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Incyte/Merck trial failure bodes ill for IDO class

The much-touted cancer immunotherapy combination fails to show improvement over Keytruda alone

Merck and Co US headquarters

Ahead of the weekend, Incyte and partner Merck & Co were rocked by the news that their much-touted cancer immunotherapy combination had failed comprehensively in its first phase III test.

The pairing of Incyte’s IDO1 inhibitor epacadostat and Merck’s well-established PD1 inhibitor Keytruda (pembrolizumab) had shown promise in mid-stage trials as a treatment for the advanced melanoma, a form of skin cancer, but was unable to show any improvement over Keytruda alone on progression-free survival in the pivotal ECHO-301 study.

The failure in the first of several phase III trials of epacadostat and Keytruda undermines the idea that IDO1 inhibition is a valid target for cancer immunotherapy, affecting not only Incyte but also other companies developing drugs against the target such as Bristol-Myers Squibb (BMS) and NewLink Genetics, which both have candidates in late-stage trials.

BMS is also partnered with Incyte on a trial of its PD-1 inhibitor Opdivo (nivolumab) with epacadostat, as is AstraZeneca with its PD-L1 blocker Imfinzi (durvalumab), so the blow is being felt widely across the immuno-oncology sector.

Incyte wasn’t attempting to downplay the implication of the trial in a conference call on Friday, saying that the failure of ECHO-301 reduced the likelihood of success in its other combination studies. It was particularly alarming that there was no hint of efficacy across any patient subgroups in the trial.

"We are disappointed that this study did not confirm the efficacy of epacadostat in combination with Keytruda in patients with unresectable or metastatic melanoma," said Steven Stein, chief medical officer of Incyte, in a press release.

"We remain dedicated to transforming the treatment of cancer and will continue to explore how IDO1 inhibition and other novel mechanisms can potentially improve outcomes for patients in need."

Analysts at Bernstein gave a direct assessment of the failure in a research note on the development, saying: “Frankly, the writing seemed to be on the wall that this combination would not work, and that IDO in general remains a questionable target.”

Roche pulled out of IDO R&D last year “and said it was not excited about the approach”, they continue, adding that Merck’s management “seemed to strike an appropriately cautious note when describing the probability of success with the approach over the past several months.” Roche dropped a NewLink-partnered candidate last year, and in January Pfizer returned rights to another IDO drug licensed from iTeos.

“The failure of IDO adds to the list of disappointment with ‘second generation’ [immuno-oncology] drugs,” said Bernstein. That means for now, PD1/PD-L1 inhibitors as monotherapy, or combined with chemotherapy or CTLA4 drugs like BMS’ Yervoy (ipilimumab) “may end up continuing to be the dominant regimens”.

Article by
Phil Taylor

9th April 2018

From: Research

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