Dive Brief:

• AstraZeneca's Imfinzi, both by itself and combined with an investigational immuno-oncology drug, failed to significantly improve overall survival when used as a first-line treatment for certain patients with metastatic non-small cell lung cancer, according to new results from the Phase 3 MYSTIC trial.
• In MYSTIC, NSCLC patients with 25% or greater PD-L1 expression were given either Imfinzi, Imfinzi plus a CTLA-4 inhibitor called tremelimumab, or standard of care chemotherapy. Results published last summer showed the combination failed to significantly improve progression free survival, dampening hopes that it would succeed on the tougher co-primary endpoint of OS.
• Indeed, the pairing missed on that measure. But more surprising, at least to analysts, was Imfinzi monotherapy failing to outperform standard of care chemotherapy. Cowen & Co. said "statistical issues" could be behind the disappointing outcome, since AstraZeneca "had to split the available statistical power of 5% into three endpoints."

Dive Insight:

Imfinzi (durvalumab) first gained approval as a bladder cancer medicine, but broke into the lung cancer market earlier this year after the Food and Drug Administration approved it for Stage 3 NSCLC patients whose tumors can't be eliminated through surgery. Key to that approval were data from the PACIFIC trial.

The lung cancer indication accounted for the vast majority of the $371 million in revenue Imfinzi brought in during the first nine months of 2018 — and should continue to prop up sales in quarters to come, according to AstraZeneca leadership.

"In the U.S., we see roughly half of the PACIFIC-eligible patients in the setting are getting an immunotherapy. The majority of those are getting Imfinzi, and we continue to see a positive impact on chemo radiation rates in the U.S. as more patients are becoming eligible for Imfinzi now within this setting," said David Fredrickson, global head of AstraZeneca's oncology business, on the company's third quarter earnings call.

The outlook isn't as positive, however, on the metastatic NSCLC front.

There, Merck & Co.'s Keytruda (pembrolizumab) holds a commanding lead over rival therapies. It's already approved as monotherapy for first-line treatment of metastatic NSCLC patients with PD-L1 expression of at least 50% or more. Additionally, Keytruda combined with chemotherapy is approved in the first-line setting for both squamous and non-squamous metastatic NSCLC patients regardless of PD-L1 expression.

What's more, the KEYNOTE-042 trial showed Keytruda monotherapy offered a significant OS benefit when used as a first-line treatment for advanced or metastatic NSCLC patients with PD-L1 expression of 1% or greater — data that could help secure a valuable label expansion.

MYSTIC, meanwhile, hasn't panned out for Imfinzi, either alone or in combination with tremelimumab​.

AstraZeneca isn't giving up, though. The company said in a Nov. 16 statement that the results "support further analysis in exploratory subgroups." It also has several other ongoing trials in the first-line NSCLC setting such as the Phase 3 POSEIDON study, which is testing Imfinzi plus chemo and a triple combination of Imfinzi, tremelimumab and chemo. A primary completion of that trial is set for September 2019.

Cowen also notes that it's unclear exactly what the ramifications of MYSTIC will be.

For instance, Bristol-Myers Squibb has also been testing a combination of its PD-1 drug Opdivo (nivolumab), and a CTLA-4 inhibitor Yervoy (ipilimumab) as a first-line therapy for NSCLC patients with high levels of a biomarker known as tumor mutational burden, or TMB.

"On the less favorable side, MYSTIC is certainly not an endorsement of the IO + IO strategy — and/or CTLA4 overall — in [first-line] NSCLC," Cowen & Co. analyst Steve Scale wrote in a Nov. 16 note. "On the positive side, should Opdivo + Yervoy hit OS (data due early 2019), it would be the only IO + IO regimen approved in [first-line] NSCLC."