Adding Metformin to Concurrent Radiotherapy Does Not Improve Survival in Locally Advanced Non–Small Cell Lung Cancer

Although metformin appears to impact tumor metabolism and has previously improved survival in combination with Tyrosine kinase inhibitors for patients with non–small cell lung cancer (NSCLC),^1,2 it did not appear to improve survival when combined with concurrent chemoradiotherapy and consolidation chemotherapy in patients with locally advanced disease.³

Findings from the phase 2 NRG-LU001 study (NCT02186847) indicated that after a median follow up of 27.7 months (range, 0.03-47.21), patients in the control group had a 1-year progression-free survival (PFS) rate of 60.4% (95% CI, 48.5%-70.4%) compared with 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Additionally, overall survival (OS) was nearly identical between the 2 treatment arms (HR, 1.03; 95% CI, 0.64-1.68; P = .89), according to the intent-to-treat analysis. Investigators reported a 1-year OS rate of 80.2% (95% CI, 69.3%-87.6%) and 80.8% (95% CI, 70.2%-87.9%) in the control and metformin arms, respectively.

“The NRG-LU001 study found no additional toxic effects, but also no survival benefit, when metformin was combined with chemoradiation in LA-NSCLC,” the authors of the study wrote. “Indeed, this survival outcome compares favorably with the experimental group of the PACIFIC trial, which examined the combination of chemoradiation with consolidation durvalumab, for which 1-year PFS was 55.9%.”⁴

The randomized, open label study enrolled patients with stage IIIA or IIIB NSCLC who were eligible for treatment with definitive chemoradiation. Eligible histologies included adenocarcinoma, adenosquamous, large cell carcinoma, squamous carcinoma, non-lobar and non-diffuse bronchoalveolar cell carcinoma, or NSCLC not otherwise specified.

The trial enrolled 170 patients from 79 global institutions. Following exclusions, investigators reported a total of 167 patients were randomized 1:1 to either the control group or the metformin group.

Patients were given 60 Gy of radiation to involved sites, followed by 2 cycles of consolidation chemotherapy once every 3 weeks with or without metformin during the concurrent and consolidation phases of treatment.

The survival analysis indicated that a higher stage was associated with significantly worse PFS (HR, 1.79; 95% CI, 1.19-2.69; P = .005). Other factors such as treatment group (HR, 1.20; 95% CI, 0.81-1.78; P = .36), histology (HR, 1.24; 95% CI, 0.83-1.85; P = .30), and performance status (HR, 0.70; 95% CI, 0.47-1.05; P = .09) were not significantly associated with PFS. In total, 90.9% of deaths in the control arm were due to disease vs 70.6% of deaths in the metformin arm—a difference that was due to an increased number of deaths from other causes.

Investigators did not report any differences in grade 3 or higher adverse effects (AE) between the 2 cohorts. In total, 68.0% of patients in the control group and 64.8% or patients in the experimental group experienced at least 1 grade 3 AE. Five grade 5 AEs were reported, including 4 patients in the control arm and 1 patient in the experimental arm. Additionally both the control (2.7%) and metformin cohorts (1.3%) yielded low rates of grade 3 or greater pneumonitis.

References

1. Chun SG, Liao Z, Jeter MD, et al. Metabolic responses to metformin in inoperable early-stage non-small cell lung cancer treated With stereotactic radiotherapy: results of a randomized phase II clinical trial. Am J Clin Oncol. 2020;43(4):231-235. doi:10.1097/COC.0000000000000632.
2. Haikala HM, Anttila JM, Marques E, et al. Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy. Nat Commun. 2019;10(1):620. doi:10.1038/s41467-019-08541-2.
3. Skinner H, Hu C, Tsakiridis T, et al. Addition of metformin to concurrent chemoradiation in patients With locally advanced non–small cell lung cancer. JAMA Oncol. Published online July 29, 2021. doi:10.1001/jamaoncol.2021.2318
4. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937