Tiragolumab (DB16409): A Comprehensive Clinical and Scientific Analysis of a First-in-Class Anti-TIGIT Immunotherapy

Executive Summary

Tiragolumab (DrugBank ID: DB16409) is an investigational, first-in-class, fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting the T-cell immunoreceptor with Ig and ITIM domains (TIGIT), an inhibitory immune checkpoint.[1] Developed by Genentech, a member of the Roche Group, tiragolumab was designed to function as an immune amplifier, primarily in combination with the anti-PD-L1 antibody atezolizumab, to synergistically reinvigorate the anti-tumor immune response.[4] The scientific rationale is predicated on the complementary roles of the TIGIT and PD-L1/PD-1 pathways in mediating T-cell exhaustion, with dual blockade hypothesized to produce a more profound and durable anti-cancer effect than targeting either pathway alone.[7]

The initial clinical development of tiragolumab was highly promising. The Phase II CITYSCAPE trial demonstrated clinically meaningful improvements in objective response rate (ORR) and progression-free survival (PFS) for the tiragolumab-atezolizumab combination in first-line, PD-L1-positive non-small cell lung cancer (NSCLC), particularly within a subgroup of patients with high PD-L1 expression.[9] These encouraging results led the U.S. Food and Drug Administration (FDA) to grant tiragolumab Breakthrough Therapy Designation in 2021, positioning it as the leading candidate in the burgeoning TIGIT inhibitor class.[4]

However, this early promise failed to translate into pivotal trial success. The extensive Phase III SKYSCRAPER clinical program, designed to confirm the CITYSCAPE findings, yielded a series of high-profile disappointments. The SKYSCRAPER-01 trial in PD-L1-high NSCLC did not meet its primary endpoints of PFS or overall survival (OS).[13] Furthermore, the SKYSCRAPER-02 trial in extensive-stage small-cell lung cancer (ES-SCLC) and the SKYSCRAPER-06 trial in non-squamous NSCLC also failed, with the latter showing inferiority to the current standard of care.[15] In stark contrast to these failures, the Phase III SKYSCRAPER-08 trial reported a statistically significant and clinically meaningful OS benefit in a population of Asian patients with esophageal squamous cell carcinoma (ESCC).[18] This singular success, however, is caveated by the trial's use of a chemotherapy-alone control arm, which is no longer the global standard of care. Following subsequent trial failures, including SKYSCRAPER-14 in liver cancer, Roche officially removed tiragolumab from its development pipeline.[20]

The trajectory of tiragolumab serves as a critical and cautionary case study in immuno-oncology. It highlights the profound challenges of translating compelling subgroup data from Phase II studies into Phase III success and underscores the complex, context-dependent nature of novel immune checkpoint pathways. Positioned within a broader TIGIT inhibitor landscape that is itself beleaguered by numerous clinical setbacks, the story of tiragolumab reveals critical lessons regarding biomarker strategy, antibody engineering, and the systemic risks of imitative research and development strategies within the pharmaceutical industry.

Molecular Profile and Immunological Rationale

The TIGIT/CD155 Axis: A Key Immune Checkpoint Pathway

The therapeutic rationale for tiragolumab is rooted in the biology of the TIGIT pathway, a critical axis for negative regulation of the immune system.

TIGIT Receptor Biology

TIGIT, also known as T cell immunoreceptor with Ig and ITIM domains, is an inhibitory receptor belonging to the immunoglobulin (Ig) superfamily.[8] Its expression is largely restricted to lymphocytes, including key effector cells such as activated cytotoxic (

CD8+) T-cells, helper (CD4+) T-cells, and Natural Killer (NK) cells. It is also highly expressed on regulatory T-cells (Tregs), a subset known for its immunosuppressive functions.[2] Within the tumor microenvironment (TME), TIGIT expression is often upregulated on tumor-infiltrating lymphocytes and is strongly correlated with T-cell exhaustion, a state of cellular dysfunction that prevents an effective anti-tumor response. Consequently, high TIGIT expression has been associated with advanced disease and poor prognosis across multiple cancer types.[8]

