medwireNews: A post-hoc analysis of a randomized trial points to the benefit of adding metformin to an EGFR–tyrosine kinase inhibitor (TKI) in advanced non-small-cell lung cancer (NSCLC) patients with a BMI of at least 24 kg/m2.
Oscar Arrieta, from the Instituto Nacional de Cancerología in Mexico City, and co-workers explain that evidence of a synergistic association between metformin and EGFR–TKIs “has been controversial, with conflicting results reported from phase 2 trials.”
They add that “[s]everal reasons have been cited for the lack of consistent results, including differences in patient demographic characteristics (ie, brain metastases), genetic background, dose of metformin used (500 mg vs 1000 mg twice a day), and study design,” but the role of BMI has not thus far been investigated.
The current analysis – published as a research letter in JAMA Oncology – included 133 diabetes-free participants of a Mexican phase 2 study that investigated the addition of metformin 500 mg twice a day to an EGFR–TKI (erlotinib, afatinib, or gefitinib) for the treatment of stage IIIB–IV NSCLC with an activating EGFR mutation.
When participants were stratified by BMI, progression-free survival (PFS) was significantly improved with the addition of metformin to an EGFR–TKI among those who had a BMI equaling or above the trial population’s median value of 24 kg/m2, at a median PFS duration of 15.83 months versus 8.34 months with an EGFR–TKI alone, and an adjusted hazard ratio (HR) for progression or death of 0.45.
Overall survival (OS) was similarly significantly better with combined treatment than with an EGFR–TKI alone in these patients; the respective median OS times were 31.44 and 18.00 months, and the HR for death was 0.55 in favor of the combination.
Conversely, no such improvements were seen with the use of metformin alongside an EGFR–TKI in patients with a BMI less than 24 kg/m2. In fact, the combination was associated with numerically lower median PFS (7.88 vs 10.31 months) and OS (20.46 vs 27.99 months) durations relative to an EGFR–TKI alone.
Arrieta and colleagues point out that the primary results of the phase 2 study are in contrast to those of another trial of metformin plus gefitinib in diabetes-free Chinese patients with advanced EGFR mutation-positive NSCLC, which showed no improvement in PFS or OS with metformin addition.
“The conflicting results could be related to anthropometric differences, which were marked between Asian and Hispanic populations (overweight rate, 64.1% in Mexico vs 33.8% in China),” they comment.
The team continues: “Given the considerable differences in overweight and obesity rates between the Mexican and Chinese populations, it is plausible that the differences in both study results were partially caused by a discrepancy in population BMI.”
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