Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

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Background Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low‐molecular‐weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. Methods Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. Results Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow‐up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28‐4.69 [P = .007]) and first‐onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13‐4.42 [P = .02]). Analysis of 6‐month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. Conclusions Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.