Domvanalimab: An Fc-Silent Anti-TIGIT Antibody for Cancer Immunotherapy

I. Executive Summary

Domvanalimab is an investigational, humanized immunoglobulin G1 (IgG1) monoclonal antibody at the forefront of a new generation of cancer immunotherapies. Developed by Arcus Biosciences in collaboration with Gilead Sciences, it targets the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a critical immune checkpoint. The central thesis of the Domvanalimab program is that its unique molecular engineering as an "Fc-silent" antibody confers a differentiated and potentially superior clinical profile compared to competing anti-TIGIT agents. This design is intended to block the TIGIT inhibitory pathway without causing the depletion of vital immune cell populations, thereby maximizing anti-tumor activity while mitigating immune-related toxicities.

The clinical development of Domvanalimab is focused on high-unmet-need solid tumors, primarily non-small cell lung cancer (NSCLC) and upper gastrointestinal (GI) cancers.[1] The strategy centers on its use in combination with an anti-PD-1 antibody, zimberelimab, with or without chemotherapy. This approach is supported by compelling, randomized Phase II data from the ARC-7 study in first-line, PD-L1-high NSCLC. In this trial, the combination of Domvanalimab and zimberelimab more than doubled median progression-free survival (PFS) compared to zimberelimab monotherapy (12.0 months vs. 5.4 months), a robust signal of efficacy that has propelled the combination into a comprehensive Phase III program.[3] Similarly, promising activity in the Phase II EDGE-Gastric study, which showed a median PFS exceeding one year in first-line upper GI cancers, has led to a pivotal Phase III trial in that setting.[6]

Domvanalimab's advancement occurs against a backdrop of significant turbulence and skepticism within the TIGIT inhibitor class. High-profile Phase III failures of other anti-TIGIT antibodies, most notably Roche's Fc-enabled tiragolumab, have cast doubt on the therapeutic viability of the TIGIT pathway itself.[8] Consequently, the trajectory of Domvanalimab represents more than the development of a single drug; it is a high-stakes test of a specific scientific hypothesis—that an Fc-silent approach is the key to unlocking the TIGIT pathway's potential. The ongoing Phase III trials, STAR-121 in NSCLC and STAR-221 in GI cancers, are therefore positioned as pivotal events. Their success could not only establish Domvanalimab as a new standard of care but also validate the Fc-silent mechanism and reinvigorate the entire TIGIT field. Conversely, failure would deepen the uncertainty surrounding this once-promising target in immuno-oncology.

II. The TIGIT Pathway: A Critical Target for Reinvigorating Anti-Tumor Immunity

The TIGIT pathway has emerged as a critical target in cancer immunotherapy due to its central role in suppressing the body's natural anti-tumor immune response.[10] TIGIT is a co-inhibitory immune checkpoint receptor expressed on the surface of key immune effector cells, including cytotoxic CD8+ T-cells and Natural Killer (NK) cells, as well as on immunosuppressive regulatory T-cells (Tregs).[2] Its expression is often upregulated on tumor-infiltrating lymphocytes (TILs), particularly those in a state of exhaustion, indicating its involvement in tumor-mediated immune evasion.[12]

The mechanism of TIGIT-mediated immunosuppression is centered on a competitive molecular interaction within the tumor microenvironment. TIGIT's primary ligand is CD155 (also known as the poliovirus receptor, PVR), a protein that is frequently overexpressed on the surface of various cancer cells, including lung, colon, and pancreatic cancers.[10] TIGIT competes with a co-stimulatory receptor, CD226 (also known as DNAM-1), for binding to CD155.[12] While CD226 binding to CD155 delivers an activating "go" signal to T-cells and NK cells, TIGIT binds to CD155 with much higher affinity.[13] This allows TIGIT to effectively outcompete CD226, leading to two key immunosuppressive outcomes: first, it prevents the delivery of the positive CD226 signal, and second, upon binding CD155, TIGIT's intracellular ITIM domain initiates a direct inhibitory signaling cascade that acts as a "brake" on immune cell proliferation and activation.[12] By exploiting this pathway, tumors can effectively neutralize the immune cells that would otherwise attack them.[15]

