On 14 April, GlaxoSmithKline announced that it was halting enrolment in its two ongoing trials and discontinuing treatment with its inducible T-cell costimulator (ICOS) agonist, GSK-3359609 (feladilimab), for the treatment of head and neck cancer squamous cell carcinoma (HNSCC), following a recommendation by the independent data monitoring committee after an interim review. The company did not provide a specific reason for halting the trials. 

GSK-3359609 is a form of immunotherapy-targeting ICOS that is under development for the treatment of advanced solid tumours, such as bladder cancer, cervical cancer, esophageal cancer, urothelial cancer, clear renal cell carcinoma and several other tumour types amenable to immuno-oncology. The ICOS co-stimulatory receptor is essential for the regulation of T-cell activation and function. This inducible co-stimulatory molecule, a member of the CD28/CTLA-4 family, is expressed on activated T-cells and plays an important role in cell signalling, immune responses and the regulation of cell proliferation.

The active drug candidate GSK-3359609 was in pivotal Phase II/III clinical trials, where it was being developed by GlaxoSmithKline for recurrent or metastatic HNSCC, specifically oral cavity (mouth), oropharyngeal, hypopharyngeal and laryngeal cancers. The INDUCE-3 (NCT04128696) and INDUCE-4 (NCT04428333) trials were assessing its efficacy for use in combination with Merck and Co’s Keytruda (pembrolizumab), with or without chemotherapy, for the first-line treatment of programmed death-ligand 1 (PD-L1) positive recurrent or metastatic HNSCC.

GSK-3359609’s Phase I INDUCE-1 (NCT02723955) trial results reported a manageable safety profile and a median progression-free survival (mPFS) of 5.6 months, which is similar to commonly adopted treatments in first-line settings in HNSCC, such as Keytruda and cetuximab. If it reaches launch, this ICOS agonist would supplement Keytruda for use in the first-line setting and could replace Keytruda-chemotherapy regimens upon demonstrating a clinically significant improvement in patient outcomes.

Since the initial safety and clinical effectiveness results for this drug looked promising, GlaxoSmithKline is likely to initiate a complete data analysis of INDUCE-3 and INDUCE-4 trials as well as an impact assessment on its overall clinical development. ICOS agonists are believed to enhance the durable clinical benefit of immune checkpoint inhibitors through their mechanism of action. ICOS agonists have, however, seen failures in recent years, with Jounce Therapeutics halting its EMERGE clinical development programme for vopratelimab in combination with Bristol Myers Squibb’s CTLA-4 inhibitor, Yervoy (ipilimumab), in non-small cell lung cancer (NSCLC).

As such, the success of ICOS as a clinically meaningful target may be questionable. Because it is a leader in antivirals and infectious disease research and development (R&D), GlaxoSmithKline’s recent efforts have focused on growing its oncology and immunology portfolio. While several other late-stage assets remain in its R&D pipeline, these recent trial failures may pose obstacles for the future commercial success of its oncology portfolio.