Last week, AstraZeneca announced that its combination of Imfinzi (durvalumab) and the experimental drug tremelimumab failed to meet its primary endpoint of improving overall survival when compared to the standard of care, platinum-based chemotherapy, in the Phase III NEPTUNE trial.

The trial investigated the combination as a first-line treatment in an all-comers population of patients with stage IV (metastatic) non-small cell lung cancer (NSCLC), with the recent results update discussing the primary analysis group of patients with a high tumor mutational burden (TMB). Imfinzi and tremelimumab are monoclonal antibodies classified as immuno-oncology (IO) treatments as they target PD-L1 and CTLA-4 proteins on tumor cells, respectively, contributing to T-cell activation and boosting the body’s immune response against cancer. Tumors with high levels of TMB are expected to express more markers on the cancer cell surface, and are therefore more visible to the immune system and more vulnerable to immunotherapy; however, it is still undetermined whether TMB status is a reliable biomarker in NSCLC treatment.

Imfinzi + tremelimumab combination clinical trials

AstraZeneca has been trialing Imfinzi as a monotherapy in the Phase III PEARL study, and in various other drug combinations in order to assess its effectiveness in metastatic NSCLC. The Imfinzi + tremelimumab combination is also being tested in combination with chemotherapy in the Phase III POSEIDON trial, but now with lower expectations of success, particularly after failure to meet its primary endpoints of OS and progression-free survival (PFS) in the Phase III MYSTIC trial for first-line treatment of metastatic NSCLC patients in November 2018. NSCLC accounts for approximately 85% of lung cancers and, particularly for patients with metastatic disease, has a poor prognosis with a five-year survival rate as low as 6%. One of the main unmet needs in NSCLC treatment is the need for more effective first-line treatment options that provide OS benefits to patients with no actionable mutations. The promise of IO therapies as life-changing cancer treatments for NSCLC was realized with the approval of Imfinzi monotherapy in February 2018 as the first immunotherapy for the treatment of unresectable stage III NSCLC.

Imfinzi is also marketed for second-line advanced bladder cancer and the combination with tremelimumab is being tested in multiple cancers such as bladder cancer, gastric cancers, liver cancers, other lung cancers. With global sales of $633M in H1 2019, a growth of nearly 244% from the same time last year, Imfinzi’s success is not being limited by its failures. Further, the company stated that it will be undergoing a deep analysis of the clinical and biomarker data from the NEPTUNE trial to gain further insights to improve IO approaches for metastatic NSCLC patients. With this in mind, AstraZeneca should remain aware of big pharma competitors also placing NSCLC as a major area for the development and commercialization of IO treatments such as Bristol-Myers Squibb’s Opdivo, Merck & Co.’s Keytruda, Roche’s Tecentriq, and Pfizer’s Bavencio.

Recently, the demand and uptake of IO therapies over targeted therapies and chemotherapies in NSCLC has risen significantly. GlobalData estimates that by 2025 IO therapies will represent 54% of the total NSCLC market in the eight major markets (8MM: US, France, Germany, Italy, Spain, the UK, Japan, and China), with the major trend in corporate strategy being the pairing of PD-1 checkpoint inhibitors with other agents.