After several high-profile failures, including BMS’ $1.5B breakup with Agenus, anti-TIGIT therapies are generating cautious optimism.
TIGIT therapeutics have the potential to extend the benefits of checkpoint inhibitors to patients who can’t yet benefit from the anti-PD-1 and anti-PD-L1 therapeutics that have revolutionized cancer treatment. While the modality has seen a spate of high-profile failures, recent mid-stage data from an anti-TIGIT therapy developed by iTeos Therapeutics shines a light on the continued interest and movement in this space.
Last month at the 2024 European Society for Medical Oncology (ESMO) Congress, iTeos and GSK revealed Phase II results showing that iTeos’ anti-TIGIT candidate belrestotug plus GSK’s anti-PD-1 therapeutic Jemperli elicited promising response rates in patients with non-small cell lung cancer (NSCLC). The data had been highly anticipated, with the prime ESMO presentation spot alone propelling a rise in iTeos’ shares, according to STAT News.
TIGIT, short for T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, is an inhibitory receptor that is expressed on the surface of the T cells and natural killer (NK) cells, as well as other immune cells, explained Hua Wang, an assistant professor at the University of Illinois Urbana-Champaign. “Anti-TIGIT therapies . . . aim to reactivate the T and NK cells,” he told BioSpace.
But while much excitement has surrounded this class of cancer therapy, companies in the space have suffered numerous setbacks, most recently in August when Bristol Myers Squibb canceled a $1.5 billion TIGIT deal and returned the asset to Agenus. Earlier in the summer, Roche and Merck each announced that recent Phase II/III studies comparing anti-TIGIT therapeutics alone or in combination, against either Keytruda or Keytruda plus chemotherapy, failed to meet the primary endpoints.
Despite the challenges, the anti-TIGIT space has remained active. Roche and Merck are both continuing TIGIT studies, for example. “We believe TIGIT is a valid target, based on data and clear activity observed in some tumor types,” a Roche spokesperson told BioSpace in an email.
Readouts for Roche’s Phase III trials of tiragolumab are expected this year in NSCLC, and for esophageal cancer and liver cancer in 2025. Meanwhile, Merck is conducting several Phase III studies evaluating a fixed-dose combination of its anti-TIGIT drug vibostolimab and Keytruda in NSCLC, including KeyVibe-003, KeyVibe-006 and KeyVibe-007.
Other companies in the TIGIT space include BeiGene and AstraZeneca, as well as partners Gilead and Arcus Biosciences. The latter two companies are moving anti-TIGIT therapy domvanalimab and anti-PD-1 antibody zimberelimab plus chemotherapy into Phase III studies for lung and gastrointestinal cancers after positive Phase II data presented in the spring, as GSK and iTeos take their combo into Phase III in first-line NSCLC.
Trial Design Matters
The recent difficulties in the TIGIT space show how trial design affects outcomes, Michel Detheux, president and CEO of iTeos, told BioSpace by email. “Roche, Merck, and Arcus (with Gilead) each evaluated their TIGIT therapeutics combined with a PD-1 and chemotherapy in first-line NSCLC despite no pattern of care having been established to indicate that chemotherapy enhanced efficacy in that setting.”
For example, in 2023, Roche’s SKY-01 Phase III trial “compared its TIGIT+PD-L1 [tiragolumab + atezolizumab] against its own PD-L1 [atezolizumab] instead of the standard of care [Keytruda, a PD-1 inhibitor], which created confusion about the performance of its TIGIT + PD-L1 and PD-L1,” Detheux said.
More recently, he continued, Merck’s Keyvive-008 evaluated vibostolimab plus Keytruda in small cell lung cancer (SCLC). “Merck was attempting to beat a newly established standard of care with its TIGIT+PD-1 therapeutic, despite SCLC being an indication where TIGIT had failed previously, and where [Keytruda] also had failed.” Merck discontinued the Keyvive-008 trial.
What the failed trials show is that “the immune checkpoint axis is perhaps more complicated than we thought,” Michael Gibson, an associate professor of medicine at Vanderbilt University, told BioSpace by email. “More components are involved in the tumor microenvironment than just the drug-target interaction.”
Setbacks should be expected, though, Gibson added. “The nature of clinical investigation teaches us that setbacks are more common than progress. We learn a great deal from so-called negative trials.”
The question of whether setbacks related to TIGIT therapeutics may be overcome “is both scientifically interesting and clinically challenging,” Gibson commented. He speculated that in the face of setbacks, this class may add therapeutic benefits as a combination therapy. While checkpoint inhibitors are the current companions of choice, there may be other possibilities.
“Some insight may lie, for example, in drug mechanisms such as bispecifics and antibody-drug conjugates, combinations of inhibitors, modulation of the tumor microenvironment and even, perhaps, by affecting the patient’s microbiome,” Gibson said.
Notably, “Roche found a correlation between the response to anti-TIGIT therapy and the expression level of CD-155 on the surface of the tumor cell. That’s very positive,” Wang said. “It suggests that patients who are not responding to anti-PD-1 or anti PDL-1 therapies who have a high expression level of CD-155 may respond to anti-TIGIT therapeutics.”
Bright Lights
Based on recent results from iTeos and GSK, as well as Gilead and Arcus, it appears the tide may be beginning to turn.
At ESMO, iTeos and GSK reported that after at least 5.6 months of follow-up, 60% of patients given the belrestotug/Jemperli combo had an objective response, compared to about 30% of those given Jemperli alone.
What sets belrestotug apart from most other TIGITs is that it has a mutli-faceted mechanism of action and appears effective at low doses, Detheux noted. TIGIT therapeutics by BeiGene, Roche and Merck required either “very high doses” or were ineffective, he said.
Belrestotug is also the only TIGIT program that has had to comply with the FDA’s Project Optimus, with a dose-ranging exercise required to understand the efficacy and safety profile of its TIGIT+PD-1 doublet, Detheux said. “We believe this will allow GSK and iTeos to succeed in selecting the optimal dose, whereas others have struggled and launched Phase III trials without conducting a more in-depth review of the dose selection.”
Meanwhile, at the 2024 American Society of Clinical Oncology conference, Gilead and Arcus presented Phase II data from a combination of domvanalimab and zimberelimab plus chemotherapy in upper GI cancers. It showed that nearly 60% of patients achieved progression-free survival at 12 months.
“By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting critical immune cells,” a Gilead spokesperson told BioSpace by email.
Currently, fewer than 40% of cancer patients respond to immunotherapy. “Therefore, we need more new technology and immunotherapies and we have to keep testing. Hopefully, patients will respond,” Wang said. But, he added, whether future therapeutic options will include anti-TIGIT therapeutics remains to be seen.
“I would be cautious about [speculating] whether anti-TIGIT therapeutics will be successful, but there’s some hope.”
