The combination of Incyte’s epacadostat and Merck & Co.’s Keytruda was supposed to pose a major threat to rival Bristol-Myers Squibb’s melanoma franchise—but the data tell a different story.
After a positive phase 1/2 trial in the skin cancer, IDO1 inhibitor epacadostat and PD-1 inhibitor Keytruda (pembrolizumab) were billed as a potential improvement over BMS’ well-established regimen of PD-1 drug Opdivo (nivolumab) and CTLA4 blocker Yervoy (ipilimumab) for advanced melanoma, with multibillion dollar sales projections.
Unfortunately, the latest phase 3 data found no benefit on progression-free survival for the duo compared to Keytruda alone—and little chance that the overall survival figures would rescue the study—and Incyte says the trial has been abandoned. Shares in the company went into steep decline after the announcement, down more than 20% premarket at last count.
It’s clear things often don’t go according to plan when it comes to testing cancer immunotherapies in the clinic, but this is a particularly worrying development for Incyte as five out of eight pivotal trials of epacadostat involve combination with Keytruda. Two more pair epacadostat with PD-1 blocker Opdivo while another involves AstraZeneca’s PD-L1 drug Imfinzi (durvalumab).
It’s also one of the first major readouts for IDO1 from a pivotal trial, elevating concerns about its role an immuno-oncology target. Scientists working on IDO1 say that tumors upregulate the enzyme to help evade detection by the immune system, and switching that mechanism off should help patients’ mount a stronger response to the malignant cells.
Epacadostat also isn’t the first IDO1 blocker to fall short in trials. Earlier this year, Pfizer returned rights to an IDO1 inhibitor it licensed from iTeos Therapeutics, saying it lacked efficacy in a brain cancer study, while Roche/Genentech abandoned work on NewLink’s GDC-0919 candidate last year after it missed the mark in metastatic breast cancer.
Initial comments by Incyte’s chief medical officer Steven Stein M.D., have understandably been guarded. In a statement, he said the results from the study “will contribute to our understanding of the role of IDO1 inhibition in combination with PD-1 antagonists, and may inform our broader epacadostat clinical development program.”
“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,” he added.
Analysts at Bernstein said in a note to clients: "The failure of IDO adds to the list of disappointment with "second generation" IO drugs – promises by companies and KOLs that the industry was just scratching the surface with anti-PDx therapies have not come true, at least yet. This means that for now, PDx monotherapy, PDx+chemotherapy, and PDx+CTLA4 may end up continuing to be the dominant regimens (evidence in support of the latter continues to build)."