A crucial aspect of TIGIT biology is its high rate of co-expression with another major immune checkpoint, PD-1, on exhausted T-cells.[15] These two pathways function as distinct, complementary brakes on anti-cancer immunity.[17] This observation provides a strong biological rationale for a dual blockade strategy. While PD-1/PD-L1 inhibitors release one major brake, tumors may still evade immune destruction by relying on the TIGIT pathway. In fact, a high level of CD155 expression on tumors has been correlated with a poor response to PD-1 inhibitor therapy alone, suggesting it may function as a compensatory resistance mechanism.[15] By simultaneously inhibiting both TIGIT and PD-1, combination therapies aim to release two independent brakes on the immune system, potentially leading to a more robust and comprehensive reactivation of the anti-tumor response than is possible with either agent alone. This strategy is not merely additive; it is designed to overcome a specific mechanism of resistance to the current standard of care in immunotherapy.

III. Domvanalimab's Molecular Design and Differentiated Mechanism of Action

Domvanalimab, also known by its code name AB154, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody specifically designed to inhibit the TIGIT immune checkpoint.[12] Its mechanism of action is predicated on two fundamental and distinct design features: high-affinity blockade of the TIGIT receptor and an engineered Fc-silent domain that sets it apart from many other agents in its class.

First, Domvanalimab functions as a direct TIGIT protein inhibitor. Upon intravenous administration, it targets and binds with high specificity to the TIGIT receptor expressed on immune cells like T-cells and NK cells.[12] This binding physically obstructs the interaction between TIGIT and its ligands, primarily CD155 and to a lesser extent CD112, which are present on tumor cells and antigen-presenting cells.[12] By preventing this interaction, Domvanalimab effectively cuts the wire on the inhibitory signal that TIGIT would otherwise deliver. This blockade "releases the brakes" on the immune system and shifts the molecular balance in the tumor microenvironment. With TIGIT blocked, its ligand CD155 is free to engage the co-stimulatory receptor CD226, which in turn activates T-cell and NK cell-mediated anti-tumor responses.[12] In this way, Domvanalimab is designed to turn an inhibitory pathway into an accelerator of anti-cancer immunity.[15]

The second, and arguably most critical, design feature of Domvanalimab is its engineered Fc-silent domain. Standard IgG1 antibodies possess an Fc region that can bind to Fc-gamma receptors (FcγR) on various immune cells, triggering effector functions like antibody-dependent cellular cytotoxicity (ADCC).[15] In the context of an anti-TIGIT antibody, this could lead to the ADCC-mediated killing of any cell expressing TIGIT, including not only immunosuppressive Tregs but also beneficial, tumor-fighting CD8+ T-cells and NK cells that have been activated.[19] Domvanalimab has been specifically engineered to be "Fc-silent," meaning its Fc region is modified to prevent binding to FcγR.[4] The central hypothesis behind this design is that pure blockade of the TIGIT signaling pathway is the optimal therapeutic approach. By avoiding ADCC, Domvanalimab is intended to preserve the populations of activated effector T-cells and NK cells essential for killing cancer cells. Furthermore, it avoids the depletion of peripheral Tregs, which are critical for maintaining overall immune homeostasis; preserving them may prevent or reduce the autoimmune toxicities and other severe immune-related side effects that can be associated with immunotherapy.[15]

This choice of an Fc-silent design represents a fundamental scientific and strategic wager by Arcus Biosciences and Gilead. It directly challenges the competing hypothesis that the therapeutic benefit of some anti-TIGIT antibodies might derive, in part, from the Fc-mediated depletion of TIGIT-high immunosuppressive Tregs within the tumor. The clinical failures of several Fc-enabled anti-TIGIT antibodies have brought this debate to the forefront. Therefore, Domvanalimab's clinical program is not just evaluating a drug; it is prospectively testing the core immunological concept that targeted pathway inhibition without the confounding variable of cell depletion is the superior strategy for targeting TIGIT.

