS based on local radiology assessments, change from baseline in the FACT‑B Trial Outcomes Index (TOI) score, time to definitive deterioration of ECOG performance status, and PFS stratified by PIK3CA mutation status assessed in circulating tumor DNA at baseline.

Radiologic disease assessments will be performed with standardized imaging modalities and evaluated according to RECIST 1.1 by investigators and local radiologists. Patient‑reported outcomes will be collected using the FACT‑B questionnaire to generate the TOI score, and performance status will be recorded with the ECOG scale. All efficacy parameters will be captured at baseline and at predefined study visits throughout treatment and follow‑up, with statistical analysis planned for time‑to‑event and response‑rate endpoints.