Metformin does not improve the progression-free survival of stage IIIA or IIIB locally advanced non-small cell lung cancer patients compared to chemoradiation alone

1. Metformin, in addition to standard chemoradiation therapy, did not improve the progression-free survival, overall survival, local-regional recurrence, or distant metastasis occurrence compared to the control group of stage IIIA or IIIB locally advanced non-small cell lung cancer patients.

2. Serious adverse events were equally as common in the metformin and control groups, however, only 63.4% of participants could tolerate the metformin protocol.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Locally advanced (LA) non-small cell lung cancer (NSCLC) has a poor prognosis due to a lack of treatments. Some evidence exists that metformin has antineoplastic effects, including in NSCLC. The primary outcome of this study was progression-free survival (PFS), defined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria of LA-NSCLC patients treated with metformin. Additionally, the overall survival (OS), local-regional recurrence (LRR), distant metastasis (DM), and toxicity, defined using the Common Terminology Criteria for Adverse Events, were secondary outcomes. Stage IIIA or IIIB, LA-NSCLC patients were randomized to standard chemoradiation therapy (n = 81) or chemoradiation with metformin (n = 86), stratified performance by participant performance status, their histology, and stage. Most participants received their radiation and chemotherapy, but only 63.4% of the metformin group patients adhered fully to the metformin protocol. The one-year PFS and OS did not differ between the metformin and control group. While there were fewer deaths due to cancer in the metformin group, there were more unexplained or other-disease deaths. LRR and DM at 2 years did not differ in the metformin group compared to in the control group. Serious adverse events were equally as common in the metformin group as in the control group. Only 39% of participants were able to maintain the metformin dose as prescribed without adjustments, limiting this study’s power. The low adherence to the chemoradiation limits the generalizability of this study. Another limitation is that the trial wasn’t blinded since the control group did not receive a placebo.

Click to read the study in JAMA Oncology

Click to read an accompanying editorial in JAMA Oncology

Relevant Reading: Metformin for non-small cell lung cancer patients: Opportunities and pitfalls

In-Depth [randomized controlled trial]: This study, NRG-LU001, was a phase 2 study comparing metformin in addition to standard therapy to standard therapy alone at treating unresectable, stage IIIA or IIIB, LA-NSCLC. Patients who did not have cancer in the past 3 years, or a history of diabetes, who could perform at least light work (“performance status”, where light = 0 and heavy = 1) were enrolled. All patients received 60 Gy of radiation, weekly carboplatin and paclitaxel chemotherapy for 28 – 42 days, and then consolidative carboplatin and paclitaxel chemotherapy every 3 weeks for 2 cycles. Half of the patients were randomized to also receive 2000 mg metformin daily. The randomization was stratified by performance status, histology (SCC vs non-SCC), and stage (IIIA vs IIIB). Recurrence was monitored using regularly scheduled contrast-enhancement computed tomography (CT) or magnetic resonance imaging (MRI). At those same scheduled time points, the patient’s performance status and toxic response were measured. 170 patients from 79 institutions in the US, Canada, and Israel were recruited, who had demographics that were representative of NSCLC for age (64 years), sex (58.1% male), and ethnicity (82.0% White). While 3 were found to be ineligible after randomization, the metformin group (n = 86) and control group (n = 81) remained balanced for age, sex, and ethnicity, and all stratified variables. 86.0% of the metformin group and 92.6% of the control group received radiation. Many patients received their radiation and chemotherapy per protocol, with the bulk who did not receive therapy per protocol instead receiving appropriate minor deviations. 63.4% of the metformin group patients took the metformin throughout the trial. Patients were followed for an average of 27.7 months. PFS at one-year was not different between the metformin group (51.3%, 95% CI = 39.8%-61.7%) and the control group (60.4%, 95% CI = 48.5%-70.4%) (HR = 1.15, 95% CI = 0.77-1.73; P = 0.24). Shorter PFS was associated with higher stage (HR = 1.79; 95%CI = 1.19-2.69; P = 0.005), but not metformin treatment (HR = 1.20; 95% CI = 0.81-1.78; P = 0.36), histology (HR = 1.24; 95% CI = 0.83-1.85; P = 0.30), or performance status (HR = 0.70; 95% CI = 0.47-1.05; P = 0.09). A sensitivity analysis supported these results (HR = 1.09; 95%CI = 0.69-1.73; P = 0.36). OS, similarly, did not differ between the metformin (80.8%, 95% CI = 70.2%-87.9%) and control group (80.2%, 95% CI = 69.3%-87.6%) (HR = 1.03; 95% CI = 0.64-1.68; P = 0.89). Fewer deaths were due to disease in the metformin group (70.6%) compared to the control group (90.9%). At 2 years follow-up, there was no differences between the groups for LRR (HR = 0.91; 95% CI = 0.51-1.62; P = 0.75) or DM (HR = 1.29; 95% CI = 0.71-2.34; P = 0.41). Grade 3 adverse events also were not more frequent in the metformin group (65.8%) compared to the control group (68.0%). 1 metformin group patient and 4 control group patients experienced a grade 5 adverse event. Pneumonitis was uncommon in both the metformin (1.3%) and control (2.7%) group.

Image: PD

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