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Metformin May Improve Outcomes in Endometrial Cancer

Jason M. Broderick @jasoncology
Published: Thursday, Sep 22, 2016

Dr. Pamela Soliman

Pamela T. Soliman, MD

Combining the diabetes drug metformin with everolimus (Afinitor) and letrozole resulted in a clinical benefit rate (CBR) of 60% in women with advanced or recurrent endometrioid endometrial cancer, according to findings from a phase II trial.1

The results, which were presented at the 2016 ASCO Annual Meeting, represent a significant improvement over the CBR previously demonstrated in a phase II study of everolimus and letrozole alone.2

“The addition of metformin to the everolimus and letrozole backbone increased the clinical benefit rate from 40% to 60%,” Pamela T. Soliman, MD, associate professor, Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, said when presenting the data at ASCO.

The single-arm, open-label, multicenter phase II study included 62 patients with advanced or recurrent endometrial carcinoma. Forty-nine patients were evaluable for response, 5 were too early in treatment to assess, and 8 were not evaluable.

The median age among the evaluable patients was 62 years (range, 40-77) and the median BMI was 34.4 kg/m2. Ninety-two percent (n = 45) of patients had pure endometrioid tumors and 8% (n = 4) had a mixed endometrioid histology. Seventy-eight percent of patients had grade 2 or 3 tumors.

Eight-eight percent of patients (n = 43) had received primary surgery and 63% (n = 31) had previous radiation. Sixty-seven percent (n = 33) of patients had received at least 1 chemotherapy regimen for recurrence. 

Initial treatment in the study consisted of a 7- to 10-day lead-in period of metformin alone, administered at 500 mg orally each day for the first 4 days and then 500 mg twice daily thereafter. Starting with cycle 1, patients received 500 mg of metformin twice daily for the remainder of treatment. Oral doses of everolimus (10 mg) and letrozole (2.5 mg) were taken together once daily throughout each 28-day cycle.

The primary endpoint of the study was CBR, which combines the complete response, partial response, and stable disease rates. Secondary outcome measures included progression-free survival and overall survival.

The median number of treatment cycles was 6 (range, 2-18), with 8 patients still on treatment at the time of the analysis. The 60% CBR comprised a 29% (n = 14) partial response rate and a 31% (n = 15) stable disease rate. Forty percent (n = 20) of patients had progressive disease. Among patients who completed more than 14 cycles, 6 had a partial response and 2 had stable disease.

In 41 patients who had tissue available for testing, 15 (37%) had KRAS mutations. The CBR was 67% (10/15) in KRAS mutation–positive patients compared with 77% (20/26) in patients without KRAS mutations (P = .49).

“At least in our preliminary evaluation, there was no difference in clinical benefit rate between those with or without a KRAS mutation, but further correlation between molecular findings and response are currently being evaluated,” said Soliman.

The toxicity of the 3 drugs was manageable, according to Soliman. Grade 3/4 toxicities occurred in 43% of patients. The most common grade 3/4 adverse events included anemia (22%; n = 11), hypertriglyceridemia (14%; n = 8), hyperglycemia (10%; n = 5), hyponatremia (8%; n = 4), thrombocytopenia (6%; n = 3), fatigue (6%; n = 3), abdominal pain (4%; n = 2), increased ALT/AST (4% n = 2), oral mucositis (4%; n = 2), and weight loss (4%; n = 2).

One patient required a dose reduction in metformin and 3 patients needed a dose reduction in everolimus. Two patients discontinued treatment due to AEs.

“Based on these findings and other studies, the use of targeted therapy in women with recurrent endometrioid endometrial cancer appears to benefit patients over standard cytotoxic chemotherapy,” Soliman said in her concluding remarks.

References

  1. Soliman PT, Westin SN, Iglesias DA, et al. Phase II study of everolimus, letrozole, and metformin in women with advanced/recurrent endometrial cancer. J Clin Oncol 34, 2016 (suppl; abstr 5506).
  2. Slomovitz BM, Jiang Y, Yates MS, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015;33(8):930-936.



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