“People went for Fc-competent [TIGITs] because it worked best in mice,” said Leerink Partners analyst Daina Graybosch, Ph.D. “They couldn\'t help themselves.\"\n Once hailed as the future of immuno-oncology, it’s been a tough few months for any remaining fans of anti-TIGIT antibodies.In April, BeOne Medicines, formerly known as BeiGene, announced it was scrapping ociperlimab over a disappointing phase 3 outlook two years after Novartis handed back the asset. Specifically, the study’s independent data monitoring committee deemed the trial unlikely to show that a combination of ociperlimab and BeOne’s own PD-1 inhibitor Tevimbra would beat Keytruda in patients with PD-L1-high non-small cell lung cancer (NSCLC).The following month brought more tough times for TIGITs, as GSK halted development of its own candidate belrestotug after deciding the iTeos Therapeutics-partnered drug in combination with anti-PD-1 inhibitor Jemperli wouldn’t score a phase 2 win in a similar NSCLC population.Even executives at Roche, whose tiragolumab appeared to buck the trend with a caveated phase 3 win in esophageal cancer in 2024, reaffirmed to Fierce Biotech earlier this year that “we stopped all of the tiragolumab trials that we could stop, and those that couldn\'t be stopped are just running out.”With Big Pharma having pumped $6 billion into this modality, what went so wrong for TIGITs?Daina Graybosch, Ph.D., a senior research analyst at Leerink Partners who covers immuno-oncology, traces the problems back to the exuberant reaction to Roche’s impressive phase 2 tiragolumab data that read out across 2020 and 2021. The Cityscape trial demonstrated that the TIGIT drug in combination with Roche’s own PD-L1 blocker Tecentriq shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.“That\'s probably the biggest point where the field went wrong, in that they looked at this massive benefit in the small phase 2, and everybody ran after it in a parallel and broad way,” Graybosch told Fierce in an interview.“We had randomized phase 2 data from Roche, from Arcus-Gilead, from iTeos-GSK, and they all consistently showed benefit in response rate and in [progression-free survival],” she added.“I think the challenge ultimately was: How much benefit is there really? Is it enough benefit to be clinically meaningful? And are we developing the drugs in the right way, in the right format, to optimize and bring that benefit to patients?”The industry’s “overenthusiasm” for the potential of TIGITs led to a “simplistic approach” to how other companies planned to develop their own candidates, according to Graybosch.If pharmas had anticipated a “more realistic demonstration of benefit,” as seen in the failed Skyscraper-01 phase 3 study in NSCLC, “I think everybody would have developed [TIGITs] differently,” she suggested.Companies swimming in the TIGIT space have broadly fallen into two camps. Roche’s tiragolumab, along with Merck & Co.’s vibostolimab, GSK and iTeos’ EOS-448, and BeOne’s ociperlimab, are all Fc-enabled. These antibodies retain a fully functional Fc region, meaning they can bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system.The theory behind Fc-enabled anti-TIGIT antibodies is that they have enhanced tumor-killing effects. However, the risk is that they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses.In fact, side effects did cast a shadow over some of the Fc-enabled TIGIT trials, with Merck halting a phase 3 trial of vibostolimab due to a higher than expected rate of discontinuations blamed on “immune-mediated adverse experiences.”“Toxicity that may lead patients to discontinue I think ended up being a contributing factor across the Fc-enabled TIGITs that are all now dead,” Graybosch said.The last TIGITs still standing—Arcus Biosciences and Gilead’s domvanalimab, as well as AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—have mutated out the Fc function. This should mean they are less toxic for patients.“People went for Fc-competent because it worked best in mice,” Graybosch explained. “They couldn\'t help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor.” Focusing on \'modest benefit\'So, what would a more measured approach to the TIGIT gold rush have meant in practice?“I think you ultimately do what Astra is doing,” said Graybosch, referring to AstraZeneca’s ongoing phase 3 trials of its bispecific rilvegostomig in a range of phase 3 studies for NSCLC or stomach cancer, including in combination with its Daiichi Sankyo-partnered antibody-drug conjugates Enhertu or Datroway.“Astra is recognizing the modest benefit,” she explained. “Their bispecific is very safe because it\'s Fc silent. And in some ways, Astra can\'t lose because [rilvegostomig] doesn\'t need to work that much for a lot of their trials to be successful.”AstraZeneca’s Puja Sapra, Ph.D., senior vice president for biologics engineering and oncology target discovery, was also upbeat about rilvegostomig’s prospects when she spoke to Fierce back in April. She pointed to the fact that engineering the bispecific to reduce Fc effector functionality should reduce unwanted side effects, while blocking both PD-1 and TIGIT at the same time “should hopefully help us increase the response rate and durability.”“At least in preclinical studies, we see that a bispecific molecule has better responses than a combination of both agents alone,” Sapra said at the time. “The molecule is doing very well in the clinic so far, so we continue to believe in this molecule.”Gilead is also staying loyal to its TIGIT candidate, which is being evaluated in phase 3 trials for first-line NSCLC as well as for locally advanced unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.The pharma’s chief medical officer Dietmar Berger, M.D., Ph.D., told Fierce earlier this month that the Arcus-partnered domvanalimab still has a chance, pointing to its Fc-silent character.“We believe there is differentiation but, of course, we need to see how those studies read out,” Berger said. “Any additional activities around that will be based on what we see in those studies.”With AstraZeneca and Gilead still holding a candle for their Fc-silent candidates, Leerink’s Graybosch doesn’t think “it\'s fair to completely write off TIGIT.”“But if you ask 99% of average investors, generalists or specialists and [key opinion leaders], I think they’ll tell you it\'s dead,” she added.Angus Liu contributed to this reporting.