Table 1: Key Characteristics of Domvanalimab

Attribute	Description	Source(s)
Generic Name	Domvanalimab	12
Code Name	AB154	12
Drug Class	Immunotherapy, Monoclonal Antibody, Antineoplastic, Immune Checkpoint Inhibitor	1
Molecular Target	TIGIT (T-cell immunoreceptor with Ig and ITIM domains)	12
Mechanism of Action	TIGIT protein inhibitor; T-lymphocyte and NK cell stimulant	1
Antibody Type	Humanized Immunoglobulin G1 (IgG1)	12
Key Design Feature	Fc-silent (engineered to prevent Fcγ receptor binding and ADCC)	15
Developers	Arcus Biosciences, Gilead Sciences, AstraZeneca, University of Texas Southwestern Medical Center, Yale University	1

IV. Clinical Development Strategy in High Unmet Need Cancers

The clinical development of Domvanalimab is being executed through a broad and ambitious strategic collaboration, primarily between Arcus Biosciences and Gilead Sciences, with AstraZeneca also involved in a key lung cancer study.[1] The program is sharply focused on addressing significant unmet medical needs in two of the most prevalent and difficult-to-treat cancer types: Non-Small Cell Lung Cancer (NSCLC) and Upper Gastrointestinal (GI) Cancers, including gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinomas.[1]

The core of the clinical strategy is to evaluate Domvanalimab not as a standalone agent but as a cornerstone of combination immunotherapy regimens. Recognizing the complementary mechanisms of the TIGIT and PD-1 pathways, the vast majority of the development program pairs Domvanalimab with the anti-PD-1 antibody zimberelimab.[22] In many of the late-stage trials, this immunotherapy doublet is further combined with standard-of-care platinum-based chemotherapy, aiming to create a multi-pronged attack on the tumor through direct cytotoxicity from chemotherapy and dual checkpoint blockade to unleash the immune system.

The program has rapidly advanced to late-stage development, with multiple large, registrational Phase III trials underway in both NSCLC and GI cancers.[1] This portfolio of studies, which includes STAR-121, ARC-10, and PACIFIC-8 in lung cancer, and STAR-221 in GI cancers, reflects a significant financial and scientific commitment to establishing the Domvanalimab-zimberelimab combination as a new backbone therapy in oncology.[23]

A particularly telling aspect of the clinical strategy is its aggressive, head-to-head design against the established standards of care. Rather than seeking approval in niche or refractory settings, the pivotal trials are designed to challenge the dominant players in the multi-billion dollar first-line treatment markets. For example, the Phase III STAR-121 study in NSCLC directly compares the Domvanalimab-based regimen against the current market leader, pembrolizumab (Keytruda), plus chemotherapy.[22] This high-risk, high-reward approach signals a profound confidence from the developers, based on preceding Phase II data, that Domvanalimab has the potential not just to be an alternative treatment, but to demonstrate superiority and become the new standard of care. This ambitious strategy positions Domvanalimab for a potentially transformative impact on cancer treatment, should the Phase III data prove positive.

Table 2: Summary of Key Clinical Trials for Domvanalimab

Trial ID (NCT)	Phase	Indication	Regimen(s) Studied	Primary Endpoint(s)	Status
ARC-7 (NCT04262856)	II	1L Metastatic NSCLC (PD-L1 ≥50%)	Dom + Zim (doublet); Dom + Zim + Etrumadenant (triplet); vs. Zim monotherapy	ORR, PFS	Data Reported 23
STAR-121 (NCT05502237)	III	1L Metastatic NSCLC (all PD-L1 levels, no actionable mutations)	Dom + Zim + Chemo vs. Pembrolizumab + Chemo vs. Zim + Chemo	PFS, OS	Recruiting 26
EDGE-Gastric (NCT05329766)	II	1L Metastatic Upper GI Adenocarcinoma	Dom + Zim + Chemo (and other combinations)	Safety, Efficacy	Data Reported 27
STAR-221 (NCT05568095)	III	1L Metastatic Upper GI Adenocarcinoma	Dom + Zim + Chemo vs. Nivolumab + Chemo	OS	Enrollment Complete 7
ARC-10 (NCT04736173)	III	1L Metastatic NSCLC (PD-L1 ≥50%)	Dom + Zim vs. Pembrolizumab	PFS, OS	Enrollment Discontinued (Strategic Reprioritization) 24
PACIFIC-8 (NCT05211895)	III	Stage III Unresectable NSCLC (post-CRT)	Dom + Durvalumab vs. Placebo + Durvalumab	PFS, OS	Recruiting 33

