Gilead and Arcus Track TIGIT-PD-1 Combination in Head and Neck Cancer Phase 2 Trial
Clinical Design and Progress
Gilead Sciences (GILD) and Arcus Biosciences (RCUS) are jointly developing VELOCITY-HNSCC Substudy-01 as a first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). NCT06727565 is a randomized, open-label Phase 2 trial enrolling approximately 100 patients and is currently in an 'Active, not recruiting' status, with ongoing treatment and follow-up. Both the domvanalimab combination arm and the control arm receive carboplatin and paclitaxel, allowing the trial to assess the pure clinical contribution of TIGIT blockade. The co-primary endpoints are objective response rate (ORR) and progression-free survival (PFS) per RECIST 1.1, with a maximum follow-up period of 36 months.
Drugs and Biological Hypothesis
Domvanalimab (AB154) is an Fc-silenced anti-TIGIT monoclonal antibody, and zimberelimab (AB122) is a PD-1-blocking monoclonal antibody; both are in development and not yet branded. The trial aims to enhance T-cell antitumor activity by dual blockade of TIGIT and PD-1, while suppressing the removal of TIGIT-expressing immune cells through Fc-silent design. The trial includes patients regardless of PD-L1 expression levels, directly testing whether the treatment can extend to PD-L1 low or negative populations. Neither candidate has an FDA-, EMA-, or PMDA-approved indication and remains a clinical development asset prior to regulatory advisory committee (AdComm) review.
Standard of Care and Competitive Landscape
The current standard of care for first-line recurrent/metastatic HNSCC centers on Merck & Co. (MRK)'s Keytruda (pembrolizumab, PD-1) as monotherapy or in combination with platinum-based and 5-FU regimens, which received FDA approval on June 10, 2019. Eli Lilly (LLY)'s Erbitux (cetuximab, EGFR) is an established comparator, FDA-approved for head and neck cancer on March 1, 2006, and used in the EXTREME regimen. Keytruda monotherapy is restricted to PD-L1 CPS ≥1, while the chemotherapy combination is PD-L1 agnostic. Therefore, this trial must demonstrate improved response depth and duration compared to existing PD-1 and chemotherapy regimens, not just patient expansion. Keytruda is projected to generate $31.7 billion in global sales in 2025, setting a high commercial benchmark for the new combination.
Market Potential and Development Risks
The global HNSCC market is projected to grow from $2.49 billion in 2025 to $4.09 billion in 2031, with a CAGR of 8.62%. A PD-L1-agnostic strategy broadens the patient population, but open-label Phase 2 ORR and PFS results alone may not be sufficient to replace standard care. Overall survival (OS), toxicity, and Phase 3 reproducibility will be critical. In particular, the TIGIT class has shown mixed results across tumor types, so the trial must demonstrate clear added efficacy over the zimberelimab-chemotherapy control arm. Success would provide Gilead and Arcus with a foundation to enter the HNSCC immuno-oncology market, though at this stage, the value remains focused on proof-of-concept rather than regulatory approval or revenue generation.
Whether the combination of domvanalimab, zimberelimab, carboplatin, and paclitaxel improves ORR and PFS compared to zimberelimab and chemotherapy in the ~100-patient Phase 2 trial will be key to short-term value shifts. From a research perspective, the trial is significant for evaluating the contribution of Fc-silent TIGIT-PD-1 dual blockade in PD-L1-agnostic HNSCC, using the same chemotherapy backbone. For the industry, it represents an early entry point into a market projected to reach $2.49 billion in 2025 and $4.09 billion in 2031, potentially disrupting the current treatment landscape dominated by Keytruda and Erbitux. However, as both candidates remain unapproved and Keytruda is expected to generate $31.7 billion in 2025 sales, long-term commercial viability will depend on OS and safety data, as well as the decision to advance to Phase 3.
Source: ClinicalTrials.gov (api_ct)