Ligand Interaction and Competitive Binding

The function of TIGIT is mediated through its interaction with ligands expressed on the surface of antigen-presenting cells (APCs) and tumor cells. TIGIT binds to two primary ligands from the nectin family: CD155 (also known as the poliovirus receptor, PVR) and CD112 (PVRL2, Nectin-2).[6] The binding affinity for CD155 is substantially higher (

Kd​=1−3 nM) than for CD112, making the TIGIT-CD155 interaction the dominant signaling axis.[8]

This interaction is part of a more complex signaling nexus that also involves the co-stimulatory receptor CD226 (DNAM-1), which shares the same ligands. While CD226 binding to CD155 delivers an activating signal to T-cells and NK cells, TIGIT binding delivers an inhibitory one. Because TIGIT has a much higher affinity for CD155 than CD226 does (Kd​=119 nM), it effectively outcompetes CD226 for ligand binding. This competitive antagonism disrupts the homodimerization and signaling of CD226, thereby shifting the balance from immune activation toward immune suppression.[8] The efficacy of a TIGIT inhibitor is therefore not only dependent on blocking TIGIT's inhibitory signal but also on the relative expression levels of TIGIT, its ligand CD155, and its competitor CD226 within the TME. This biological complexity likely contributes to the variable clinical responses observed and presents a significant challenge for developing predictive biomarkers beyond simple PD-L1 expression.

Downstream Signaling and Immune Suppression

Upon binding to CD155, the immunoreceptor tyrosine-based inhibitory motif (ITIM) and Ig tail-tyrosine (ITT)-like motif within TIGIT's cytoplasmic tail become phosphorylated, initiating a downstream inhibitory signaling cascade.[8] This cascade directly suppresses the activation and proliferation of T-cells and NK cells. Key consequences include the diminished production of critical effector cytokines, such as interferon-gamma (

IFN−γ), and the impairment of the cytotoxic functions required to kill target tumor cells.[2]

Tiragolumab: Drug Characteristics and Mechanism of Action

Tiragolumab was engineered to specifically disrupt the TIGIT-mediated immunosuppressive pathway.

Drug Profile

Tiragolumab is a biotech drug classified as a fully human IgG1/kappa monoclonal antibody, produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells.[2] It has an intact, functional fragment crystallizable (Fc) region, a design choice with significant mechanistic implications. The molecule has a molecular weight of approximately 149 kDa and is identified by the CAS Number 1918185-84-8. It has been referred to by several development codes, including RO7092284, RG6058, and MTIG7192A.[5]

Mechanism of Blockade

As an immune checkpoint inhibitor, tiragolumab functions by selectively binding to the TIGIT receptor with high affinity. This binding physically obstructs the interaction between TIGIT and its ligands, CD155 and CD112.[2] This blockade is hypothesized to "release the brakes" on the anti-tumor immune response through a dual mechanism. First, it prevents the direct inhibitory signaling cascade initiated by TIGIT. Second, by preventing TIGIT from monopolizing the CD155 ligand, it allows the co-stimulatory receptor CD226 to bind CD155, thereby promoting the activation of T-cells and NK cells.[8] This process is intended to reinvigorate exhausted immune cells within the TME, restoring their capacity to recognize and eliminate malignant cells.[6]

The design of tiragolumab as an Fc-competent IgG1 antibody was a deliberate scientific decision. Such antibodies can engage Fcγ receptors on other immune cells (e.g., macrophages, NK cells) to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). The presumed therapeutic intent was to leverage ADCC to deplete the population of highly TIGIT-expressing immunosuppressive Tregs within the TME. However, this design presents a potential paradox, as the same mechanism could also lead to the depletion of TIGIT-expressing effector T-cells and NK cells—the very populations the therapy aims to activate. This "double-edged sword" characteristic could result in a net therapeutic benefit or detriment, depending on the specific cellular composition of a patient's TME, and represents a key point of differentiation from competitor anti-TIGIT antibodies developed with a non-functional, or "silent," Fc region.

The Rationale for Dual Checkpoint Blockade with PD-L1 Inhibition

The clinical development strategy for tiragolumab has centered almost exclusively on its combination with atezolizumab, an anti-PD-L1 antibody.

