Tiragolumab

iStock/ Marcin Klapczynski After several high-pro 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-pro 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-Champagne. “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 pro 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.”

iStock, Tati Campelo High response rates reported by GSK and iTeos at the 2024 European Society for Medical Oncology Congress offer a ray of light for anti-TIGIT therapies after a string of failures. GSK and iTeos Therapeutics revealed data Saturday from the Phase II GALAXIES Lung-201 platform Phase II study, showing that Jemperli and the investigational anti-TIGIT therapy belrestotug elicited promising response rates in patients with non-small cell lung cancer. After at least 5.6 months of follow-up, the combination treatment resulted in a confirmed objective response rate of approximately 60% for every dose. In iTeos’ news release of the data drop, the partners called this effect a “clinically meaningful improvement,” noting that it represented an increase of around 30% versus Jemperli (dostarlimab) alone. Circulating tumor DNA levels also dropped by 94% and 97% from baseline to week 7 in patients who received 400 mg and 1,000 mg of belrestotug, respectively. Jemperli monotherapy counterparts, on the other hand, saw a 65% dip in circulating tumor DNA during this time frame. GSK and iTeos presented these data at the 2024 European Society for Medical Oncology Congress (ESMO 2024). Michel Detheux, iTeos’ president and CEO, noted in a statement that the partners are “encouraged” by these data, which points to the “potential differentiation” of combining an anti-TIGIT therapy with a PD-1 treatment. “The improvement in depth of response in tumor measurement in patients treated with the doublet compared to those treated with PD-1 alone holds promising therapeutic potential for a patient population with limited options,” Detheux added. GALAXIES Lung-201 is a randomized and open-label study that pit the doublet therapy against Jemperli monotherapy in non-small cell lung cancer patients deemed to have high expression levels of PD-L1. To be eligible for inclusion, patients should have been previously untreated and have unresectable and locally advanced or metastatic disease. Aside from efficacy, GALAXIES Lung-201 also looked at the safety of Jemperli plus belrestotug. Results showed that the doublet resulted in higher rates of immune-related adverse events, though these were “generally manageable,” according to Saturday’s news release. Common treatment-related toxicities include skin and subcutaneous disorders, and endocrine disorders. GSK and iTeos are continuing to push the combo regimen toward registration with the recently launched GALAXIES Lung-301 study, which will focus on the same treatment setting and indication. Belrestotug is an IgG1 monoclonal antibody designed to target TIGIT, a crucial inhibitory receptor that cancer cells exploit to suppress the body’s innate and adoptive immune responses. By blocking TIGIT, belrestotug boosts the body’s anti-tumor response, helping to release cytokines and activate antibody-dependent cell-killing mechanisms. With the ESMO 2024 readout, belrestotug returns some much-needed enthusiasm in the TIGIT space, which in recent months has hit a rough patch. In May 2024, Merck scrapped its Phase III melanoma program after the anti-TIGIT antibody vibostolimab, when combined with Keytruda (pembrolizumab), elicited high rates of study dropout due to side effects. In July, Roche was also forced to end a Phase II/III study after its anti-TIGIT therapy tiragolumab, plus Tecentriq (atezolizumab), failed to boost progression-free survival in non-squamous NSCLC patients versus Keytruda plus chemotherapy. A month later, in August 2024, BMS turned its back on a $1.5 billion contract with Agenus and gave back the rights to the anti-TIGIT bispecific antibody AGEN1777.