Bioregnum, R&D

AstraZeneca wants a do-over on MYSTIC combo data. But a changeup in focus won’t end the death watch on this pairing

AstraZeneca CEO Pascal Soriot’s decision to bet big on a checkpoint R&D strategy that relied heavily on its in-house combo of PD-L1 and CTLA-4 is starting to look like a blockbuster loser. And this week’s pushback on a subset of the data related to high tumor mutation burden will likely do very little to change the odds here.

John Carroll at the US-China Biopharma Innovation and Investment Summit in Shanghai on October 23, 2018; Credit: Endpoints News, PharmCube

Bioregnum Opinion Column by John Carroll

Researchers for the pharma giant $AZN turned up at the European Society for Medical Oncology Immuno-Oncology 2018 Congress in Geneva this week with more stunningly poor data for the combination of Imfinzi and tremelimumab, which was outperformed by Imfinzi alone — though the monotherapy also failed to stand out in advanced cases of non-small cell lung cancer.

We already knew that the hazard ratio for the combination was a poor 0.85, but Imfinzi’s 24-month overall survival rate was 38.3% compared to an embarrassing 35.4% for the PD-L1 plus CTLA-4 approach.

From AstraZeneca:

Among patients receiving Imfinzi, 40.4% of patients experienced a grade 3 or 4 adverse event (AE) vs. 47.7% with the Imfinzi plus tremelimumab combination and 46.0% with chemotherapy. 5.4% of patients discontinued Imfinzi due to treatment-related AEs vs. 13.2% with the combination and 9.4% on chemotherapy.

Chloé Thépaut

The company’s research team, though, was hoping to pull a victory out of the mouth of defeat by pointing to a much better performance among patients identified with a high tumor mutation burden — putting them on the exact same path that Bristol-Myers Squibb has tried to employ with Opdivo plus Yervoy. In that group there was a 36% drop in risk of death, with a hazard ration of 0.64.

That would have to be confirmed in a new study, though, before regulators would consider it for approval — which may in turn spur another follow-up to Bristol-Myers with a changeup in an ongoing trial to bring that closer to reality.

Bristol-Myers’ own approach to carving out market share among TMB patients, though, has failed to impress analysts as more data came out. Credit Suisse in particular noted a similarity in survival benefit for the low and high TMB groups in Bristol-Myers’ data set, which bodes ill for their market prospects.

And all of this is playing out as Merck continues to rack up big gains using a combination of Keytruda and chemo in lung cancer, which increasingly gains strength as the right combo to turn to initially to improve performance.

CTLA-4 already has a bad reputation for toxicity and marginal OS improvements that’s made it a target for others looking to do better. Eventually, Yervoy is likely to go down in history as the checkpoint that revealed where these therapies could go. It was a massively important starting point in a story that has many chapters to come.

Meanwhile, the tidal wave of checkpoints and combo trials is coming up on the horizon, with plenty of opportunities for someone else to make their mark as AstraZeneca continues to focus on MYSTIC and tremelimumab.

But that game may already be over, especially after another readout for the AstraZeneca combo just days ago underscored its failure in head and neck cancer.

Earlier this week, Chloé Thépaut, senior oncology analyst for GlobalData, put it like this:

Unless data in further indications, such as that expected from the KESTREL trial, can demonstrate superiority of Imfinzi + tremelimumab over the standard-of-care, or show impressive efficacy or promising safety versus competing combinations, it is unlikely that AstraZeneca will have a differentiation point sufficient for the combination to be taken up onto the market.

It may not be time yet to prepare the eulogy on this one, but it’s already on death watch.

Image: Pascal Soriot. GETTY IMAGES

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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