Complementary and Non-Redundant Pathways

The TIGIT and PD-1/PD-L1 pathways represent two distinct, non-redundant mechanisms of immune suppression. Both checkpoints are frequently co-expressed on the same exhausted T-cells within the TME, suggesting they may cooperate to maintain an immunosuppressive state.[6] Preclinical studies provided a strong rationale for dual blockade, demonstrating that while monotherapy targeting either pathway had modest effects, their simultaneous inhibition resulted in a synergistic anti-tumor response. This synergy was observed even in tumor models that had developed resistance to anti-PD-1 therapy alone, suggesting that TIGIT may be a key escape mechanism for tumors under pressure from PD-1/PD-L1 blockade.[3]

Synergistic Immune Reinvigoration

The central hypothesis is that combining tiragolumab and atezolizumab would lead to a more comprehensive reactivation of the immune system. Atezolizumab, by blocking the PD-L1/PD-1 interaction, works to reverse T-cell exhaustion. The addition of tiragolumab is intended to amplify this effect by not only further enhancing T-cell function but also by activating NK cells, a cell type less directly affected by PD-1/PD-L1 blockade.[6] This multi-pronged approach is expected to produce a more robust and sustained anti-tumor immune response than could be achieved by targeting either pathway in isolation.[7]

Characteristic	Description
Drug Name	Tiragolumab
DrugBank ID	DB16409
Type	Biotech, Monoclonal Antibody
CAS Number	1918185-84-8
Developer	Genentech / Roche 1
Synonyms	RO7092284, RG6058, MTIG7192A 5
Classification	Fully human IgG1/kappa monoclonal antibody 2
Molecular Target	T-cell immunoreceptor with Ig and ITIM domains (TIGIT) 2
Mechanism of Action	Immune checkpoint inhibitor; blocks TIGIT from binding its ligands (e.g., CD155), restoring T-cell and NK-cell anti-tumor activity 2
Molecular Weight	~149 kDa 27
Table 1: Key Characteristics of Tiragolumab. This table provides a consolidated reference for the fundamental properties of the drug.

Foundational Clinical Development and Safety Profile

Phase I/Ib GO30103 Trial: Establishing Safety, Tolerability, and Recommended Dosing

The clinical journey of tiragolumab began with the GO30103 study (NCT02794571), a first-in-human, open-label, non-randomized trial designed to assess its fundamental clinical properties.[3] The study consisted of a dose-escalation phase for tiragolumab monotherapy (Phase 1a) and for its combination with atezolizumab (Phase 1b), followed by dose-expansion cohorts in specific tumor types. The primary objectives were to evaluate safety, determine the maximum tolerated dose (MTD), and establish the recommended Phase 2 dose (RP2D).[29]

The dose-escalation phase demonstrated that tiragolumab was well-tolerated. No dose-limiting toxicities were observed, and an MTD was not reached.[29] Based on these findings, the RP2D was established as 600 mg administered via intravenous infusion every 3 weeks (Q3W). This dose and schedule were subsequently used across the extensive Phase II and III SKYSCRAPER clinical program.[2]

While the trial was primarily focused on safety, it also provided the first signals of clinical activity that would shape the drug's future development. As a monotherapy, tiragolumab showed minimal efficacy, with a confirmed objective response rate (ORR) of 0%.[29] However, the combination with atezolizumab demonstrated promising preliminary anti-tumor activity. In the dose-expansion cohorts, the combination achieved a confirmed ORR of 46% (6 of 13 patients) in patients with immunotherapy-naive metastatic NSCLC and 28% (5 of 18 patients) in patients with metastatic esophageal cancer.[29] These early efficacy signals provided the crucial rationale for advancing the combination into larger, randomized trials in these specific indications.

Comprehensive Safety and Tolerability Analysis

Across its clinical development program, tiragolumab, both alone and in combination with atezolizumab, has demonstrated a consistently manageable safety profile.

