AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer

One of AstraZeneca’s big hopes, a combo of its new I-O med with another experimental cancer drug, has missed a key primary endpoint in first-line lung cancer patients.

The phase 3 test was seeking to boost progression-free survival (PFS) in advanced, first-line non-small cell lung cancer patients using either its PD-L1 checkpoint inhibitor Imfinzi (durvalumab) as a monotherapy, or Imfinzi in combo with CTLA-4 drug tremelimumab.

The medications were pitted against platinum-based standard-of-care, but after much speculation the British-based drugmaker said it had failed to improve PFS when compared to chemo in patients whose tumors express PD-L1 on 25% or more of their cancer cells.

AZ isn’t giving up completely, however, and said: “The trial will continue to assess two additional primary endpoints of overall survival (OS) for Imfinzi monotherapy and OS for the Imfinzi plus tremelimumab combination.”

Final OS readouts from both endpoints are expected during the first half of next year.

Sean Bohen, EVP of global medicines development and CMO at AstraZeneca, said: “While the results from the Mystic trial for progression-free survival in first-line Stage IV non-small cell lung cancer compared with standard of care are disappointing, the trial was designed to assess overall survival and we look forward to evaluating the remaining primary endpoints of overall survival for both mono- and combination therapy.”

There has been increasing speculation about the Mystic trial in recent months, with reports from an Israeli newspaper suggesting that AZ CEO Pascal Soriot was set to leave the company for Teva; he has since denied these reports.

AZ really needed a win from this trial and comes after several setbacks in cancer and asthma over the past 18 months. It also comes after tremelimumab flunked a mesothelioma test last February, as the company refocused the med as a combo therapy. 

Analysts at Jefferies said in a note this morning: “We have modeled $5.1 billion peak sales around Mystic, but heavily risk-adjusted: We currently model around $3.3 billion in peak sales for durvalumab in metastatic NSCLC and around $1.8 billion for tremelimumab, which is primarily predicated on the outcome of Mystic.

“Of the $3.3 billion durvalumab peak in metastatic NSCLC, only around $500 million is in monotherapy, with the remaining $2.8 billion assumed to be in combo use with tremelimumab. Even without final clarification from the OS endpoints, we expect the stock to largely reflect the full failure of Mystic today.” Since its launch in May, Imfinzi has made $1 million, and was fifth to market, years after leaders Bristol-Myers Squibb and Merck. 

Jefferies' model now assumes 65% and 33% probabilities of success for the mono and combo arms of Mystic, respectively. It said to expect takeover talk to crop up today on the failure and to see its shares down by around 10% to 15%. It was in fact down nearly 16% in London in early trading this morning.

RELATED: AZ's Mystic shortfall is an I-O shakeup for Bristol and a bolster for Merck and Roche

The results came amid its financials, which also highlighted three NMEs that have been removed from phase 2 testing, namely MEDI4076, an anti-miR103/107 oligonucleotide in fatty liver disease NASH; MEDI4166, a PCSK9/GLP-1 mAb + peptide fusion diabetes/cardiovascular drug; and verinurad, a selective uric acid reabsorption inhibitor (URAT-1) chronic treatment of hyperuricemia in patients with gout.

It also said that core R&D spend dropped by 7% (4% at CER) to $2.61 billion ($3.43 billion) for the first half. It says this comes as AZ continues "to focus on resource prioritization and cost discipline."

RELATED: Top biopharma R&D budgets 2016: AstraZeneca

On its results call this morning, Soriot said its financials were "overshadowed" by the Mystic data, and by the rumors of his departure. He didn't offer the firmest of denials, but said he was "committed" to AstraZeneca and was not a "quitter." He added: "The only thing I tell you is I'm here today" and "proud to lead AstraZeneca."

On the combo data, Bohen said: "We haven't had time to dig deep into Mystic data yet, but pseudoprogression is unlikely to have been confounding factor," adding that he was still optimistic about hitting the OS target, the gold standard in oncology trials.