Abbreviations: 1L = First-Line; CRT = Chemoradiotherapy; Dom = Domvanalimab; Zim = Zimberelimab; ORR = Objective Response Rate; OS = Overall Survival; PFS = Progression-Free Survival.

V. Clinical Efficacy and Safety in Non-Small Cell Lung Cancer (NSCLC)

NSCLC represents the primary indication and the most mature area of clinical investigation for Domvanalimab. The data generated in this setting, particularly from the randomized ARC-7 study, provides the strongest evidence to date for the clinical potential of an Fc-silent anti-TIGIT antibody and serves as the foundation for the ongoing Phase III registrational program.

A. ARC-7: Randomized Proof-of-Concept (NCT04262856)

The ARC-7 study was a pivotal Phase II, randomized, open-label, multicenter trial that provided the first randomized data for an Fc-silent anti-TIGIT antibody.[23] The trial enrolled 150 treatment-naïve patients with metastatic NSCLC characterized by high PD-L1 expression (Tumor Proportion Score ≥50%) and no actionable EGFR or ALK mutations.[3] Patients were randomized in a 1:1:1 ratio to one of three arms:

1. Zimberelimab (Z) monotherapy: The anti-PD-1 backbone.
2. Domvanalimab + Zimberelimab (DZ) doublet: The primary combination of interest.
3. Domvanalimab + Zimberelimab + Etrumadenant (EDZ) triplet: Investigating the additional effect of an adenosine receptor antagonist.[23]

The co-primary endpoints were objective response rate (ORR) and progression-free survival (PFS).[23]

Efficacy Analysis

Multiple interim analyses of the ARC-7 study consistently demonstrated clinically meaningful and statistically significant improvements in efficacy for the Domvanalimab-containing arms compared to zimberelimab monotherapy.[5] An analysis presented with a median follow-up of approximately 12 months showed a dramatic benefit for the DZ doublet. The median PFS for the doublet was 12.0 months, more than double the 5.4 months observed in the monotherapy arm.[3] This corresponded to a 45% reduction in the risk of disease progression or death, with a hazard ratio (HR) of 0.55.[3] The benefit was sustained over time, with a 12-month PFS rate of 41% for the doublet versus 25% for monotherapy.[38]

The ORR was also substantially improved, with a confirmed ORR of 41% in the doublet arm versus 27% in the monotherapy arm.[3] The EDZ triplet arm showed similar efficacy to the doublet (median PFS of 10.9 months, ORR of 40%), suggesting that the addition of etrumadenant did not provide a significant further benefit in this patient population.[3] This finding was strategically important, as it allowed the development program to focus on the simpler and highly effective two-drug doublet regimen. The magnitude of the PFS improvement seen with the addition of Domvanalimab provided a powerful and unambiguous signal of its anti-tumor activity, directly countering the narrative that TIGIT was a failed target following setbacks with other agents.

Safety Analysis

The safety profile of the Domvanalimab-containing regimens in ARC-7 was favorable and manageable.[5] Crucially, the addition of Domvanalimab to zimberelimab did not increase overall toxicity. In fact, the incidence of Grade ≥3 treatment-emergent adverse events (TEAEs) was numerically lower in the DZ doublet arm (47%) compared to the Z monotherapy arm (58%).[3]

The data provided direct clinical support for the intended benefit of the Fc-silent design. The incidence of infusion-related reactions, a potential concern with monoclonal antibodies, was low and identical between the monotherapy and doublet arms at 4%.[5] This demonstrated that adding Domvanalimab did not increase this specific risk. Furthermore, there was no increase in the overall rate of immune-related adverse events (IRAEs) in the doublet arm compared to monotherapy (47% vs. 48%).[4] The safety profile of the doublet was well-tolerated and consistent with that of an anti-PD-1 agent alone, suggesting a highly favorable therapeutic window.[3]