Monotherapy Profile (Phase 1a)

In the monotherapy arm of the GO30103 trial, tiragolumab was well-tolerated. The most frequently reported treatment-related adverse event (TRAE) was fatigue, occurring in 21% of patients. Immune-mediated adverse events (imAEs), a key concern for checkpoint inhibitors, were observed in 17% of patients but were predominantly low-grade (Grade 1 or 2).[29]

Combination Profile (Phase 1b and beyond)

The combination of tiragolumab with atezolizumab maintained a favorable safety profile, with no new or unexpected toxicities emerging from the addition of the anti-TIGIT antibody.[29] This observation held true in subsequent, larger trials like CITYSCAPE and the SKYSCRAPER series, where the safety profile of the combination was consistently reported as being similar to that of the atezolizumab-containing control arms.[7] The most common TRAEs associated with the combination included pruritus (itching), rash, and fatigue.[29]

The rate of severe (Grade ≥3) TRAEs was not substantially increased by the addition of tiragolumab. For instance, in the CITYSCAPE trial, Grade ≥3 TRAEs occurred in 14.9% of patients in the combination arm versus 19.1% in the atezolizumab-alone arm.[10] Similarly, in the large SKYSCRAPER-02 trial, Grade 3/4 AEs were reported in 64.0% of patients in the tiragolumab arm versus 63.8% in the control arm.[36]

This consistently manageable safety profile, even with an Fc-competent antibody design, is a notable finding. It suggests that the theoretical risk of widespread, harmful depletion of effector T-cells via ADCC did not translate into significant clinical toxicity at the selected 600 mg Q3W dose. The ultimate failure of the tiragolumab program was driven by a lack of superior efficacy, not by prohibitive toxicity, a distinction that is critical for interpreting the results and for the broader TIGIT field.

Phase	Cohort	N	Confirmed ORR	Most Common TRAEs	Grade ≥3 TRAEs	imAEs Rate
Phase 1a	Monotherapy	24	0%	Fatigue (21%), Pruritus (13%)	4%	17%
Phase 1b	Combination (Dose Escalation)	49	6%	Pruritus (10%), Fatigue (8%)	4%	59%
Phase 1b	NSCLC Expansion	13	46%	N/A	N/A	N/A
Phase 1b	Esophageal Cancer Expansion	18	28%	N/A	N/A	N/A
Table 2: Summary of Efficacy and Safety from the Phase I GO30103 Trial. This table summarizes the foundational data from the first-in-human study that justified the subsequent clinical program. Data compiled from.3

The Clinical Development Journey in Non-Small Cell Lung Cancer (NSCLC)

The story of tiragolumab is most defined by its dramatic trajectory in NSCLC, which saw spectacular early results give way to definitive late-stage failure.

The Phase II CITYSCAPE Trial: Initial Promise and Breakthrough Designation

The CITYSCAPE trial (NCT03563716) was a randomized, double-blind Phase II study that provided the first robust evidence for the tiragolumab-atezolizumab combination. The trial enrolled 135 patients with first-line, PD-L1-positive (tumor proportion score ≥1%) metastatic NSCLC, comparing the combination against placebo plus atezolizumab.[10]

At its primary analysis, with a median follow-up of 5.9 months, CITYSCAPE met both of its co-primary endpoints. The combination arm demonstrated a statistically significant improvement in ORR (31.3% vs. 16.2% for atezolizumab alone) and a 43% reduction in the risk of disease progression or death, with a median PFS of 5.4 months versus 3.6 months (hazard ratio 0.57).[10]

The most striking results emerged from a pre-planned exploratory analysis of the subgroup with high PD-L1 expression (TPS ≥50%). In these 58 patients, the combination produced a profound benefit, with an ORR of 55.2% versus 17.2% and a 67% reduction in the risk of progression or death (HR 0.33).[10] Long-term follow-up data presented after 2.5 years reinforced these findings, showing the benefit was durable. In the PD-L1-high subgroup, the median PFS was 16.6 months for the combination versus 4.1 months for atezolizumab alone (HR 0.29), and a clinically meaningful OS benefit was observed, with the median OS not reached in the combination arm versus 12.8 months in the control arm (HR 0.23).[9]

These highly encouraging results, particularly from the PD-L1-high subgroup, generated immense excitement and led the FDA to grant Tiragolumab Breakthrough Therapy Designation in January 2021 for this specific indication. This designation accelerated its development and solidified its status as the frontrunner in the anti-TIGIT class.[1]

