Abstract
Genentech's TIGIT-targeted antibody tiragolumab missed its endpoints in two late-stage lung cancer trials, raising doubts about one of the most widely studied next-generation checkpoint targets in immuno-oncology. But numerical signs of benefit among certain patients with metastatic non–small cell lung cancer suggest that TIGIT blockade still has potential—if drug developers can successfully identify the best indications, drug combinations, or patient populations.
The TIGIT-targeted antibody tiragolumab (Genentech) missed its endpoints in two late-stage lung cancer trials, raising doubts about one of the most widely studied next-generation checkpoint targets in immuno-oncology.
But the drug, when administered with the anti–PD-L1 inhibitor atezolizumab (Tecentriq; Genentech), did show a hint of potential efficacy among certain patients with metastatic non–small cell lung cancer (NSCLC), leading some to conclude that the therapeutic premise of TIGIT blockade is still sound—if drug developers can identify the best indications, drug combinations, or patient populations.
“I'm going to give TIGIT a break for the moment,” says Daina Graybosch, PhD, a senior research analyst at SVB Securities in New York, NY. “This isn't clearly yet a bad target.” But, she adds: “We're going to see some skepticism until we have some more data.”
More than a dozen TIGIT-directed antibodies are in clinical testing. Each is intended to prevent the inhibitory receptor—found on cytotoxic T cells, natural killer cells, and regulatory T cells—from binding its ligand, CD155, a checkpoint receptor that tumor cells use to elude immune destruction.
Tiragolumab was the first to enter phase III testing, in 2020, making it the TIGIT frontrunner. But Genentech reported last month that, in the 534-person SKYSCRAPER-01 trial, the drug did not significantly prolong progression-free survival (PFS) compared with placebo when administered with atezolizumab as a first-line therapy for patients with PD-L1–high NSCLC.
Similarly, Genentech announced in March that tiragolumab did not extend PFS for patients with extensive-stage small-cell lung cancer. It did not seem to improve overall survival (OS) either.
To Farahnaz Forozan, PhD, the negative outcome in small-cell lung cancer wasn't unusual because few other checkpoint inhibitors show much activity against the disease. But Forozan, an oncology drug development consultant in Los Angeles, CA, expected better in NSCLC, where earlier-stage trials of tiragolumab plus atezolizumab in patients with elevated PD-L1 expression demonstrated a dramatic benefit (Cancer Discov 2020;10:1086–7). “That surprised me,” says Forozan, who previously oversaw anti-TIGIT antibody programs at Bristol Myers Squibb.
Still, the NSCLC study was not a complete failure, notes Forozan. Genentech did report “numerical” improvements in final PFS and interim OS analyses among participants of SKYSCRAPER-01, although the magnitude of benefit was undisclosed. That trial will continue until more mature OS results are available, and “we'll get a better understanding once these data come in,” Forozan says. “It did obviously miss its first endpoint, but let's see what happens” with OS, a coprimary endpoint.
If those trial results trend in the right direction, Graybosch anticipates that developers of other anti-TIGIT therapies may adapt their study designs accordingly—increasing sample sizes, for example, or altering endpoints—to maximize their likelihood of demonstrating a statistically meaningful benefit.
Graybosch also sees room for better patient selection criteria. For example, trial investigators could enroll only patients with high levels of CD226 on their NSCLC-infiltrating CD8+ T cells. Genentech scientists reported that the expression of this costimulatory molecule, which competes with TIGIT for CD155 binding, was associated with responsiveness to atezolizumab—and they hypothesize that TIGIT blockade could help unleash the full benefit of CD226 signaling in these individuals (Immunity 2022;55:512–26).
The choice of combination checkpoint inhibitor could affect outcomes too, notes Terry Rosen, PhD, cofounder and CEO of Arcus Biosciences in Hayward, CA. For NSCLC trials of its drug, domvanalimab, Arcus and Gilead Sciences are pairing the anti-TIGIT therapy with the companies’ experimental anti–PD-1 agent zimberelimab as well as with the approved PD-L1 inhibitor durvalumab (Imfinzi; AstraZeneca) in phase III trials launching this year.
“The science is strong,” Rosen says. “We've got a randomized phase II dataset that looks great,” with interim analyses showing an improved overall response rate and duration of response with domvanalimab. “So, we're full steam ahead,” he says. –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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