B. STAR-121: The Path to Registration (NCT05502237)

Building on the robust proof-of-concept established in ARC-7, Arcus and Gilead launched the STAR-121 trial, a global, randomized, open-label, Phase III study designed for regulatory submission.[22] The trial is enrolling a broader patient population of approximately 720 to 1,069 patients with first-line metastatic NSCLC, including all levels of PD-L1 expression and both squamous and non-squamous histologies, provided they do not have actionable EGFR or ALK mutations.[21]

The trial design is a direct challenge to the current standard of care. The primary comparison is between the experimental arm and the control arm, randomized in a 4:4 ratio:

• Arm A (Experimental): Domvanalimab + Zimberelimab + platinum-doublet chemotherapy.[26]
• Arm B (Control): Pembrolizumab + platinum-doublet chemotherapy.[26]

A smaller third arm (Arm C: Zimberelimab + chemotherapy) is included for contribution-of-effect analysis.[26] The ambitious dual primary endpoints are PFS and Overall Survival (OS), aiming to demonstrate the superiority of the Domvanalimab-based regimen over the established market leader.[22] Enrollment for STAR-121 began in October 2022 and is ongoing, with final study completion estimated for 2027-2028.[26] While no efficacy results are yet available, this trial represents the definitive test of Domvanalimab's potential to redefine the first-line treatment paradigm for a broad population of patients with NSCLC.

Table 3: Efficacy Results from the ARC-7 Phase II Trial (NSCLC)

Data from analysis with DCO of Feb 7, 2023; n=50 per arm

Endpoint	Zimberelimab Monotherapy (Z)	Domvanalimab + Zimberelimab (DZ)	Dom + Zim + Etrumadenant (EDZ)
Objective Response Rate (ORR)	30% (95% CI: 17.9, 44.6)	40% (95% CI: 26.4, 54.8)	44% (95% CI: 30.0, 58.7)
Median PFS (months)	5.4 (95% CI: 2.7, 9.7)	9.3 (95% CI: 4.1, NE)	9.9 (95% CI: 4.8, 14.6)
PFS Hazard Ratio vs. Z	-	0.67 (95% CI: 0.40, 1.13)	0.72 (95% CI: 0.63, 1.8)
6-Month PFS Rate	45% (95% CI: 30, 59)	58% (95% CI: 43, 72)	62% (95% CI: 48, 76)
12-Month PFS Rate	25% (95% CI: 11, 40)	41% (95% CI: 26, 56)	44% (95% CI: 29, 59)
Source:.38 Note: Earlier analyses reported different median PFS values as data matured.3 CI = Confidence Interval; NE = Not Evaluable.

Table 4: Safety Profile Summary from the ARC-7 Trial

Data from safety population as of Aug 31, 2022

Adverse Event Category	Zimberelimab Monotherapy (Z) (n=50)	Domvanalimab + Zimberelimab (DZ) (n=49)	Dom + Zim + Etrumadenant (EDZ) (n=50)
Any Grade ≥3 TEAE	58%	47%	52%
Immune-Related AEs (IRAEs)	48%	47%	60%
Infusion-Related Reactions	4%	4%	10%
Rash (any grade)	12%	10%	18%
Pruritus (any grade)	Not Reported	Not Reported	Not Reported
Source:.5 TEAE = Treatment-Emergent Adverse Event.

VI. Clinical Efficacy and Safety in Upper Gastrointestinal (GI) Cancers

In addition to NSCLC, Domvanalimab is being aggressively developed for first-line treatment of locally advanced unresectable or metastatic upper GI cancers, including gastric, GEJ, and esophageal adenocarcinoma. This indication represents a significant area of unmet need and a potential first-to-market opportunity for Domvanalimab within the TIGIT inhibitor class, as it is the only anti-TIGIT antibody currently being studied in a Phase III trial for this disease.[7]

