Metformin With Chemoradiotherapy Is Not Recommended for the Treatment of Locally Advanced Non–Small Cell Lung Cancer

Investigators advise against the use metformin in addition to chemoradiotherapy for patients with locally advanced non–small cell lung cancer due to progression-free survival and overall survival was not substantial.

Metformin (Glucophage) in addition to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects than the combined treatment modality therapy alone for patients with locally advanced non–small cell lung cancer (LA-NSCLC), according to findings from the phase 2 OCOG-ALMERA study (NCT02115464).

Within 1-year, treatment failure was noted in 18 patients (69.2%) who were treated with metformin compared with 42.9% of control patients (n = 12; P = .05). Investigators do not recommend LA-NSCLC metformin for patients who are eligible for chemoradiotherapy. The conventional progression-free survival (PFS) for patients who received metformin was 34.8% (95% CI, 16.6%-53.7%) compared with 63.0% (95% CI, 42.1%-78.1%) for patients in the control arm (HR, 2.42; 95% CI, 1.14-5.10). The data indicated that patients treated with metformin had a worse overall survival (OS; 47.4%; 95% CI, 26.3%-65.9%) than patients in the control cohort (85.2%; 95% CI, 65.2%-94.2%; HR; 3.80; 95% CI, 1.49-9.73).

“Experimental studies suggested that metformin inhibits growth and sensitizes NSCLC cells and tumors to radiotherapy and chemotherapy. Based on such findings, we hypothesized that metformin could improve outcomes in patients with LA-NSCLC,” the authors of the study wrote. “Not only did this study fail to demonstrate improved efficacy with the addition of metformin, but the metformin arm was inferior to the control arm in terms of the primary outcome: the proportion of patients with a failure event within 12 months (labeled as PFS in the protocol).”

The randomized study enrolled 54 patients, 30 women (55.6%) and 24 men (44.4%). Most patients were given cisplatin plus etoposide (n = 39; 72.2%). Among the 25 patients who were randomized to receive metformin and began radiotherapy, 5 patients (20.0%) did not complete the protocol-specified treatment, and 3 were hospitalized due to treatment-related toxic effects. In the control arm, there were 27 patients who underwent radiotherapy and were treated with 60 to 63 Gy/30 daily fractions.

Of the patients in the metformin group, 14 (56.0%) received 2 cycles of chemotherapy. Additionally, 4 patients within the cohort who received both cycles required dose modification due to of weight loss, neutropenia or thrombocytopenia, and patient withdrawal. Additionally, 7 patients only received 1 cycle due to tinnitus, dehydration, neutropenia or thrombocytopenia, esophagitis, and patient withdrawal.

In the control group, 21 (77.8%) patients completed 2 cycles of chemotherapy. A total of 4 patients did not receive their last dose of weekly therapy due to complications such as chest infection, neutropenia, and low platelet counts. 

Investigators noted that of the 25 patients in the metformin group, 6 completed 1 year of treatment. The reasons for discontinuation were progressive disease or death, patient request, toxic effects, intercurrent illness, and nonadherence. Additionally, there were 7 patients in the control arm and 4 in the metformin arm who received durvalumab (Imfinzi) immunotherapy.

In the metformin arm, 18 patients experienced events, including local progression (n = 2), distant progression (n = 10), withdrawal (n = 3), and death before detection of progression (n = 2). In the control arm, 12 patients experienced events, including local progression (n = 2), distant metastasis (n = 7), new primary (n = 1), and withdrew (n = 2) within 1 year of being randomized (P = .05). Investigators identified a risk difference for completing 1-year of treatment of -26.4% (95% CI, -0.9% to -51.0%).

Among the patients who were treated with radiotherapy (n = 52), 19 were given modulated radiotherapy, 11 were given 3-dimensional conformal radiotherapy, and 22 were given volume modulated arc therapy. In this study there was no interaction effect with the treatments and no association between the type of radiotherapy.

In terms of safety, 53.8% of patients (n = 14) patients in the metformin arm and 25.0% (n = 7) patients in the control arm experienced adverse effects of grade 3 or higher. The most common AEs experienced by patients in the metformin cohort included esophagitis (19.2%; n = 5) and lung infection (23.1%; n = 6).

“Although our primary outcome was not the conventional time-to- event end point, the robustness of this result is supported by the consistency of the inferiority with metformin for all secondary measures of efficacy, including conventional PFS and OS,” concluded investigators.

Reference:

Tsakiridik T, Pond G, Wright J, et al. Metformin in combination with chemoradiotherapy in locally advanced non–small cell lung cancer: The OCOG-ALMERA randomized clinical trial. JAMA Oncol. Published Online July 29, 2021. doi:10.1001/jamaoncol.2328