Investigational Drug
Domvanalimab
HealthScout AI Analysis
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Overview
Domvanalimab (AB-154; GS-0154) is an investigational, Fc‑silent humanized IgG1 monoclonal antibody that targets TIGIT, an inhibitory receptor on T cells and NK cells. It is being developed primarily in combination with anti‑PD‑1 therapy (notably zimberelimab) across lung and gastrointestinal cancers, among others. Randomized clinical data have been reported in first‑line PD‑L1–high metastatic NSCLC (ARC‑7, phase 2; ARC‑10, randomized study) and early phase results are available in first‑line upper GI adenocarcinoma (EDGE‑Gastric, phase 2). (ascopubs.org)
Mechanism of action
- Target: TIGIT (T‑cell immunoreceptor with Ig and ITIM domains), which competes with the activating receptor CD226 for binding to CD155/CD112; TIGIT engagement dampens anti‑tumor immunity. Blocking TIGIT can enhance T‑ and NK‑cell function and complements PD‑1 blockade. (aacrjournals.org)
- Antibody design: Domvanalimab is Fc‑silent (engineered to minimize FcγR engagement), aiming to avoid depletion of TIGIT‑expressing effector cells and to reduce Fc‑mediated toxicities while maintaining checkpoint blockade. Preclinical and translational work supports anti‑tumor activity of Fc‑silent anti‑TIGIT in combination with PD‑1 inhibitors. (aacrjournals.org)
Efficacy
Non–small cell lung cancer (NSCLC), first‑line, PD‑L1–high
- ARC‑7 (phase 2, randomized; NCT04262856): Domvanalimab + zimberelimab (DZ) improved outcomes versus zimberelimab alone (Z).
- ORR: 41% with DZ vs 27% with Z; median PFS: 12.0 vs 5.4 months; HR for PFS 0.55 (95% CI 0.31–1.0), with consistent benefit also seen for the triplet that added etrumadenant. (ascopubs.org)
- ARC‑10 (randomized study in PD‑L1–high NSCLC): Part 1 results reported a 36% reduction in risk of death for DZ vs Z (OS HR 0.64); median OS not reached with DZ, ~2 years with Z; PFS and ORR also favored DZ over Z and over chemotherapy. (Late‑breaking SITC 2024 poster; detailed peer‑reviewed manuscript not yet available.) (investors.arcusbio.com)
Gastroesophageal adenocarcinoma, first‑line
- EDGE‑Gastric Arm A1 (phase 2): DZ + FOLFOX showed ITT ORR 59% (confirmed ORR 54%); 6‑month PFS rate 75%. In PD‑L1‑high tumors, confirmed ORR 67% and 6‑month PFS 93%. Subsequent update reported median PFS exceeding 1 year in the cohort. A phase 3 trial (STAR‑221) is ongoing with the same regimen. (ascopubs.org)
Hepatocellular carcinoma (post–anti‑PD‑(L)1 refractory)
- LIVERTI (phase 2, single‑arm): DZ in 29 patients produced a confirmed ORR 17.2% (95% CI 5.8–35.8) and median PFS 4.4 months; treatment was generally tolerated. (Peer‑reviewed publication 2025.) (pubmed.ncbi.nlm.nih.gov)
Key ongoing phase 3 programs include STAR‑121 (DZ + chemotherapy vs pembrolizumab + chemotherapy in metastatic NSCLC without actionable drivers) and STAR‑221 (upper GI adenocarcinomas). (ascopubs.org)
Safety
Across studies to date, domvanalimab‑containing regimens have shown safety profiles broadly consistent with PD‑1–based therapy, without unexpected signals:
- ARC‑7: Grade ≥3 treatment‑emergent AEs occurred in 47% (DZ) vs 58% (Z); immune‑related AEs were generally low and manageable; infusion reactions were uncommon (≈4%). (ascopubs.org)
- ARC‑10 (Part 1): Treatment‑related discontinuations with DZ were reported at 10.5%, lower than with chemotherapy (23.5%). (investors.arcusbio.com)