A. EDGE-Gastric: Encouraging Phase II Signals (NCT05329766)

The foundation for the late-stage GI cancer program was laid by the Phase II EDGE-Gastric trial, a multi-arm study evaluating various Domvanalimab-based combinations.[27] Data from Arm A1, which investigated the triplet regimen of Domvanalimab, zimberelimab, and standard chemotherapy (FOLFOX or CAPOX), showed highly encouraging results in 41 patients with previously untreated upper GI adenocarcinoma.[25]

Efficacy Analysis

Preliminary data from the study demonstrated promising anti-tumor activity that appeared to exceed historical benchmarks for the standard of care (anti-PD-1 plus chemotherapy).[7] An updated analysis presented in June 2024, with a median time on treatment of nearly one year, showed a median PFS of 12.9 months and a 12-month PFS rate of 57.6%.[7] The confirmed ORR was 58.5%, including a complete response rate of 7.3%.[41] The activity was observed irrespective of PD-L1 expression, though it was particularly pronounced in patients with PD-L1-high tumors, who achieved an ORR of 80% in an earlier analysis.[27] These robust and durable responses provided strong justification for advancing the regimen into a pivotal Phase III study.

Safety Analysis

The triplet combination of Domvanalimab, zimberelimab, and chemotherapy was found to be generally well-tolerated.[7] The safety profile was consistent with the known profiles of each individual component, particularly the adverse events associated with an anti-PD-1 plus chemotherapy backbone.[27] The most common adverse events reported were chemotherapy-related, such as neutropenia (59%) and nausea (54%).[27] Importantly, no unexpected safety signals emerged. There were no serious immune-mediated adverse events and no treatment-emergent deaths, reinforcing the favorable tolerability profile of the Domvanalimab-based regimen.[27]

B. STAR-221: A First-to-Market Opportunity (NCT05568095)

Based on the strength of the EDGE-Gastric data, the sponsors initiated STAR-221, a large-scale, global, randomized Phase III trial.[25] This study is the first and only Phase III trial evaluating an anti-TIGIT antibody in upper GI adenocarcinoma, positioning Domvanalimab for a potential first-in-class approval in this setting.[7]

Trial Design

The STAR-221 trial enrolled approximately 1,050 patients with previously untreated, locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.[7] The study is designed to compare the Domvanalimab-based triplet regimen directly against the current standard of care:

• Experimental Arm: Domvanalimab + Zimberelimab + Chemotherapy (FOLFOX or CAPOX).[7]
• Control Arm: Nivolumab (Opdivo) + Chemotherapy (FOLFOX or CAPOX).[7]

Endpoints & Status

The primary endpoint of the study is Overall Survival (OS), evaluated in both the PD-L1-high population and the overall intent-to-treat population.[7] Secondary endpoints include PFS, ORR, and duration of response.[7] In mid-2024, Arcus Biosciences announced the completion of patient enrollment for the trial.[7] The first data readout from this pivotal study is anticipated in 2026, an event that could establish a new standard of care for patients with upper GI cancers.[25]

Table 5: Efficacy Results from the EDGE-Gastric Phase II Trial (Upper GI Cancers)

Data from analysis with DCO of March 12, 2024; n=41

Endpoint	Overall Population (n=41)	PD-L1 High Subgroup (n=15)*	PD-L1 Low Subgroup (n=24)*
Confirmed ORR	58.5% (95% CI: 42.1, 73.7)	73% (95% CI: 45, 92)	46% (95% CI: 26, 67)
Median PFS (months)	12.9 (95% CI: 9.8, 13.8)	Not Reached	Not Reached
6-Month PFS Rate	77% (95% CI: 64, 90)	93% (95% CI: 81, 100)	68% (95% CI: 48, 88)
12-Month PFS Rate	57.6% (95% CI: 41.7, 73.5)	Not Reported	Not Reported
*Sources:.7	Subgroup data from earlier DCO of Sep 4, 2023.27

VII. Consolidated Safety and Tolerability Analysis

A comprehensive review of safety data from across the Domvanalimab clinical program—spanning the ARC-7, EDGE-Gastric, and ARC-10 trials in both NSCLC and upper GI cancers—reveals a remarkably consistent and favorable tolerability profile. A recurring theme is that the addition of Domvanalimab to an anti-PD-1 backbone, with or without chemotherapy, has been well-tolerated and has not introduced new or unexpected safety signals.[5] This consistent safety record is a cornerstone of Domvanalimab's potential best-in-class profile and provides clinical validation for its differentiated molecular design.