The Phase III SKYSCRAPER-01 Trial: A Pivotal Setback

SKYSCRAPER-01 (NCT04294810) was the large-scale (n=534), global Phase III trial designed to confirm the promising findings from CITYSCAPE. The study mirrored the design of the earlier trial, evaluating the tiragolumab-atezolizumab combination versus placebo plus atezolizumab in first-line, PD-L1-high (TPS ≥50%) metastatic NSCLC.[13]

Despite the strong preceding data, Roche announced in May 2022 that the study failed to meet its co-primary endpoint of PFS at the first interim analysis.[39] The study continued to assess the other co-primary endpoint of OS. In November 2024, the company confirmed that at the final analysis, the trial also failed to demonstrate a statistically significant improvement in OS.[13] While numerical improvements were observed—a median PFS of 7.0 months vs. 5.6 months (HR 0.78) and a median OS of 23.1 months vs. 16.9 months (HR 0.87)—these differences did not meet the threshold for statistical significance.[13]

The Phase III SKYSCRAPER-06 Trial: Failure Against the Standard of Care

To assess its competitiveness in the real-world landscape, the SKYSCRAPER-06 trial (NCT04619797) was designed to compare tiragolumab plus atezolizumab and chemotherapy against the established market-leading standard of care: pembrolizumab (Keytruda) plus chemotherapy.[30]

The outcome was unequivocally negative. In July 2024, Roche announced the termination of the study because the tiragolumab-containing arm demonstrated reduced efficacy compared to the standard therapy. The median PFS was 8.3 months in the tiragolumab arm versus 9.9 months in the pembrolizumab arm (HR 1.27), and the median OS was 18.9 months versus 23.1 months, respectively (HR 1.33).[15] This result not only confirmed the lack of benefit from adding tiragolumab but also suggested that the atezolizumab-based backbone was inferior to the pembrolizumab-based standard in this setting.

Synthesis and Post-Mortem of the NSCLC Program

The failure of tiragolumab in NSCLC, particularly the inability of SKYSCRAPER-01 to replicate the CITYSCAPE results, serves as a classic cautionary tale in oncology drug development. The dramatic effect size observed in the small PD-L1-high subgroup of CITYSCAPE (n=58) appears to have been a statistical anomaly that could not be reproduced in a much larger, more robust confirmatory trial (n=534). This highlights the inherent risks of making significant investment and strategic decisions based on exploratory subgroup analyses before they are prospectively validated. While such analyses are vital for hypothesis generation, they must be interpreted with extreme caution. The tiragolumab program exemplifies the potential for random chance in small datasets to generate overly optimistic results that do not reflect the true therapeutic effect. The subsequent failure of SKYSCRAPER-06 against the real-world standard of care provided a final, definitive verdict, effectively closing the door on this combination's utility in NSCLC.

Endpoint	CITYSCAPE (Phase II, PD-L1 High, n=58)	SKYSCRAPER-01 (Phase III, PD-L1 High, n=534)
Median PFS (Combo vs. Control)	16.6 mo vs. 4.1 mo	7.0 mo vs. 5.6 mo
PFS Hazard Ratio (95% CI)	0.29 (0.15−0.53)	0.78 (0.63−0.97)
ORR (Combo vs. Control)	69.0% vs. 24.1%	N/A
Median OS (Combo vs. Control)	Not Reached vs. 12.8 mo	23.1 mo vs. 16.9 mo
OS Hazard Ratio (95% CI)	0.23 (0.10−0.53)	0.87 (0.71−1.08)
Table 3: Comparative Efficacy Outcomes in First-Line PD-L1-High NSCLC (CITYSCAPE vs. SKYSCRAPER-01). This table directly contrasts the Phase II and Phase III results, illustrating the failure to replicate the initial promising efficacy signals. Data compiled from.9

