Durvalumab Plus Chemotherapy: FDA Approval for First-Line dMMR Uterine Cancer Treatment
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On 14 June 2024, the United States Food and Drug Administration (FDA) approved durvalumab (Imfinzi, AstraZeneca UK Limited) with carboplatin and paclitaxel followed by single-agent durvalumab immunotherapy for patients with advanced or recurrent endometrial cancer. This first-line treatment approval applies to patients whose tumors have mismatch repair (MMR) deficiency (dMMR) (this specific genetic condition is explained in detail below).
Previously, on 31 July 2023, for first-line treatment of patients in the same setting, dostarlimab immunotherapy combined with chemotherapy received FDA approval.
Endometrial cancer, the most common subtype of uterine cancer, is among the few cancers with increasing incidence and mortality. It is the third most common cancer among women worldwide and the fourth leading cause of cancer-related death.
More than half of patients with endometrial cancer are diagnosed early because it typically causes noticeable symptoms such as abnormal vaginal bleeding. These symptoms generally prompt women to seek medical attention, enabling earlier diagnosis. Nevertheless, approximately 25-30% of patients are diagnosed at stages 3 and 4. Survival rates for women with advanced or metastatic endometrial cancer have changed little over the past 40 years, reflecting limited advances in systemic therapy.
What Are dMMR and pMMR?
dMMR and pMMR refer to DNA repair mechanisms in endometrial tumors. MMR stands for "mismatch repair," a DNA repair mechanism that corrects mismatched base pairs.
dMMR (Mismatch Repair-Deficient) tumors have lost this mechanism's function and cannot correct mismatched DNA base pairs. This causes a genetic alteration called microsatellite instability-high (MSI-H). Such tumors tend to be more aggressive and more sensitive to the immune system, so they may respond better to immunotherapy.
pMMR (Mismatch Repair-Proficient) tumors have a properly functioning MMR mechanism that can correct mismatched DNA base pairs. These tumors are called microsatellite-stable (MSS) and tend to produce a weaker immune response. Understanding how immunotherapy works in these tumors is therefore important.
Approximately 30% of endometrial cancers are known to be dMMR, and these tumors are generally MSI-H.
The Trial Behind FDA Approval of Durvalumab in Endometrial Cancer
Durvalumab's effectiveness was evaluated in DUO-E, a randomized, multicenter, double-blind, placebo-controlled clinical trial enrolling patients with advanced or recurrent endometrial cancer. Tumor MMR status was determined by immunohistochemical testing of tumor tissue. Patients were randomized 1:1:1 to the following treatment arms:
- Durvalumab: Patients received 1120 mg durvalumab with carboplatin and paclitaxel every 3 weeks for 6 cycles. After chemotherapy, they received 1500 mg durvalumab every 4 weeks until disease progression.
- Placebo: Patients received placebo with carboplatin and paclitaxel every 3 weeks for 6 cycles. After chemotherapy, they received placebo every 4 weeks until disease progression.
- An additional investigational combination regimen.
The primary efficacy endpoint, assessed by investigators according to RECIST v1.1, was progression-free survival (PFS).
Results
Durvalumab with carboplatin and paclitaxel significantly improved PFS compared with carboplatin and paclitaxel alone in the overall population. However, this improvement was particularly pronounced in patients with dMMR tumors.
Among 95 patients with dMMR tumors,
median PFS was not reached (NR) in the durvalumab arm (95% CI: NR, NR), versus 7 months in the placebo arm (95% CI: 6.7, 14.8), with a hazard ratio of 0.42 [95% CI: 0.22, 0.80]. Overall survival, an additional efficacy endpoint, was not yet mature at the PFS analysis.
Side Effects
The most common adverse reactions (more than 25%) to durvalumab with carboplatin and paclitaxel are peripheral neuropathy, musculoskeletal pain, nausea, hair loss, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting and cough. The full adverse reaction list is in the prescribing information.
Recommended Durvalumab Dosage
For patients weighing ≥ 30 kg, the recommended dose is 1120 mg durvalumab with carboplatin and paclitaxel every 3 weeks, followed by 1500 mg durvalumab every 4 weeks. For patients weighing < 30 kg, the recommended dose is 15 mg/kg durvalumab with carboplatin and paclitaxel every 3 weeks, followed by 20 mg/kg durvalumab every 4 weeks.
This new treatment option represents an important advance for patients with dMMR endometrial cancer, with the potential to improve survival and quality of life.
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How Is dMMR Tested?
Testing for dMMR (mismatch repair-deficient) tumors generally involves taking tissue samples and examining them in molecular pathology or genetics laboratories. Two main methods are used:
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Immunohistochemistry (IHC): this method detects absent or low levels of dMMR-related proteins. IHC uses antibodies to target specific proteins, providing information about their presence or absence. The MMR proteins are MLH1, MSH2, MSH6 and PMS2. Detecting absent or low levels of one or more proteins may indicate a dMMR tumor.
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Microsatellite Instability (MSI) Testing: MSI testing compares DNA samples from tumor and normal tissue. It looks for changes in microsatellite regions (short repetitive DNA sequences), which can indicate impaired MMR function. MSI results are generally divided into three categories: MSI-high (MSI-H), MSI-low (MSI-L) and microsatellite-stable (MSS). MSI-H indicates dMMR tumors.
The two methods are generally used together, because results from one can be confirmed with the other. This helps achieve more accurate, reliable diagnosis of dMMR tumors.
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