Related Experiment Video
Updated: Jun 28, 2025
Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
Published on: June 20, 2015
Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin
Antonio Llombart-Cussac1,2, José Manuel Pérez-Garcia2,3, Manuel Ruiz Borrego4
1Hospital Arnau de Vilanova, Universidad Católica de Valencia, Valencia, Spain.
Background:
Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC).
Methods:
Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively.
Findings:
233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2).
Interpretation:
In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia.
Funding:
Novartis Pharmaceuticals.
Insights
Prophylactic metformin significantly reduced the incidence and severity of hyperglycemia in patients with HR+/HER2- PIK3CA-mutated advanced breast cancer receiving alpelisib. This strategy improves treatment tolerability for advanced breast cancer patients.
Area of Science:
- Oncology
- Pharmacology
- Endocrinology
Background:
- Hyperglycemia is a common adverse event associated with alpelisib treatment in patients with HR+/HER2- PIK3CA-mutated advanced breast cancer (ABC).
- The METALLICA trial investigated the efficacy of prophylactic metformin in preventing or mitigating alpelisib-induced hyperglycemia.
Purpose of the Study:
- To evaluate the effectiveness of prophylactic metformin in reducing the occurrence and severity of hyperglycemia in patients with HR+/HER2- PIK3CA-mutated ABC treated with alpelisib plus endocrine therapy.
- To assess the safety profile, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR) of this treatment regimen.
Main Methods:
- A phase 2, multicentre, single-arm trial (NCT04300790) enrolled 68 patients with HR+/HER2- PIK3CA-mutated ABC, divided into two cohorts based on baseline glycemic status (normal or prediabetes).
- Patients received prophylactic metformin concurrently with alpelisib and endocrine therapy (ET).
- The primary endpoint was the incidence of grade 3-4 hyperglycemia within the first 8 weeks of treatment. Secondary endpoints included safety and efficacy measures.
Main Results:
- The incidence of grade 3-4 hyperglycemia was low: 2.1% in the normal glycemic cohort and 15.0% in the prediabetes cohort, meeting the primary objective.
- Serious treatment-related adverse events were infrequent (10.3%), with rash, vomiting, and diarrhea being the most common. No alpelisib discontinuations were due to hyperglycemia.
- Median PFS was 7.3 months, ORR was 20.6%, and CBR was 52.9%, indicating favorable efficacy outcomes.
Conclusions:
- Prophylactic metformin administered before alpelisib plus endocrine therapy significantly lowers the incidence and severity of hyperglycemia in patients with HR+/HER2- PIK3CA-mutated ABC.
- This prophylactic approach appears safe and effective, potentially improving treatment tolerability and outcomes for patients with this specific breast cancer subtype.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
11:13Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Related Concept Videos
01:26Oral Hypoglycemic Agents: Biguanides and Glitazones
01:23Dipeptidyl Peptidase 4 Inhibitors
01:06Oral Hypoglycemic Agents: Glinides
01:15Hypoglycemia and Glucagon
01:19Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
Acarbose and miglitol are...
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...