FDA Approves Durvalumab Plus Chemotherapy for dMMR Primary Advanced or Recurrent Endometrial Cancer

FDA

The FDA had approved durvalumab (Imfinzi) in combination with carboplatin plus paclitaxel, followed by single-agent durvalumab, for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR).¹

The regulatory decision was supported by data from the phase 3 DUO-E trial (NCT04269200), which showed that patients with dMMR tumors treated in the durvalumab arm (n = 46) experienced a median progression-free survival (PFS) that was not reached (NR; 95% CI, NR-NR) compared with 7 months (95% CI, 6.7-14.8) for patients in the placebo arm (n = 49; HR, 0.42; 95% CI, 0.22-0.80).

In a news release, the FDA stated that although a statistically significant improvement in PFS was observed with the durvalumab regimen in the overall population (HR, 0.71; 95% CI, 0.57 to 0.89; P = .003), the improvement was attributed to patients with dMMR tumors, based on an exploratory analysis of MMR status.^1,2

The global, double-blind, placebo-controlled DUO-E trial enrolled patients at least 18 years of age with newly diagnosed advanced stage III/IV or recurrent endometrial cancer of epithelial histology, excluding sarcomas. For patients with recurrent disease,previous systemic anticancer treatment was allowed only if given in the adjuvant setting with the last dose occurring at least 12 months prior to relapse. Known MMR status was required for enrollment.²

Patients were randomly assigned 1:1:1 to receive durvalumab plus carboplatin/paclitaxel, followed by durvalumab monotherapy; placebo plus carboplatin/paclitaxel, followed by maintenance placebo; or durvalumab plus carboplatin/paclitaxel, followed by maintenance durvalumab plus olaparib (Lynparza).

PFS in the durvalumab arm compared with the placebo and durvalumab/olaparib arms served as the trial's primary end point.

In the dMMR population in the durvalumab and placebo arms, the median age was 63 years (range, 34-85), and 47% of patients were 65 years of age or older. Sixty-two percent of patients were White, 31% were Asian, 2% were Black or African American, 7% were Hispanic or Latino, 1% were American Indian or Alaska Native, and 4% were other or not reported.³

Additionally, 55% of patients had an ECOG performance status of 0, and 45% had a score of 1. Notably, 48% of patients had newly diagnosed disease, including 11% who had stage III endometrial cancer and 38% who had stage IV disease. The remaining 52% of patients had recurrent disease. Histologic subtypes in the study included endometrioid (78%), mixed epithelial (6%), carcinosarcoma (5%), serous (4%), undifferentiated (1%), and other (5%).

Data from exploratory analyses demonstrated a PFS benefit in the dMMR subgroup (HR for durvalumab vs placebo, 0.42; 95% CI, 0.22-0.80; HR for durvalumab plus olaparib vs placebo, 0.41; 95% CI, 0.21-0.75) and the MMR-proficient (pMMR) subgroup (HR for durvalumab vs placebo, 0.77; 95% CI, 0.60-0.97; HR for durvalumab plus olaparib vs placebo, 0.57; 95% CI, 0.44-0.73). A PFS benefit was also observed in PD-L1–positive subgroups (HR for durvalumab vs placebo, 0.63; 95% CI, 0.48-0.83; HR for durvalumab plus olaparib vs placebo, 0.42; 95% CI, 0.31-0.57).

Although overall survival data were immature, trends were observed favoring durvalumab vs placebo (HR, 0.77; 95% CI, 0.56-1.07; P = .120) and durvalumab plus olaparib vs placebo (HR, 0.59; 95% CI, 0.42-0.83; P = .003).

The most common adverse effects reported in more than 25% of patients treated with durvalumab plus chemotherapy included peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.¹

The recommended dose of durvalumab is 1,120 mg with carboplatin plus paclitaxel every 3 weeks for 6 cycles, followed by single-agent durvalumab 1,500 mg every 4 weeks, in patients with a body weight of at least 30 kg. In patients with a body weight of less than 30 kg, durvalumab is recommended at 15 mg/kg in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by 20 mg/kg of durvalumab every 4 weeks.

References

1. FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer. FDA. June 14, 2024. Accessed June 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrent
2. Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
3. Imfinzi. Prescribing information. June 2024. Accessed June 14, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761069s045lbl.pdf