- EDGE‑Gastric: Toxicities largely reflected chemotherapy; grade ≥3 AEs related to DZ were infrequent (≈12%); infusion reactions 10–20%, mostly attributed to chemotherapy. (ascopubs.org)
The Fc‑silent design is intended to reduce Fc‑mediated depletion of TIGIT‑expressing lymphocytes; preclinical work shows Fc‑silent anti‑TIGIT can potentiate anti‑tumor immunity without Treg depletion, supporting the observed clinical tolerability. (aacrjournals.org)
Further reading
- ARC‑7 randomized phase 2 NSCLC abstract (ASCO): ORR and PFS improvements with domvanalimab combinations. (ascopubs.org)
- ARC‑10 SITC 2024 late‑breaking poster press release (OS benefit of DZ vs Z). (investors.arcusbio.com)
- EDGE‑Gastric phase 2 ASCO plenary abstract and 2024 update. (ascopubs.org)
- Fc‑silent anti‑TIGIT translational/preclinical data (Cancer Research 2024). (aacrjournals.org)
- AB154 (domvanalimab) preclinical characterization (AACR abstracts). (aacrjournals.org)
- Trial overviews: STAR‑121, VELOCITY‑Lung, ARC‑7 (protocols/abstracts). (ascopubs.org)
Notes - All data above are investigational and subject to change pending full peer‑reviewed publications and final readouts. Where only conference abstracts or company communications are available (e.g., ARC‑10), the figures should be interpreted accordingly. (investors.arcusbio.com)
Last updated: Oct 2025
Active trials using Domvanalimab
Found 4 active trials using this drug:
HealthScout AI summary: First-line study for adults with recurrent/metastatic, non-nasopharyngeal HNSCC (ECOG 0–1, measurable disease, no prior PD-1/TIGIT; prior curative-intent platinum allowed if relapse >6 months) comparing zimberelimab (anti–PD-1) plus carboplatin/paclitaxel with or without domvanalimab, an Fc-silent anti-TIGIT antibody that augments T-cell activity. Aims to determine whether adding anti-TIGIT to PD-1 blockade and platinum-taxane chemotherapy improves ORR and PFS.
ClinicalTrials.gov ID: NCT06727565
HealthScout AI summary: Adults with metastatic pancreatic adenocarcinoma/squamous histology who have at least stable disease after 4–6 months of first‑line FOLFIRINOX are randomized to switch‑maintenance immunotherapy with domvanalimab (anti‑TIGIT) + zimberelimab (anti‑PD‑1) + APX005M/sotigalimab (CD40 agonist) versus continued maintenance FOLFIRI. Key exclusions include progression on FOLFIRINOX, prior checkpoint or CD40 therapy, significant autoimmune disease, active HBV/HCV/HIV, and germline BRCA1/2 mutations; crossover to the immunotherapy arm at progression is allowed.
ClinicalTrials.gov ID: NCT05419479
HealthScout AI summary: This trial enrolls adults with newly diagnosed stage IV NSCLC without EGFR, ALK, ROS1, NTRK, BRAF, RET, or other actionable mutations, randomizing them to standard chemotherapy plus either pembrolizumab (PD-1 inhibitor), zimberelimab (PD-1 inhibitor), or zimberelimab combined with domvanalimab (TIGIT inhibitor) as first-line therapy. Eligible patients must have good performance status (ECOG 0-1) and no prior immune checkpoint inhibitor exposure.
ClinicalTrials.gov ID: NCT05502237
HealthScout AI summary: Adults with cutaneous melanoma (non-mucosal/ocular/acral) that has progressed on prior anti–PD-1/L1 therapy receive zimberelimab (anti–PD-1) plus domvanalimab (Fc-silent anti-TIGIT) every 3 weeks, with continuation for disease control up to 24 months. Prior CTLA-4 and, if BRAF-mutant, BRAF/MEK therapy allowed; requires ECOG 0–1, excludes active autoimmune disease, prior TIGIT therapy, and uncontrolled/active CNS disease (treated, stable brain mets allowed).
ClinicalTrials.gov ID: NCT05130177