Clinical Evaluation in Other Malignancies

A Notable Success in Esophageal Cancer: The SKYSCRAPER-08 Trial

In a surprising turn, the SKYSCRAPER-08 trial (NCT04540211) delivered the only positive Phase III results for the tiragolumab program. This randomized, double-blind study enrolled 461 patients from Asia with previously untreated, unresectable or metastatic esophageal squamous cell carcinoma (ESCC).[18] The trial evaluated a triplet combination of tiragolumab, atezolizumab, and chemotherapy (cisplatin and paclitaxel) against placebo plus chemotherapy.[46]

The study successfully met both of its primary endpoints. At the final analysis, the tiragolumab-containing regimen demonstrated a statistically significant and clinically meaningful improvement in OS, with a median OS of 15.7 months compared to 11.1 months in the chemotherapy-alone arm (HR 0.70; p=0.0024).[18] A significant benefit was also observed for PFS, with a median of 6.2 months versus 5.4 months (HR 0.56;

p<0.0001). The benefit was reported to be consistent across subgroups, including by PD-L1 status.[18] Secondary endpoints, including ORR (59.7% vs. 45.5%) and duration of response (7.1 vs. 4.3 months), also favored the investigational arm.[18]

Despite these positive results, the trial's design carries a significant limitation. The control arm of chemotherapy alone is no longer considered the global standard of care for first-line ESCC, which now typically includes an anti-PD-1 agent (such as nivolumab or pembrolizumab) combined with chemotherapy.[18] Because the trial did not include an arm with atezolizumab plus chemotherapy, it is impossible to definitively parse the individual contributions of tiragolumab and atezolizumab to the observed benefit. The positive outcome may be driven by atezolizumab, tiragolumab, or their combination being superior to chemotherapy alone. This design flaw complicates the interpretation of the results and limits their applicability in a modern treatment landscape. Nonetheless, the trial provides the most compelling clinical evidence to date that TIGIT blockade can contribute to a therapeutic effect, though perhaps only in a very specific biological or ethnic context.

Disappointment in Small Cell Lung Cancer: The SKYSCRAPER-02 Trial

The SKYSCRAPER-02 trial (NCT04256421) evaluated the addition of tiragolumab to the established standard-of-care regimen for extensive-stage small-cell lung cancer (ES-SCLC): atezolizumab plus chemotherapy (carboplatin and etoposide).[16] This large Phase III study enrolled 490 patients.

The results were unequivocally negative. The addition of tiragolumab conferred no additional benefit over the active control regimen. The co-primary endpoints of PFS (median 5.4 months in the tiragolumab arm vs. 5.6 months in the control arm; HR 1.11) and OS (median 13.1 months in both arms) were not met.[16] This failure is particularly instructive, as it was not a failure to beat a placebo but a failure to improve upon an already active and effective immunotherapy-based regimen. This suggests that in the context of ES-SCLC, either TIGIT is not a dominant immune evasion pathway, or any TIGIT-mediated suppression is already sufficiently overcome by the combination of chemotherapy and PD-L1 blockade.

Ongoing and Completed Exploratory Studies

Beyond lung and esophageal cancers, tiragolumab was investigated across a broad range of malignancies. These included studies in hepatocellular carcinoma (MORPHEUS-Liver, SKYSCRAPER-14), oral cavity squamous cell carcinoma (NCT05681039), cervical cancer (SKYSCRAPER-04), and various other advanced solid tumors.[41] However, following the repeated failures in the lung cancer program, Roche began to curtail development. The quiet discontinuation of the pivotal SKYSCRAPER-14 trial in liver cancer in mid-2025 marked the effective end of the program and led to the removal of tiragolumab from Roche's publicly disclosed pipeline.[20]

Endpoint	Tiragolumab + Atezo + Chemo (n=229)	Placebo + Chemo (n=232)	Hazard Ratio (95% CI)	P-value
Median OS	15.7 months	11.1 months	0.70 (0.55−0.88)	0.0024
12-month OS Rate	~65%	~50%	N/A	N/A
18-month OS Rate	~45%	~30%	N/A	N/A
Median PFS	6.2 months	5.4 months	0.56 (0.45−0.70)	<0.0001
12-month PFS Rate	24%	6%	N/A	N/A
ORR	59.7%	45.5%	N/A	N/A
Median DoR	7.1 months	4.3 months	N/A	N/A
Table 4: Primary and Secondary Efficacy Outcomes from the Phase III SKYSCRAPER-08 Trial in ESCC. This table details the sole positive Phase III result for the tiragolumab program. OS rate percentages are approximated from graphical data. Data compiled from.18

The TIGIT Inhibitor Class: A Landscape of High Hopes and Hard Realities

Competitive Analysis

The development of TIGIT inhibitors has been a story of "target contagion," where the initial promise of tiragolumab's CITYSCAPE data sparked a multi-billion dollar industry-wide investment rush, followed by a wave of collective disappointment.[14] The competitive landscape is now defined more by its failures than its successes.