The data strongly support the hypothesis that the Fc-silent engineering of Domvanalimab translates into a tangible clinical benefit. A key piece of evidence is the low incidence of infusion-related reactions. In the ARC-7 study, the rate of these reactions in the Domvanalimab-plus-zimberelimab doublet arm was 4%, identical to the rate in the zimberelimab monotherapy arm, demonstrating that the addition of Domvanalimab did not increase this risk.[5] Similarly, in the ARC-10 study, infusion-related reactions remained low at 7.9% for the combination.[18] This contrasts with potential concerns for other antibody-based therapies and suggests the inert Fc region is functioning as intended.

Furthermore, the overall burden of severe adverse events and treatment discontinuations has been manageable. In ARC-7, the rate of Grade ≥3 TEAEs was unexpectedly lower in the Domvanalimab doublet arm (47%) than in the anti-PD-1 monotherapy arm (58%).[3] In the ARC-10 trial, treatment-related adverse events leading to discontinuation were substantially lower for the Domvanalimab-zimberelimab combination (10.5%) compared to the chemotherapy arm (23.5%).[18] In the EDGE-Gastric study, the safety profile of the Domvanalimab-based triplet was comparable to what has been historically reported for anti-PD-1 plus chemotherapy alone, with no serious immune-mediated AEs observed.[27]

This consistent pattern of tolerability across different tumor types, patient populations, and combination regimens is not merely a positive attribute but is the clinical manifestation of the core scientific hypothesis underpinning Domvanalimab's development. The data strongly suggest that by avoiding ADCC-mediated depletion of TIGIT-expressing immune cells, the Fc-silent design may successfully uncouple the desired immune checkpoint blockade from off-target toxicities. This could represent a decisive competitive advantage in a therapeutic landscape where physicians and patients must constantly weigh the balance between efficacy and the quality of life impact of treatment-related side effects.

VIII. The TIGIT Inhibitor Landscape: Navigating a Field of High Hopes and High-Profile Failures

The development of TIGIT inhibitors has been a tumultuous journey, characterized by immense initial optimism followed by significant clinical setbacks that have reshaped the competitive landscape. Initially hailed as the most promising immune checkpoint target after PD-1 and CTLA-4, TIGIT attracted billions of dollars in research and development investment from numerous pharmaceutical companies, all racing to be the first to market.[11]

This initial wave of enthusiasm was severely dampened by a series of high-profile clinical trial failures, most notably from the program once considered the frontrunner: tiragolumab, an Fc-enabled IgG1 anti-TIGIT antibody developed by Roche/Genentech.[8] The Phase III SKYSCRAPER-01 trial in PD-L1-high NSCLC and the Phase III SKYSCRAPER-02 trial in extensive-stage small cell lung cancer both failed to meet their primary endpoints of improving survival.[8] These failures, from a program that had previously shown promising Phase II data in the CITYSCAPE trial, sent shockwaves through the field, leading to widespread investor skepticism and a narrative that the TIGIT pathway might not be a viable therapeutic target after all.[9]

It is within this challenging context that Domvanalimab has emerged as a leading and differentiated candidate. The positive, randomized data from the ARC-7 trial, which directly contrasted with the failures of tiragolumab, served as a critical proof-of-concept for the TIGIT pathway and, more specifically, for the Fc-silent approach.[4] The failures of Fc-enabled antibodies like tiragolumab inadvertently created a significant strategic opportunity for Domvanalimab. They cleared the competitive field of its perceived leader and intensified scientific scrutiny on the role of the antibody's Fc domain. This has framed the narrative in a way that positions Domvanalimab's unique design as the potential solution to the TIGIT puzzle.

