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The preliminary failure of AstraZeneca’s MYSTIC lung cancer trial

A mere bump in the road towards the ultimate success of cancer immunotherapies

Last Thursday, AstraZeneca (AZN) announced the results of the MYSTIC trial, one of the most highly anticipated clinical trials of the year investigating the combination immunotherapy approach of durvalumab (durva) and tremelimumab (treme) in patients with non-small cell lung cancer. To the dismay of lung cancer patients around the world, the trial was a failure. The combination of durva and treme was not able to demonstrate a statistically significant improvement in progression-free survival (PFS) over standard of care chemotherapy. Does this signal the end of combination immunotherapy approaches for cancer? We argue, absolutely not. One reason for AZN’s preliminary failure could have been due to the design of the MYSTIC trial rather than the mechanism of the investigational therapy itself. Unlike Bristol-Myers Squibb (BMY), which is currently conducting a similar combination immunotherapy trial for lung cancer (estimated read-out: first quarter of 2018), AZN may have not gathered enough preliminary data in patients to optimize the dose of durva and treme before heading into the pivotal phase 3 clinical trial. Furthermore, the MYSTIC trial has multiple clinical trial “endpoints” and AZN chose to allocate more “statistical power” to the overall survival (OS) endpoint (estimated read-out: first half of 2018 ) relative to the PFS endpoint, which failed. Thus, technically, the MYSTIC trial could still succeed on the OS endpoint.

With a current combined annual run-rate of ~$9 billion in sales, there is no doubt that cancer immunotherapies such as BMY’s OPDIVO are here to stay. On the combination immunotherapy front, BMY’s OPDIVO + YERVOY has already gained approval from regulatory agencies such as the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, a type of skin cancer. With encouraging early data for other combination strategies including inhibitors of IDO or LAG-3 presented recently at the annual American Society of Clinical Oncology meeting, combination cancer immunotherapy approaches seem to only be getting hotter. As evidence, simultaneously with the news of the failed MYSTIC trial read-out, AZN announced a new partnership with Merck and Co. (MRK), worth up to $8.5 billion, combining AZN’s PARP inhibitor, LYNPARZA, with MRK’s immunotherapy drug, KEYTRUDA. Not to get leapfrogged by their competitor, within a matter of days, BMY fought back by announcing a new collaboration to combine OPDIVO with Clovis Oncology’s PARP inhibitor, Rubraca. Thus, despite the unfortunate preliminary failure of AZN’s MYSTIC trial, cancer immunotherapy approaches are looking stronger than ever. With currently over 40 novel immunotherapy targets (including IL-2, TGF-b, GITR, CSF-1R, and toll-like receptors) being investigated, combination immunotherapy is gaining momentum and poised to extend the lives of hundreds of thousands of cancer patients around the world.


Tasuku Kitada, Ph.D., Senior Biotechnology Analyst