The “miracle drug” metformin has no anticancer efficacy?

A large number of studies in recent years has shown that the cancer incidence of diabetes patients who take metformin has been quite low, and metformin is associated with the decline of cancer mortality compared to insulin and sulfonylureas for diabetes; for lung cancer patients, the survival of patients with stage IV lung cancer complicated with diabetes has been significantly increased after taking metformin.

Then, can cancer patients without diabetes delay the targeted drug resistance and prolong PFS (progression-free survival) and OS (overall survival) by taking metformin? There have been many studies on metformin at the ASCO Meeting this year. Let’s check the study results below.

1. Combination of metformin and gefitinib could not improve the PFS or OS of nondiabetic advanced NSCLC patients

According to the basic research, metformin can strengthen the efficacy of EGFR-TKI, however, this has not been proved by clinical trials. In view of this, researchers from Daping Hospital of China have conducted a multicenter, double-blind, placebo-controlled Phase II clinical study, and the results have been announced at the 2019 ASCO Meeting.

The study enrolled previously untreated 224 patients with stage IIIb or IV NSCLC and EGFR mutation, who were randomly assigned to the group receiving 250mg gefitinib (oral, once daily) plus 500mg metformin (oral, once weekly) or the group receiving  the said gefitinib plus placebo, with metformin escalated to 1,000mg (oral, twice daily) 2 weeks later. The primary endpoint was PFS rate at 1 year, and the secondary endpoints were PFS, OS, ORR, and safety.

Baseline characteristics were well balanced between the two groups. The results showed that the PFS rate at 1 year was separately 41.2% and 42.9% in the metformin group and placebo group, with the difference not statistically significant (P=0.6268). The combination with metformin did not increase the PFS (10.3 months vs. 11.4 months), OS (22.0 months vs. 27.5 months), or ORR (66.0% vs. 66.7%) over placebo. No survival advantages of the combination with metformin were detected across subgroups either. The two groups had similar adverse reactions, except for a remarkably higher incidence of diarrhea in the placebo group (78.38% vs. 43.24%).

Therefore, researchers held that the combination with metformin could not improve the prognosis of nondiabetic advanced NSCLC patients with EGFR mutation after receiving TKI therapies.

2. Combination of metformin and concurrent chemoradiotherapy did not lead to survival benefits

Professor Theodoros Tsakiridis from Canada Juravinski Cancer Center led the NRG-LU001 Phase II study to assess whether metformin can improve the efficacy of radical concurrent chemoradiotherapy in stage ⅢA/ⅢB NSCLC not complicated with diabetes.

The enrolled 170 patients were randomized 1:1 to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and metformin (2,000mg/d) during chemotherapy therapy (Experimental Arm) between Apr. 2014 and Dec. 2016.

According to the study results, 1- and 2-year PFS was 60.4% and 40.1% in the Control Arm vs. 51.3% and 34.5% in the Metformin Arm, with the difference not statistically significant. OS at 2 years was 65.4% for the Control Arm and 64.9% for the Metformin Arm, both of which were close.

The combination of metformin and concurrent chemoradiotherapy for locally advanced NSCLC was well-tolerated, however, metformin did not improve patients’ PFS or OS and did not alter the rates of local-regional failure or distant metastasis.

3. Metformin could not bring benefits to prostate cancer patients

TAXOMET, a prospective multicenter randomized controlled Phase II study, was conducted to compare docetaxel plus metformin versus docetaxel plus placebo in metastatic castration-resistant prostate cancer (mCRPC), with the primary endpoint being PFS response rate (≥50% decrease) and secondary endpoints including objective response rate (ORR), PFS, OS, toxicity, and quality of life (QoL). The study enrolled 99 patients, and no differences were observed in the metformin combination group and placebo group, wherein, the PSA response rate was 72% in both groups, ORR was 28% in both groups, clinical or biological median PFS was separately 7.3 months and 5.8 months in the two groups, with P=0.848, and the median OS was separately 24.2 months and 19.7 months in the two groups (P=0.53). In terms of adverse events, except a trend for diarrhea to be more common with the metformin group (70% vs. 50%, P=0.072, few grade 3-4 events), there was no difference between the two groups. There was no difference in QoL according to the QLQ-C30 score between the two groups during the treatment period. TAXOMET study showed that the addition of metformin did not bring any benefits to patients.

According to the above studies, cancer patients with diabetes can try the combination of the targeted drugs and metformin, which have been proved to be effective by many studies, however, it’s basically clear that nondiabetic cancer patients could not benefit from metformin. If you want to know more about metformin, Pharmasource, a professional platform for medical supplies suppliers and buyers.

Finally, I’d like to add that the above studies negated the treatment benefits of metformin to nondiabetic cancer patients, however, there are also many studies on the anticancer efficacy of metformin, for example, a Phase III clinical trial showed that metformin had some anticancer effects on nondiabetic intestinal cancer patients. Metformin and heme could inhibit the growth of triple-negative breast cancer; metformin could degrade PD-L1 to lift cancer cells’ suppression on immune cells and improve the anti-cancer ability, etc.

A recent study from West China Hospital of Stomatology, Sichuan University also discovered that metformin could eliminate the stem cell properties of initiating cells of head and neck cancer to stop them from turning into cancer.

In a word, there have been many studies in recent years on the anticancer mechanism of metformin, however, there has been no unified conclusion in terms of clinical translation. Therefore, it’s necessary to pay special attention to patients’ personalized therapies in clinical medication, especially, the use of the so-called "miracle drug".

References:

1. 2019 ASCO abstr 9035；8502；5004；

2. Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial.

3. Wu X, Yeerna H, Goto Y, et al. Metformin inhibits progression of Head and Neck Squamous Cell Carcinoma by acting Directly on Carcinoma Initiating Cells. 

About  the Author:    

Yefenghong

Ye  Fenghong, a medical editor specializing in oncology at a healthcare internet  company, has conducted in-depth research on the pathogenesis and clinical  treatment of lung cancer and breast cancer. She has previously been involved  in the design and synthesis of anti-tumor drugs and has some experience in  computer-aided drug design. She is currently devoted to introducing  cutting-edge cancer treatment drugs to a wide range of readers, aiming to  help more people avoid cancer pain and embrace good health.    

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