The current late-stage landscape is now more consolidated. Besides Domvanalimab, key competitors include BeiGene's ociperlimab and Merck's vibostolimab, both of which are also Fc-enabled IgG1 antibodies, similar in design to tiragolumab.[11] While these programs are still advancing, they face the challenge of differentiating themselves from the failed tiragolumab approach. Domvanalimab's distinct Fc-silent mechanism, backed by positive randomized Phase II data, gives it a clear and compelling scientific rationale for why its clinical outcomes might be different. If Domvanalimab's ongoing Phase III trials succeed where others have failed, it will be viewed not just as a clinical victory, but as the definitive validation of a superior molecular design, potentially securing a dominant market and intellectual position.

Table 6: Comparative Overview of Late-Stage Anti-TIGIT Antibodies

Molecule	Developer(s)	Fc Design	Key Indication(s) in Late-Stage Dev.	Key Public Data Summary
Domvanalimab	Arcus / Gilead	Fc-silent	NSCLC, GI Cancers	Positive PhII ARC-7: Doubled PFS vs. PD-1 mono (12.0 vs 5.4 mo). Positive PhII EDGE-Gastric: mPFS of 12.9 mo. 3
Tiragolumab	Roche / Genentech	Fc-enabled (IgG1)	NSCLC, SCLC, Esophageal, Cervical	Negative PhIII SKYSCRAPER-01 & -02: Failed to meet primary survival endpoints. Mixed PhII results. 8
Ociperlimab	BeiGene	Fc-enabled (IgG1)	NSCLC, Esophageal, Cervical	Advancing in PhIII trials; limited randomized data public. 11
Vibostolimab	Merck & Co.	Fc-enabled (IgG1)	NSCLC, Melanoma	PhI/II data showed ORR of 26% with pembrolizumab in NSCLC. Currently in PhIII trials. 16

IX. Regulatory Trajectory and Future Outlook

Domvanalimab is currently an investigational molecule and has not received marketing approval from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or any other global regulatory authority for any indication.[15] Its entire clinical program is being conducted under Investigational New Drug (IND) applications and equivalent international filings. The regulatory pathway for Domvanalimab is contingent on the results of its ongoing, large-scale Phase III registrational trials.

Procedurally, the EMA's Paediatric Committee (PDCO) has granted product-specific waivers for Domvanalimab in the treatment of lung cancer and in the treatment of gastric, GEJ, and esophageal carcinomas.[44] These waivers exempt the sponsor from the requirement to conduct pediatric studies for these indications on the grounds that these specific cancers primarily occur in adult populations. This is a standard administrative step in the European regulatory process for adult-focused oncology drugs and does not reflect any judgment by the agency on the drug's safety, efficacy, or likelihood of eventual approval.

The future of Domvanalimab, and arguably the entire TIGIT therapeutic class, now rests on the outcomes of the STAR-121 (NSCLC) and STAR-221 (Upper GI Cancers) Phase III trials. These studies are the ultimate arbiters of the drug's fate. The history of oncology development is filled with examples of therapies that showed promising results in Phase II only to fail in the more rigorous, larger, and better-controlled Phase III setting.

Nonetheless, the body of evidence for Domvanalimab provides a strong basis for cautious optimism. Its differentiated Fc-silent design offers a compelling scientific rationale for a superior safety and efficacy profile. This rationale is supported by robust, randomized Phase II data from the ARC-7 trial, which demonstrated a magnitude of clinical benefit rarely seen from the addition of a single agent. This efficacy was achieved alongside a consistently well-tolerated safety profile across multiple studies, a finding that provides clinical validation for the Fc-silent hypothesis.

Given the high-profile failures that have plagued the TIGIT field, the pressure on the Domvanalimab program is immense. These trials carry the weight of not just one drug's potential approval but also the validation of a biological target in which the industry has invested billions of dollars. A positive outcome in either STAR-121 or STAR-221 would represent a major breakthrough for patients, a landmark achievement in immuno-oncology, and a powerful revival for the TIGIT pathway. A negative result, however, would be a devastating blow, likely signaling the end of major investment in this target and leaving the future of TIGIT-directed therapy in profound uncertainty. The upcoming data readouts are therefore among the most highly anticipated events in oncology.

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