After months of trickling out terse updates, Gilead and partner Arcus Biosciences on Monday unveiled long awaited clinical trial results for an experimental cancer immunotherapy they’ve been developing.
Yet, while the study technically succeeded, the data were not strong enough to convince analysts of the drug’s potential as an addition to current lung cancer treatment, nor did they dispel doubts about its target, an immune cell protein that’s drawn pharmaceutical companies’ interest.
In the trial, which enrolled 149 patients with a common type of lung cancer, adding a drug targeting the protein, called TIGIT, to another type of immunotherapy helped lower the risk of disease progression versus that immunotherapy alone.
But the overall response rate to the two-drug combination, as well as the length of time treated patients went without their cancers growing, fell on the low end of analysts’ expectations. The data also appeared to be below benchmarks from previous trials of similar drugs.
In particular, the other immunotherapy that Arcus used as a comparator, which targets an immune protein called PD-1, appeared less effective than Merck & Co.’s dominant PD-1-blocking drug Keytruda.
“Although today's data are technically ‘positive’ and show TIGIT combos [are] better than monotherapy PD-1 alone, the data are not better than others ahead of them,” wrote Michael Yee, an analyst at Jefferies, in a note to clients.
Li Watsek, an analyst at Cantor Fitzgerald, called the data “a mixed picture” in a client note, adding that she “expects questions to be raised around the low overall response rate and potential underperformance of the PD-1 arm.”
The trial is an important test of Arcus’ experimental cancer drugs, which Gilead has invested heavily in via a 10-year collaboration the companies set up in 2020 and through a Nov. 2021 deal for rights to several of them. The trial is also viewed as a barometer for the potential of drugs targeting TIGIT, which Roche, Merck, Bristol Myers Squibb and GSK have also seen as a promising target for new cancer immunotherapies.
But the failure of two studies testing Roche’s anti-TIGIT drug tiragolumab have diminished early confidence in the target’s promise. The “mixed picture” presented by Gilead and Arcus’ results could add to growing skepticism.
“We think a lot of shine has come off TIGIT,” said Brian Skorney, an analyst at Baird, in a client note. Shares in Gilead fell by a few percentage points in early morning trading, while Arcus stock was down 32%.
Gilead and Arcus have already advanced their TIGIT-blocker, dubbed domvanalimab, into four Phase 3 studies. In a statement, Gilead’s therapeutic area head for oncology, Bill Grossman, said the company “remains committed to accelerating our joint development program with Arcus.”
The companies’ Phase 2 study enrolled patients with non-small cell lung cancer that had not been previously treated and expressed high levels of a protein called PD-L1. Trial participants were randomized to receive either Arcus’ experimental PD-1 inhibitor zimberelimab, a combination of domvanalimab and zimberelimab, or a triplet regimen of both drugs plus a third called etrumadenant.
Results released Monday were from the companies’ fourth interim data analysis, and included 133 patients who had at least 13 weeks of follow-up and two imaging scans. Forty-one percent of patients given the two-drug combination responded, compared to 27% of those given zimberelimab and 40% of those on the triplet regimen.
Both the two- and three-drug combinations reduced the risk of cancer progression versus zimberelimab alone, although the doublet resulted in slightly longer median progression-free survival.
Melissa Johnson, director of lung cancer research at the Sarah Cannon Research Institute and leader of the study, said the “preliminary improvements observed ... reinforce our confidence in the potential therapeutic benefit of inhibiting the TIGIT pathway,” in a statement provided by the companies.
Still, the response rate and progression-free survival marks for the doublet were below what Roche reported from an earlier study of tiragolumab, called CITYSCAPE. To analysts, this was a potentially worrisome sign as Roche’s drug later missed its first goal in a larger trial named SKYSCRAPER-01. Additionally, they questioned whether the underperformance of zimberelimab versus expectations might have flattered the benefit Gilead and Arcus reported for their anti-TIGIT combination.
“We also anticipate skeptics doubling down, as the zim[berelimab] monotherapy arm’s striking numerical underperformance versus historical benchmarks questions whether zim[berelimab] is inferior to [Keytruda] and draws a somber reminder of Roche’s CITYSCAPE experience, where the observed benefit in [progression-free survival] did not translate to the Phase 3,” wrote SVB Securities analyst Daina Graybosch in a note to clients.
In one of the Phase 3 studies Gilead and Arcus have begun, the combination of domvanalimab plus zimberelimab are being compared to Keytruda. Data from that trial aren’t expected until 2025, however.
Before then, Roche will have more data from SKYSCRAPER-01, including on whether tiragolumab helped patients survive longer. Those results, anticipated as early as next quarter, could go far in settling the debate over TIGIT’s merits as a cancer drug target.
“We think if this study fails, it likely indicates a failure of TIGIT,” wrote Skorney.