Metformin Meets Primary Endpoint in Study of ALP-Induced Hyperglycemia in Advanced Breast Cancer

The METALLICA (NCT04300790) phase 2 study met its primary endpoint and showed that metformin prevents and/or reduces the incidence of all-grade alpelisib [(ALP) Piqray; Novartis]-induced hyperglycemia in PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (ABC), according to a poster presentation at the San Antonio Breast Cancer Conference in Texas on December 7, 2022.

Prophylactic use of metformin substantially reduced the incidence and severity of ALP-related hyperglycemia with no additional toxicities and could be a new standard for patients with PIK3CA-mutated, HR-positive/HER2-negative ABC receiving ALP plus fulvestrant (Faslodex; AstraZeneca) or another endocrine therapy (ET), according to the presentation.

The efficacy and safety profile of ALP in combination with metformin was comparable to those reported in the BYLieve (NCT03056755) and SOLAR-1 (NCT02437318) studies, according to the presentation.

Hyperglycemia is an on-target adverse effect (AE) of P13K inhibition reported in 63.7% of patients with HR-positive/HER2-negative ABC treated with ALP plus fulvestrant in the SOLAR-1 study. Hyperglycemia was the most frequent AE, leading to a discontinuation rate of 6.3%.

Metformin reduces systemic insulin resistance and suppresses P13K and Ras signaling. The METALLICA study assessed the prophylactic use of metformin for the prevention of ALP-induced G3-4 hyperglycemia in patients with PIK3CA-mutated, HR-positive/HER2-negative ABC with normal fasting or prediabetic criteria.

The open-label, phase 2, single-arm trial took place between August 30, 2020, and March 10, 2020, and placed its 68 adult participants at 18 sites into 2 cohorts. The median age was 55 years, but participants ranged from 29 to 79 years of age, and 58% of all the patients had visceral disease and ECOG PS of 0.

A total of 66 patients were previously treated with a CDK4/6i and 13 had received chemotherapy for advanced disease. Sixty-three patients received fulvestrant as ET.

With a median follow-up of 8 months, 28 patients remained on study treatment. Disease progression, reported by 32 patients, was the main reason for discontinuation.

The first cohort was comprised of 48 patients with normal fasting glycemia < 100 mg/dL and glycosylated hemoglobin (HbA1c) <5.7%. The second cohort was comprised of patients with prediabetic fasting glycemia of 100 to 140 mg/dL and/or HbA1c of 5.7% to 6.4%. Patients received oral ALP 300 mg per day, starting from C1D8, in combination with ET and oral metformin 1000 mg per day on days 1 to 3 and 2000 mg per day thereafter.

The primary endpoint was G3-4 hyperglycemia incidence as per NCI-CTCAE v. 4.03 during the first 2 cycles of treatment. Secondary endpoints included clinical benefit rate (CBR), duration of response (DoR), overall response rate (ORR), progression-free survival (PFS), and safety.

Median PFS in all patients was 7.4 months. Among patients with measurable disease, the ORR was achieved in 14 patients. CBR and DoR were immature at the time of analysis.

The most common AEs were diarrhea, nausea, and fatigue. Serious AEs occurred in 15 patients, and these were rash and vomiting.

No treatment deaths were reported, according to the presentation.

Reference

Llombart-Cussac A, Perez-Garcia JM, Ruiz Borrego M, et al. Metformin (MET) for the prevention of alpelisib (ALP)-related hyperglycemia (HG) in PIK3CA-mutated, hormone receptor-positive (HR[+]) HER2-negative (HER2[-]) advanced breast cancer (ABC). Poster presentation. San Antonio Breast Cancer Conference in Texas. December 7, 2022.