Vibostolimab

In a landscape marred by high-profile setbacks for TIGIT inhibitors, Arcus Biosciences has emerged with a potential bright spot. The biotech is reporting positive overall survival (OS) and progression-free survival (PFS) data from a now-discontinued study evaluating domvanalimab, an Fc-silent anti-TIGIT monoclonal antibody partnered with Gilead Sciences, in combination with the PD-1 inhibitor zimberelimab.Results from the ARC-10 study, shared at the Society for Immunotherapy of Cancer (SITC) annual meeting this week, come as the TIGIT inhibitor class struggles to deliver on its promise. Fizzling enthusiasm for the approach follows clinical failures for Roche's tiragolumab, while Merck & Co. has scrapped studies of vibostolimab in both lung cancer and melanoma. See – Spotlight On: Another vibostolimab setback sets somber tone for any prevailing TIGIT expectations.However, new data from iTEOS Therapeutics and GSK reignited hope in September, with the addition of TIGIT inhibitor belrestotug and the latter's PD-1 inhibitor Jemperli (dostarlimab) showing promising response rates in lung cancer. For more, read KOL Views Q&A: New TIGIT, LAG-3 data suggest transformative potential still on table for at least one in NSCLC.ARC-10 began as a randomised Phase III trial and was later amended to compare domvanalimab plus zimberelimab against Merck's Keytruda (pembrolizumab) in a second part of the study. The first part of the trial, whose results were reported at the SITC meeting, evaluated domvanalimab plus zimberelimab, zimberelimab alone, or platinum doublet chemotherapy in countries where anti-PD-(L)1 monotherapy was not yet standard of care.Arcus and Gilead decided earlier this year to discontinue enrollment in ARC-10, citing a "strategic prioritisation" in favour of advancing two other late-stage trials, STAR-121 and STAR-221, in lung and gastrointestinal cancers, respectively.The data presented at the SITC conference focused on patients with advanced or metastatic NSCLC who had a high level of the PD-L1 marker (TPS ≥50%) and no genetic mutations that could be treated with targeted therapies. As of the May 17 data cutoff, 95 participants had received treatment in the first part of the study.OS benefit of 36%According to Arcus, pairing domvanalimab with zimberelimab led to a 36% reduction in the risk of death compared to zimberelimab alone. Median OS for the combination arm was not reached, while the zimberelimab and chemotherapy arms reached median OS of 24.4 months and 11.9 months. respectively. PFS was also improved with the combo, at 11.5 months versus 6.2 months for zimberelimab and 9.6 months for chemotherapy."These are the first results demonstrating an improvement in overall survival reported for domvanalimab and zimberelimab," said Dimitry Nuyten, chief medical officer of Arcus. "They add to the growing body of evidence that domvanalimab…may have a differentiated efficacy, safety and tolerability profile relative to published data from studies with Fc-enabled anti-TIGIT antibodies."Regarding safety, the combination of domvanalimab plus zimberelimab was also generally well tolerated, with lower rates of treatment-related adverse events (TRAEs) leading to discontinuation compared to chemotherapy. Patients were more likely to stop treatment due to side effects with chemotherapy (23.5%) than with the combination (10.5%) or zimberelimab alone (7.5%).Grade ≥3 TRAEs were also more common with chemotherapy (47.1%) than with the combination (21.1%) or zimberelimab monotherapy (15%). Deaths related to treatment were lower in the combo arm (2.6%, one case of sudden death) compared to zimberelimab (10%, various causes) and chemotherapy (11.8%, various causes).

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.”