Will Mystic make it? That’s been the pressing question for AstraZeneca’s immuno-oncology portfolio for months, as data came in from the trial combining its newly approved Imfinzi and experimental tremelimumab.
Answer: It didn’t, at least not yet. And it’s not just AstraZeneca’s rep riding on that news, because Mystic was seen as a scrying glass of sorts. It would foretell which cancer cocktails would dominate over the next few years.
That’s because several companies—including Bristol-Myers Squibb—are invested in the same type of combo as Imfinzi plus tremelimumab, a CTLA4 drug. Others—including Merck & Co.—went the chemo-combo route instead. As Mystic went, so too would the other PD-1/L1-plus-CTLA4 cocktails.
The gist of Mystic’s results so far is this: Imfinzi plus tremelimumab failed to stave off lung cancer progression better than chemotherapy or Imfinzi alone. Imfinzi would not have hit a PFS endpoint either, the company says. The trial will go on—with the hope of showing AZ’s combo prolongs patients’ lives—but with progression-free survival falling short, overall survival success looks less likely.
Analyst notes started flying early Thursday after the company uncloaked its Mystic data, parsing the results, parsing the prospects for similar combo trials and predicting not only that AstraZeneca’s shares would tank when the market opened in its home country—and they did—but that Bristol-Myers’ shares would suffer, too. On the other side of the coin, Merck and Roche, which also have chemo combos in the works, could well get a boost.
“Investors have thought intently on how the Mystic coin will fall with an obsession bordering on mania,” Bernstein analyst Tim Anderson wrote in an early Thursday note to investors. His prediction for the day’s open: “With this first news as ‘bad news,' we expect [AZ] shares to open down sharply. As the other manufacturer leveraged to CTLA4 combination, Bristol-Myers will open downward in sympathy.”
Leerink analyst Seamus Fernandez lined up Mystic alongside Bristol-Myers’ ongoing CheckMate-227 trial, testing its Opdivo PD-1 med with Yervoy, a CTLA4. The company said early this year that it wouldn’t pursue an accelerated approval for the Opdivo-Yervoy cocktail in first-line lung cancer, raising questions on the heels of Opdivo’s failure in a solo first-line lung cancer trial. The combo is approved to treat advanced melanoma.
“The read through is an obvious negative,” Fernandez wrote in an investor note. “While there are differences in trial design between Mystic and CM-227, the inability for Imfinzi + treme to demonstrate a benefit in patients with relatively high PD-L1 expression sharply reduces the chances of success for BMS’ combo in lung cancer, in our view.”
There are caveats here, of course. The trial designs differ, as Fernandez points out. Evercore ISI analyst Umer Raffat mentions a couple, including PD-1 biomarker status in the Bristol-Myers trial and Mystic’s limited dosing versus extended dosing for Opdivo-plus-Yervoy. But still, Fernandez figures those differences “are unlikely to result in meaningfully different outcomes.”
What does this mean for Merck and Roche, with their chemo-combo approach? Merck has already won a quick FDA approval for the Keytruda-chemo regimen, which is expected to put Keytruda in an even better spot in lung cancer. Results are expected later this year from Roche’s pairing of the PD-L1 Tecentriq with chemo, in the phase 3 IMpower-150 trial. With Keytruda’s success there, Roche is handicapped favorably.
There is hope for CTLA4 combos, however. Mystic could yet deliver a surprise, Raffat points out. Several other I-O trials have missed on the progression-free survival front and hit overall survival down the road; consider Roche’s Oak trial in previously treated lung cancer patients, for instance, he said. The drugs didn’t stave off cancer but did prolong patients’ lives, which is really the gold standard for evaluating cancer meds. If Mystic delivers OS benefits, then that’s another story for CTLA4 prospects.
The Opdivo-Yervoy combo could prove out, too, with its Checkmate-227 results, due next year. Merck felt strongly enough about CTLA4 to set up a test of Keytruda with its own candidate of that type, MK-1308. That’s a phase 1 test, though, announced in June of this year. Pfizer, too, is taking a big stab at CTLA4, with a $250 million deal it set up last September with OncoImmune. Pfizer and partner Merck KGaA recently won a nod for their PD-1 med Bavencio, though they haven’t specified combo development with this OncoImmune candidate. Ironically enough, Pfizer offloaded tremelimumab to AstraZeneca back in 2011.
But with BMS' results coming next year and the others in earlier phases, more substantial info on CTLA4 combos won’t come for a while yet, and it’s important to understanding the whole landscape, chemo combos included, Anderson noted. “Absolutely essential to long-term forecasting—whether for AstraZeneca, Merck, or any of the other companies—will be the side-by-side comparison of CTLA4 combination data to chemo combination data. With Mystic failing to hit PFS, this will not be possible now until 2018, most likely.”