iTeos' TIGIT Inhibitor Shows Promise in Lung Cancer, Reviving Interest in the Target
Key Insights
iTeos Therapeutics' belrestotug, combined with GSK's Jemperli, demonstrated encouraging tumor shrinkage in lung cancer (search) patients, with overall response rates significantly higher than Jemperli alone.
The Phase 2 trial results have sparked renewed interest in TIGIT (search) as a therapeutic target, despite previous setbacks with other TIGIT inhibitors from companies like Roche and Merck (search).
Safety concerns exist, as the combination therapy was associated with a higher incidence of serious side effects and treatment-related deaths compared to Jemperli monotherapy.
Small biotechnology company iTeos Therapeutics is generating renewed interest in TIGIT (search) inhibitors with positive results from a mid-stage clinical trial. The trial showed that adding iTeos’ drug, belrestotug, to GSK’s immunotherapy Jemperli shrank lung tumors in roughly twice as many people as GSK’s therapy alone. The data, presented at the European Society for Medical Oncology (ESMO) Congress, offer a potential path forward for a class of drugs that has faced numerous setbacks.
Promising Efficacy Data
The Phase 2 trial enrolled 124 people with untreated advanced or metastatic non-small cell lung cancer (search) (NSCLC). Patients received one of three doses of belrestotug in combination with Jemperli, or Jemperli alone. Initial overall response rates (ORR), which assess how much tumors shrink, ranged between 63% and 77% across the three combination arms, compared to 38% for Jemperli alone. Confirmed ORRs, based on repeat tumor imaging scans four weeks or later, were roughly 60% in each of the combination groups, versus 28% for Jemperli.
Michel Detheux, iTeos’ president and CEO, expressed enthusiasm about the results, stating, "We are really reaching a stage where we can confirm our best-in-class strategy."
Analysts had set a bar for success at response rates in the range of 55% to 70%, with the iTeos data meeting or exceeding these expectations. For context, Merck (search)’s immunotherapy Keytruda, a standard treatment for this patient population, is associated with overall response rates of around 40%.
Safety Concerns
While the efficacy data are promising, the combination of belrestotug and Jemperli was associated with a higher incidence of serious side effects. Between 25% and 37% of patients in each combination dose group experienced serious side effects related to treatment, compared to 9% in the Jemperli group. Discontinuation rates from these adverse events ranged from 16% to 40% in the combination arms, versus 6% in the control arm. Three patients in the trial died from immune-related inflammation that study investigators judged as related to treatment.
ITeos, in an email to BioPharma Dive, stated that it expects the safety profile of its regimen to be in line with existing immunotherapy combinations. However, the increased risk of serious adverse events will need to be carefully considered in future trials and clinical practice.
TIGIT as a Target
TIGIT (search), short for T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, is an inhibitory receptor expressed on T cells and natural killer (NK) cells. Blocking TIGIT is thought to unleash the immune response against cancer cells. Pharmaceutical companies, including Roche, Merck (search) & Co., Gilead Sciences and Bristol Myers Squibb, have invested heavily in TIGIT inhibitors, but several important studies have failed to show a benefit, leading some companies to scale back their research efforts.
Despite these setbacks, iTeos' data could rekindle some of that interest. Hua Wang, an assistant professor at the University of Illinois Urbana-Champagne, explained that anti-TIGIT (search) therapies aim to reactivate the T and NK cells.
Trial Design and Future Directions
Michel Detheux, president and CEO of iTeos, emphasized the importance of trial design, noting that previous failed TIGIT (search) trials may have been compromised by the inclusion of chemotherapy or by comparing TIGIT inhibitors to inappropriate control arms.
With GSK, Iteos has already begun a Phase 3 test of belrestotug and Jemperli against Keytruda. The study is ongoing, and Iteos intends to report further data in the future. Roche’s SKYSCRAPER-01 study has been running for years and final survival data are expected this year. Preliminary data that was inadvertently disclosed in 2023 suggested a benefit was emerging, but at the time wasn’t strong enough to be statistically clear.