Mismatch Repair Status as a Predictive Biomarker for Anti-PD-L1 Immunotherapy

Clinical Trial Results: Durvalumab in Endometrial Cancer

• July 17, 2019
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Between May 31 and June 4, 2019, the ASCO 2019 Annual Meeting in Chicago presented results from the PHAEDRA Phase II clinical trial evaluating the efficacy, safety, and biomarker associations of durvalumab monotherapy in treatment-experienced endometrial cancer patients stratified by mismatch repair (MMR) status.

Trial Design and Patient Population

The PHAEDRA Phase II clinical trial enrolled 71 treatment-experienced endometrial cancer patients with either proficient MMR (pMMR, n=36) or deficient MMR (dMMR, n=35) status. Patients received durvalumab monotherapy 1,500 mg intravenously every four weeks. The primary endpoint was objective response rate (ORR), with secondary endpoints including disease control rate (DCR) at week 16 and safety assessments.

Rationale for MMR-Based Patient Selection

Clinical rationale for this trial design was based on two key observations:

1. Approximately 15% of endometrial cancer patients demonstrate dMMR phenotype
2. Prior trials reported exceptionally high PD-L1 expression in endometrial cancer patients (up to 90%)

These characteristics suggested that endometrial cancer patients with dMMR status might represent an enriched population for anti-PD-L1 immunotherapy response.

Clinical Trial Results

Primary Endpoint - Objective Response Rate:

• dMMR group: 40%
• pMMR group: 3%

Secondary Endpoint - Disease Control Rate (at week 16):

• dMMR group: 60%
• pMMR group: 19%

Safety Profile

Immune-related adverse events (irAEs) were observed in 14 patients, including:

• Hyperthyroidism: 6 patients
• Hypothyroidism: 6 patients
• Pneumonitis: 1 patient
• Hepatitis: 1 patient

Clinical Conclusions

Principal investigator Yoland Catherine Antill concluded that dMMR-phenotype endometrial cancer patients demonstrate robust anti-tumor response to durvalumab monotherapy. Conversely, pMMR endometrial cancer patients demonstrate limited treatment efficacy, suggesting that mismatch repair deficiency serves as a predictive biomarker for durable response to PD-L1 checkpoint inhibition.

Data Source

Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601). 2019 ASCO Annual Meeting, Abstract No:5501.

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