• Vibostolimab (Merck): Co-formulated with the anti-PD-1 antibody pembrolizumab, vibostolimab has encountered significant setbacks. Multiple Phase III trials, including KeyVibe-002 in second-line NSCLC, KeyVibe-008 in SCLC, and KeyVibe-010 in adjuvant melanoma, were halted due to a lack of efficacy and, in some cases, increased immune-related toxicity.[23]
• Ociperlimab (BeiGene): After being licensed and then returned by Novartis, BeiGene halted the development of ociperlimab when its Phase III trial in first-line NSCLC was terminated for futility in early 2025.[23]
• Belrestotug (iTeos/GSK): This program showed a promising ORR in the Phase II GALAXIES Lung-201 trial but failed to demonstrate a meaningful improvement in the key secondary endpoint of PFS. Consequently, GSK and iTeos terminated their collaboration and all development programs for belrestotug in May 2025.[66]
• Domvanalimab (Arcus/Gilead): As one of the few remaining late-stage assets, domvanalimab stands out due to its "Fc-silent" design. It has demonstrated encouraging randomized Phase II data in NSCLC (ARC-7 and ARC-10 studies) and upper GI cancers (EDGE-Gastric), showing improvements in PFS and OS when combined with an anti-PD-1 antibody. It is currently advancing in several Phase III studies.[60]
• Rilvegostomig (AstraZeneca): This asset is a bispecific antibody targeting both PD-1 and TIGIT. AstraZeneca is pursuing a broad Phase III development program across multiple tumor types, including lung, gastric, and biliary tract cancers, betting that a bispecific format may offer advantages over combination approaches.[66]

The Fc-Enabled vs. Fc-Silent Hypothesis: A Critical Scientific Debate

The widespread failures have focused attention on a key molecular design choice: the functionality of the antibody's Fc region.

• Fc-Enabled Design (e.g., Tiragolumab): Most first-generation TIGIT inhibitors, including tiragolumab, were designed as human IgG1 antibodies with a functional, or "enabled," Fc region. This design allows the antibody to bind to Fcγ receptors on immune cells and mediate ADCC.[80] The therapeutic hypothesis was that this would lead to the beneficial depletion of immunosuppressive, TIGIT-high Tregs in the TME. However, this approach carries the inherent risk of also depleting beneficial TIGIT-expressing effector T-cells and NK cells, potentially counteracting the desired immune activation or causing off-target toxicity.[83] The clinical trial results from Fc-enabled antibodies have been largely disappointing, suggesting this dual-function approach may be flawed.
• Fc-Silent Design (e.g., Domvanalimab): An alternative strategy involves engineering the antibody's Fc region to be "silent" or "null," preventing it from binding to Fcγ receptors and mediating ADCC.[86] The rationale for this design is to achieve a "clean" blockade of the TIGIT checkpoint without the confounding and potentially detrimental effects of cell depletion. This approach aims to preserve the population of effector T-cells and NK cells while still preventing TIGIT's inhibitory signaling.[86] The more promising data emerging from the Fc-silent domvanalimab program suggest that the initial hypothesis favoring an Fc-enabled design may have been incorrect, and that a pure checkpoint blockade mechanism may be the more viable path forward for TIGIT inhibition.

