- AstraZeneca revealed Thursday its checkpoint inhibitor Imfinzi failed to improve progression-free survival (PFS) in the closely watched MYSTIC study of lung cancer patients, dealing a major blow to the British drugmaker's hopes of catching rivals in immuno-oncology.
- A combination pairing Imfinzi with AstraZeneca's experimental CTLA-4 inhibitor tremelimumab fell short of MYSTIC's PFS primary endpoint in first-line treatment of metastatic non-small cell lung cancer. In a further disappointment, Imfinizi monotherapy also would not have beaten out standard-of-care treatment, AstraZeneca said — although that secondary objective was not formally tested.
- Shares in the drugmaker plunged more than 15% in early Thursday trading on the news, reflecting the importance of this trial in AstraZeneca's bid to become an oncology leader and shake off damaging patent expiries.
As anticipation of MYSTIC study's outcome steadily grew this summer, AstraZeneca worked to temper expectations and caution that a miss on PFS would not spell complete failure for Imfinzi in first-line lung cancer.
And, largely, that's how AstraZeneca is framing MYSTIC's initial failure, despite the large implications for the company and for CEO Pascal Soriot. "Despite the outcome of the initial readout, we must be patient as the MYSTIC trial continues as planned to evaluate overall survival," AstraZeneca CEO Pascal Soriot said in a statement provided to BioPharma Dive Thursday morning.
That overall survival (OS) data is expected in the first half of 2018, giving AstraZeneca and its investors a sliver of hope that either Imfinzi monotherapy or the combination could still eke out a small win.
Given the fast-moving nature of the immuno-oncology field, though, and continued progress from rivals, MYSTIC's miss risks leaving AstraZeneca on the outside looking in. And the chances of hitting on OS are certainly not improved by a failure on PFS measures.
"We are skeptical of Mystic's ability to show an OS benefit for both mono and combo following the PFS fails, given that it will be further confounded by cross over," wrote Jefferies analyst Jeffrey Holford in a July 27 note calling the news a "significant blow."
AstraZeneca still believes it has a shot, noting carefully that OS results can differ from PFS data in immuno-oncology. "We need OS to fully qualify the clinical profile of the I/O medicines, which is why we refined the trial design [for MYSTIC]," Chief Medical Officer Sean Bohen said on Thursday's conference call. In March, AstraZeneca modified MYSTIC so it would assess both PFS and OS for both the combination and Imfinzi monotherapy, hoping to build in multiple chances at success.
AstraZeneca tested Imfinzi plus tremelimumab in patients whose tumors expressed PD-L1 levels higher than 25%, a cut-off designed to help Imfinzi chances of showing a benefit. Higher expression of PD-L1 is thought to be generally correlated with an increased rate of response, although limiting treatment to only "expressers" reduces the number of patients who could potentially be treated.
Bristol-Myers Squibb famously learned that lesson the hard way, pushing to test its flagship checkpoint inhibitor Opdivo (nivolumab) in lung cancer patients with 5% or greater PD-L1 expression. That study failed last year, opening the door for Merck & Co. to gain an advantage with its competing Keytruda (pembrolizumab). Merck had initially been more conservative, opting to study its drug only in patients with 50% or higher expression levels.
Billion-dollar cancer partnership
While Bristol-Myers still earns more in sales from Opdivo, Merck is now widely seen as the leader in the space. AstraZeneca certainly seems to agree, announcing alongside its statement on MYSTIC that it would join up with Merck in an $8.5 billion cancer partnership.
That deal gives Merck rights to 50% of revenues earned from AstraZeneca's PARP inhibitor Lynparza (olaparib) and another experimental treatment (if approved), while AstraZeneca will receive $1.6 billion upfront and another $750 million for license options. AstraZeneca gets some immediate cash at the cost of giving up half of Lynparza's commercial returns, and hedges against a reduced ability to carve out market share with a slower-growing Imfinzi.
Yet AstraZeneca hopes positive results from the earlier PACIFIC study in Stage 3 unresectable NSCLC could give Imfinzi a head start in an indication without any current competition from other immuno-oncology agents. Company oncology chief Jamie Freedman said AstraZeneca is likely two to three years ahead of its rivals in this market, and could reap blockbuster sales from that indication alone.
Whether that materializes remains to be seen, and without MYSTIC, Imfinzi's ability to compete in the broader lung cancer market is markedly reduced.
Editor's note: A previous version of this article incorrectly identified the PD-L1 expression cut-off used in Bristol-Myers Squibb's Checkmate-026 study of Opdivo in non-small cell lung cancer. The article has been updated with the correct 5% expression level used as a threshold.