AstraZeneca and MedImmune, its global biologics research and development arm, announced that DETERMINE, the phase IIb clinical trial of 10 mg/kg tremelimumab monotherapy in second or third-line treatment of unresectable malignant mesothelioma, did not meet its primary endpoint of overall survival.
Robert Iannone, senior vice president, head of immuno-oncology, global medicines development at AstraZeneca, said, “We are disappointed that tremelimumab monotherapy did not demonstrate a survival benefit in this patient population with no approved medicines beyond first-line treatment. However, we remain confident in tremelimumab’s clinical activity in combination, as shown in our recently published Study 006 trial of tremelimumab and durvalumab in non-small cell lung cancer.”
In addition to investigation as monotherapy for patients with mesothelioma, tremelimumab is being studied in combination with AstraZeneca’s anti-PD-L1 investigational immunotherapy durvalumab in multiple tumour types, including non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, bladder, pancreatic, gastric and liver cancers. Preclinical data have suggested that targeting both PD-L1 and CTLA-4 may have additive or synergistic effects. In the recently published Study 006, combination treatment with durvalumab and tremelimumab demonstrated antitumour activity in patients with locally advanced or metastatic NSCLC, irrespective of PD-L1 status.
The company will complete a full evaluation of the final DETERMINE data, which will be submitted for presentation at an upcoming medical meeting in 2016.
Mesothelioma is a rare and deadly form of cancer that affects the lining of the lungs or abdomen. There is a high unmet medical need for mesothelioma treatments, with median overall survival 9 to 12 months after initial diagnosis. The disease causes approximately 43,000 deaths per year globally. In 2015, tremelimumab was granted Orphan Drug Designation by the US Food and Drug Administration.
DETERMINE is a randomised, double-blind, placebo-controlled phase IIb global trial with 571 patients across multiple countries. The trial evaluated the safety and efficacy of tremelimumab versus placebo in the treatment of unresectable pleural or peritoneal malignant mesothelioma.
Tremelimumab is an investigational, selective human antibody directed against cytotoxic T- lymphocyte-associated protein 4 (CTLA-4). By blocking the activity of CTLA-4, tremelimumab “releases the brakes” on T cell activation and boosts the immune response against cancer cells. Tremelimumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with durvalumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers. In 2015, the US Food and Drug Administration granted tremelimumab Fast Track designation and Orphan Drug designation as a potential treatment for malignant mesothelioma, an aggressive, rare form of cancer that affects the lining of the lungs and abdomen.
Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 expression enables tumours to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumour's immune- evading tactics. Durvalumab is being developed alongside other immunotherapies to activate the patient's immune system to attack the cancer. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers. In 2015, durvalumab received Fast Track Designation for the treatment of patients with PD-L1–positive metastatic SCCHN, and in 2016, durvalumab was granted Breakthrough designation by the US Food and Drug Administration as a potential treatment for metastatic urothelial bladder cancer.