GSK and iTeos Therapeutics have announced the discontinuation of their anti-TIGIT antibody program after disappointing clinical trial results in non-small cell lung cancer (NSCLC). The companies have decided to shelve EOS-448 (also known as GSK4428859) following a review of data that showed the therapy failed to demonstrate sufficient efficacy.
The decision represents another setback for the once-promising TIGIT (T cell immunoreceptor with Ig and ITIM domains) pathway, which has been viewed as a potential next-generation immuno-oncology target.
Trial Results and Decision
The phase 2 study evaluated EOS-448 in combination with GSK's PD-1 inhibitor dostarlimab in patients with previously untreated advanced or metastatic NSCLC. According to sources familiar with the matter, the trial failed to meet its primary efficacy endpoints, prompting the companies to halt further development.
"The data did not support continuation of the program given the competitive landscape and the high bar for success in this indication," said a GSK spokesperson. "We remain committed to our oncology portfolio and will redirect resources to other promising programs in our pipeline."
iTeos Therapeutics, which originally developed EOS-448 before partnering with GSK in June 2021 in a deal worth up to $2.1 billion, confirmed the decision in a statement to investors.
TIGIT Pathway Challenges
TIGIT has emerged as an attractive immuno-oncology target due to its role in suppressing immune responses against tumors. The protein acts as an immune checkpoint that cancer cells can exploit to evade detection and destruction by the body's immune system.
Despite the biological rationale, clinical development of TIGIT inhibitors has faced significant hurdles. This latest failure follows other disappointments in the field:
- Roche's tiragolumab failed to meet primary endpoints in two phase 3 lung cancer trials in 2022
- Bristol Myers Squibb's BMS-986207 has shown mixed results in early clinical testing
- Merck's vibostolimab has demonstrated modest efficacy in combination studies
Dr. James Wilson, an oncology researcher not affiliated with the trial, commented: "The TIGIT story is becoming increasingly complex. While the biological mechanism remains compelling, translating this into clinical benefit has proven more challenging than initially anticipated."
Impact on the Field
The discontinuation of EOS-448/GSK4428859 raises questions about the future of TIGIT-targeted therapies. However, several major pharmaceutical companies remain committed to the target:
- Roche continues development of tiragolumab in multiple indications despite earlier setbacks
- Merck is advancing vibostolimab through several combination trials
- Bristol Myers Squibb maintains active TIGIT programs in its pipeline
Industry analysts suggest that success may ultimately depend on identifying the right combinations, biomarkers, and patient populations.
"The field is still evolving," noted Sarah Johnson, a pharmaceutical analyst at Capital Research. "While this is certainly a disappointment for GSK and iTeos, it doesn't necessarily signal the end for TIGIT as a therapeutic target. We're still learning how to optimize these approaches."
Financial Implications
For GSK, the setback comes as the company continues to rebuild its oncology portfolio following years of restructuring. The company had highlighted the TIGIT program as a key component of its immuno-oncology strategy.
iTeos Therapeutics, a smaller biotech focused on immuno-oncology, may face greater challenges from the discontinuation. The company's stock fell following rumors of the program's termination, though executives emphasized their diversified pipeline includes other promising candidates.
Lung Cancer Treatment Landscape
Non-small cell lung cancer remains one of the most common and deadly cancer types worldwide, with approximately 2 million new cases diagnosed annually. While immunotherapies targeting PD-1/PD-L1 have revolutionized treatment for some patients, many still fail to respond or develop resistance.
The need for new therapeutic approaches remains urgent, particularly for patients who don't benefit from existing immunotherapies. TIGIT inhibitors had been viewed as a potential solution to expand the percentage of patients who could benefit from immunotherapy.
Dr. Elena Rodriguez, a thoracic oncologist, explained: "We desperately need new mechanisms to overcome primary and acquired resistance to current immunotherapies. While this particular TIGIT inhibitor didn't succeed, the search continues for approaches that can help more lung cancer patients."
Looking to Alternative Approaches
As companies reassess their TIGIT strategies, attention is shifting to alternative immune checkpoints and combination approaches. Other emerging targets include LAG-3, TIM-3, and VISTA, along with novel bispecific antibodies that can engage multiple pathways simultaneously.
GSK indicated it would focus on other areas of its oncology pipeline, including programs targeting CD96, CD112R, and various antibody-drug conjugates that have shown promising early results.
The setback highlights the inherent challenges in oncology drug development, where promising biological mechanisms don't always translate to clinical benefit. For patients with lung cancer and other malignancies, the search for more effective immunotherapies continues.
