EU CHMP Recommends Lynparza and Imfinzi Combo for Advanced/Recurrent Endometrial Cancer

AstraZeneca’s Imfinzi (durvalumab) and Lynparza (olaparib) have been recommended for approval in the European Union (EU) for patients with primary advanced or recurrent endometrial cancer. The combination of Imfinzi plus chemotherapy as a first-line treatment followed by Lynparza and Imfinzi is recommended for patients with mismatch repair proficient (pMMR) disease. For those with mismatch repair deficient (dMMR) disease, the recommendation is for Imfinzi plus chemotherapy followed by Imfinzi alone.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on a prespecified exploratory subgroup analysis by mismatch repair (MMR) status from the DUO-E Phase III trial, published in the Journal of Clinical Oncology in October 2023.

This analysis showed a 43% reduction in the risk of disease progression or death for pMMR patients in the Lynparza and Imfinzi arm (median 15.0 months vs. 9.7 months, hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.44-0.73) compared to the control arm. For dMMR patients, the Imfinzi arm showed a 58% reduction in the risk of disease progression or death (median not reached vs. 7.0 months, HR 0.42; 95% CI 0.22-0.80).

Endometrial cancer is the fourth most common cancer in women in Europe, with nearly 125,000 diagnoses and more than 30,000 deaths in 2022. Patients diagnosed at an early stage have a five-year survival rate of approximately 80-90%, but this falls to less than 20% for those with advanced disease. There is a significant need for new treatment options, especially for the 70-80% of patients with pMMR disease. This recommendation highlights the importance of MMR testing at diagnosis, which is well established and widely available.

Els Van Nieuwenhuysen, a Gynaecological Oncologist at UZ Leuven, Belgium, and trial investigator, said: “Patients with advanced or recurrent endometrial cancer currently have a very poor prognosis, especially those with mismatch repair proficient disease. This recommendation underscores the significant benefit shown with durvalumab as well as with the olaparib and durvalumab combination for patients with both mismatch repair deficient and mismatch repair proficient status. This marks an important step toward improving outcomes for these patients in Europe.”

Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, said: “Today’s recommendation for approval in the EU recognises the potential of the Lynparza and Imfinzi combination to provide clinical benefit for patients with endometrial cancer, especially for those with mismatch repair proficient disease who have few available treatments today. If approved, patients in Europe will have a new option for combination treatment that brings the additional benefit of PARP inhibition to immunotherapy.”

The safety profiles of both experimental regimens were manageable, well-tolerated, and broadly consistent with the known profiles of the individual agents.

Regulatory submissions for Imfinzi and Lynparza are currently under review in Japan and several other countries based on the DUO-E trial. Imfinzi plus chemotherapy was recently approved for dMMR patients with primary advanced or recurrent endometrial cancer in the US.

Endometrial cancer: This heterogeneous disease originates in the tissue lining of the uterus and is most common in postmenopausal women, with the average age at diagnosis being over 60. The majority of patients are diagnosed at an early stage, where the cancer is confined to the uterus and typically treated with surgery and/or radiation, resulting in a high five-year survival rate of approximately 80-90%. However, for patients with advanced disease (Stage III-IV), the five-year survival rate falls to less than 20%. Immunotherapy combined with chemotherapy is emerging as a new standard of care for advanced endometrial cancer, particularly for patients with dMMR disease, who make up about 20-30% of all patients. There remains a high unmet need for treatments for the remaining 70-80% of patients with pMMR disease.

DUO-E trial: This is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib) as maintenance therapy versus platinum-based chemotherapy alone for patients with newly diagnosed advanced or recurrent endometrial cancer. The trial randomised 699 patients to receive either Imfinzi or placebo with standard-of-care chemotherapy. The dual primary endpoint was progression-free survival (PFS), with key secondary endpoints including overall survival (OS), safety, and tolerability. The trial continues to assess OS for both Imfinzi monotherapy and Imfinzi plus Lynparza as maintenance therapy in the overall trial population.

Imfinzi: Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein, blocking its interaction with PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses. It is approved for several indications, including lung cancers, biliary tract cancer, and hepatocellular carcinoma. Since its first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. It is being tested as a single treatment and in combination with other anti-cancer treatments across multiple cancer types.

Lynparza: Lynparza is a first-in-class PARP inhibitor targeting DNA damage response (DDR) in cells/tumours with homologous recombination-related (HRR) gene deficiencies, such as BRCA1 and BRCA2 mutations. It is approved for multiple tumour types, including ovarian, breast, pancreatic, and prostate cancers. Lynparza is being jointly developed and commercialised by AstraZeneca and MSD and has been used to treat approximately 140,000 patients worldwide. The companies are exploring its effects as a monotherapy and in combination across various cancer types.

AstraZeneca in immuno-oncology (IO): AstraZeneca is pioneering the introduction of immunotherapy into clinical areas of high unmet medical need. The company’s diverse IO portfolio includes immunotherapies designed to overcome tumour evasion and stimulate the immune system to attack tumours. AstraZeneca aims to transform cancer care with Imfinzi and other novel immunotherapies, exploring their use in earlier disease stages with the potential for cure.

AstraZeneca in oncology: AstraZeneca is focused on some of the most challenging cancers, aiming to provide cures through persistent innovation. The company has built a diverse portfolio and pipeline, with the potential to change medical practices and transform patient experiences.

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