Collective Setbacks and the Future of TIGIT as a Target

The TIGIT inhibitor class has transitioned from being hailed as the next major breakthrough in immuno-oncology to a field facing an existential crisis. The repeated, high-profile failures of pivotal trials, led by Roche's SKYSCRAPER program, have largely invalidated the initial hypothesis that simple dual blockade of TIGIT and PD-L1 would yield broad benefits across major cancer types like NSCLC.[14]

The future of TIGIT as a therapeutic target is now uncertain and rests on the success of the remaining, differentiated programs. The key lessons learned from the failures include the critical need for more sophisticated predictive biomarkers beyond PD-L1 status, a deeper understanding of tumor-specific immune biology to identify patient populations most likely to benefit, and the importance of intelligent antibody engineering, as exemplified by the Fc-silent and bispecific approaches. The TIGIT saga underscores the immense challenge of demonstrating incremental benefit over increasingly effective standards of care and serves as a powerful reminder that even the most promising preclinical and Phase II data do not guarantee success in Phase III.

Drug Name (Developer)	Antibody Design (Fc Type)	Key Indication(s)	Phase	High-Level Outcome/Status
Tiragolumab (Roche/Genentech)	Fc-Enabled (IgG1)	NSCLC, SCLC, ESCC, HCC	III	Failed in NSCLC, SCLC, HCC; Positive in ESCC. Program discontinued.18
Domvanalimab (Arcus/Gilead)	Fc-Silent	NSCLC, GI Cancers	III	Positive randomized Phase II data; advancing in Phase III.72
Vibostolimab (Merck)	Fc-Enabled (IgG1)	NSCLC, SCLC, Melanoma	III	Multiple Phase III trials halted for futility/toxicity.61
Belrestotug (iTeos/GSK)	Fc-Enabled (IgG1)	NSCLC, H&N Cancer	III	Failed to meet PFS criteria in Phase II; program terminated.66
Ociperlimab (BeiGene)	Fc-Enabled (IgG1)	NSCLC	III	Phase III trial terminated for futility.64
Rilvegostomig (AstraZeneca)	Bispecific (PD-1/TIGIT)	NSCLC, GI Cancers	III	Broad Phase III program ongoing.77
Table 5: Comparative Overview of Key TIGIT Inhibitors in Clinical Development. This table provides a snapshot of the competitive landscape, highlighting molecular design and clinical status. Data compiled from sources including.20

Conclusion and Future Outlook

Tiragolumab pioneered the clinical exploration of TIGIT as a novel immune checkpoint target, embarking on a journey marked by immense initial promise and, ultimately, profound disappointment in its primary indications. While the drug consistently demonstrated a manageable safety profile, its clinical efficacy proved to be highly variable and context-dependent. The singular, qualified success in the SKYSCRAPER-08 trial for esophageal squamous cell carcinoma was decisively overshadowed by a series of definitive failures in non-small cell and small-cell lung cancer, culminating in the discontinuation of the entire development program by Roche in mid-2025.[20]

The story of tiragolumab offers several critical lessons for the field of immuno-oncology. First, it serves as a stark reminder of the perils of extrapolating from small, exploratory subgroup analyses in Phase II trials, as the spectacular efficacy signal in the CITYSCAPE PD-L1-high cohort could not be replicated in a larger, more definitive study. Second, it highlights the increasing difficulty of demonstrating a clinically meaningful benefit on top of potent, established standards of care, as shown by its failure against a pembrolizumab-based regimen. Finally, the divergent outcomes across different tumor types underscore that the biological relevance of a given immune checkpoint pathway is not universal but is instead dictated by the unique tumor microenvironment of each malignancy.

The future of TIGIT as a therapeutic target is now tenuous. The widespread failures across the first wave of Fc-enabled antibodies have cast significant doubt on the initial therapeutic hypothesis. Any remaining hope for the pathway now rests on the shoulders of next-generation approaches that may have learned from the setbacks of tiragolumab and its peers. These include Fc-silent antibodies like domvanalimab, which aim for a more precise blockade without the confounding effects of ADCC, and bispecific antibodies like rilvegostomig, which offer a novel way to co-target TIGIT and PD-1. The success or failure of these remaining programs will deliver the final verdict on whether TIGIT inhibition can find a place in the armamentarium of cancer therapies. For tiragolumab, its legacy is now cemented not as a therapeutic breakthrough, but as a pivotal and cautionary chapter in the ongoing effort to understand and overcome immune resistance in cancer.

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