Recent studies have shown that hyperglycemia (high blood sugar), can be a risk factor for breast cancer. In addition, it has been found that patients who have hyperglycemia and breast cancer have increased mortality due to its effects on efficacy of chemotherapy which can lead to chemoresistance. Hyperglycemia will increase the glucose available for breast cancer cells, which can provide them with extra nutrients that will lead to significant cell proliferation. Controlling hyperglycemia, therefore, is an important need for breast cancer patients.
In addition, developing high blood sugar while being treated with alpelisib and fulvestrant for HR+/HER2- advanced breast cancer is the most frequent side-effect and also the most common reason for dose adjustments and treatment discontinuations of alpelisib.
The METALLICA study is evaluating the effect of metformin to prevent hyperglycemia in HR+/HER2- PIK3CA-mutated advanced breast cancer patients who are being treated with alpelisib plus endocrine therapy. Male or female patients >= to 18 years are eligible for the trial if they have: an ECOG performance status of 0-1, histologically proved diagnosis of advanced breast cancer, documented recurrent ER+ and/or PgR+8, measurable disease per RECIST v.1.1, the presence of a PIKCA mutation, progressed on AI regimen, central nervous system metastasis, had at least one prior line of endocrine therapy, and had no more than one prior chemotherapy containing regimen for metastatic disease.
There are two cohorts for the trial, with both receiving apelisib, fulvestrant, and metaformin. Cohort A patients will have a normal fasting glycemia with fasting plasma glucose (FPG) at ≤100 mg/dL (5.6 mmol/L) and glycosylated hemoglobin (HbA1c) < 5.7. Cohort B patients with have fasting glycemia with FPG 100 mg/dL (5.6 mmol/L) to 140 mg/dL (7.8 mmol/L) (IFG) and HbA1c < 5.7 to 6.4%.
Results for the trial were shared at the 2022 San Antonio Breast Cancer Symposium on December 8th in the poster spotlight session. The primary endpoint of the study was rate of severe hyperglycemic episodes over the first two cycles of treatment and results demonstrated that this rate of hyperglycemia dropped substantially in both cohorts (Cohort A: 1 (2.1%) patient (95%CI, 0.8–9.5;p < 0.001); Cohort B: 3 (15%) patients (95%CI, 4.5–33; p = 0.012)) without compromising treatment efficacy (median progression-free survival in all patients was 7.4 months (95%CI, 6–NA)). Additional analysis on the safety and efficacy in terms of progression-free survival, overall response rate, time to progression, and clinical benefit rate will also be assessed.
"Results of METALLICA trial provide evidence to guide treating oncologists on the management of alpelisib-related hyperglycemia and therefore, improving their patients’ treatment,” said Dr. Llombart-Cussac.
These findings support changes in the current clinical practice for PIK3CA-mutated, HR[+]/HER2[-] advanced breast cancer patients receiving alpelisib plus fulvestrant or other endocrine therapy by proving that prophylactic metformin is a suitable approach to prevent alpelisib-related hyperglycemia, and therefore minimizing alpelisib dose adjustments and discontinuations.
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