Ociperlimab (BGB-A1217): A Comprehensive Clinical and Scientific Monograph on a Discontinued Anti-TIGIT Immunotherapy

Executive Summary

Ociperlimab, also known as BGB-A1217, was an investigational humanized monoclonal antibody developed by BeiGene targeting the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a novel immune checkpoint. The scientific rationale for ociperlimab was rooted in the hypothesis that blocking the inhibitory TIGIT pathway, particularly in combination with PD-1 blockade, could restore and amplify anti-tumor immune responses. A key differentiating feature of ociperlimab was its design as an Fc-competent immunoglobulin G1 (IgG1) antibody, intended to mediate additional anti-tumor effects such as antibody-dependent cellular cytotoxicity (ADCC) against immunosuppressive regulatory T-cells.

The drug's development trajectory was initially marked by promising preclinical data and encouraging early-phase clinical results. The Phase 1/1b AdvanTIG-105 study established a manageable safety profile and demonstrated notable antitumor activity in expansion cohorts for non-small cell lung cancer (NSCLC), gastric cancer, and esophageal cancer, particularly when combined with chemotherapy. This early promise culminated in a landmark option and collaboration agreement with Novartis in December 2021, featuring a $300 million upfront payment, which served as a significant external validation of the program and the broader TIGIT therapeutic class.

However, the program's momentum faltered. In July 2023, Novartis declined its option, returning full rights to BeiGene—a decision that foreshadowed subsequent challenges. The definitive turning point came in April 2025 with the announcement that the pivotal Phase 3 AdvanTIG-302 trial in first-line, PD-L1-high NSCLC was being terminated. The decision followed a recommendation from an independent data monitoring committee based on a futility analysis, which concluded the study was unlikely to meet its primary endpoint of overall survival. Consequently, BeiGene discontinued the entire ociperlimab development program.

The failure of ociperlimab was not an isolated event but rather a significant data point in the challenging and disappointing narrative of the TIGIT inhibitor class, especially in NSCLC. Its discontinuation followed similar high-profile failures from Roche, Merck, and GSK/iTeos in the same indication. This comprehensive monograph details the scientific basis, preclinical evidence, clinical development history, corporate strategy, and ultimate discontinuation of ociperlimab, placing its story within the critical context of the evolving and increasingly complex landscape of cancer immunotherapy.

Scientific Rationale and Preclinical Profile

The development of ociperlimab was predicated on a deep understanding of the TIGIT pathway as a critical regulator of anti-tumor immunity and a molecular design intended to maximally exploit this biology.

The TIGIT Pathway: A Key Co-Inhibitory Axis in Cancer Immunology

TIGIT has emerged as a promising target in cancer immunotherapy, functioning as a co-inhibitory immune checkpoint receptor.[1] It is primarily expressed on the surface of key immune cells, including activated CD8+ and CD4+ T-cells, Natural Killer (NK) cells, and immunosuppressive regulatory T-cells (Tregs).[3] In the tumor microenvironment, cancer cells often overexpress TIGIT's primary ligands, CD155 (also known as the poliovirus receptor, PVR) and CD112 (PVRL2 or nectin-2).[3]

The engagement of TIGIT by these ligands initiates a cascade of inhibitory signals within the immune cell, mediated by its immunoreceptor tyrosine-based inhibitory motif (ITIM) domain.[3] This signaling suppresses T-cell and NK-cell proliferation and activation, leading to a state of functional exhaustion and enabling tumor cells to evade immune destruction.[1]

Furthermore, the TIGIT pathway operates in a competitive balance with a co-stimulatory receptor, CD226 (also known as DNAM-1), which is also expressed on T-cells and NK cells and binds to the same CD155 and CD112 ligands.[3] TIGIT binds to CD155 with higher affinity than CD226, effectively outcompeting the activating receptor. This competition disrupts CD226-mediated signaling, which is essential for a robust anti-tumor response, thereby tipping the balance from immune activation toward immunosuppression.[3] The dual blockade of TIGIT and the well-established PD-1/PD-L1 pathway was hypothesized to produce synergistic effects, as the two pathways represent distinct but complementary mechanisms of immune suppression frequently co-expressed on exhausted tumor-infiltrating lymphocytes.[7]

Molecular Profile of Ociperlimab (BGB-A1217): A Differentiated, Fc-Competent Design

Ociperlimab (BGB-A1217) is a novel, humanized monoclonal antibody of the IgG1 kappa isotype, derived from a murine clone and engineered to bind human TIGIT with high affinity and specificity.[3] Its primary mechanism of action is to function as a blocking antibody. By binding to TIGIT on immune cells, ociperlimab physically prevents the interaction with its ligands CD155 and CD112 on tumor cells.[3] This blockade is designed to achieve two main objectives: first, to prevent the transmission of direct inhibitory signals through the TIGIT receptor, and second, to allow the co-stimulatory receptor CD226 to bind its ligands, thereby restoring a crucial immune activation signal.[3]

A central and deliberate feature of ociperlimab's design was its intact, wild-type IgG1 Fc region, making it an "Fc-competent" antibody.[4] This design choice was a core component of its therapeutic hypothesis and a key point of differentiation from other anti-TIGIT antibodies that were engineered to be "Fc-silent" to minimize Fc receptor interactions. The rationale for an active Fc region was to engage Fc-gamma receptors (

FcγR) on other immune cells, such as macrophages and NK cells, to mediate additional anti-tumor functions. The most prominent of these functions was hypothesized to be ADCC, which could lead to the selective depletion of TIGIT-expressing cells. Given that Tregs, a major driver of immunosuppression in the tumor microenvironment, highly express TIGIT, the Fc-competent design of ociperlimab was intended to specifically target and eliminate these cells, further reducing immune suppression.[4]

Preclinical Evidence Supporting Clinical Development

An extensive preclinical research program provided a strong foundation for advancing ociperlimab into clinical trials. These studies validated both its primary blocking activity and the functional importance of its Fc-competent design.

In vitro studies confirmed that ociperlimab binds to the extracellular domain of human TIGIT with high affinity, exhibiting a dissociation constant (KD​) of 0.135 nM, and effectively blocks the binding of TIGIT to its ligands PVR (CD155) and PVRL2 (CD112).[4] Cell-based functional assays demonstrated that this blockade translated into enhanced T-cell activity.[4] Moreover, the preclinical data strongly supported the Fc-competent hypothesis. Ociperlimab was shown to induce ADCC against TIGIT-positive Treg cells, activate NK cells and monocytes, and promote the removal of TIGIT from T-cell surfaces via trogocytosis in an Fc-dependent manner.[4]

The importance of this design was further substantiated in in vivo models. In syngeneic mouse models where the mice were "knocked-in" with human TIGIT, ociperlimab demonstrated potent anti-tumor efficacy, both as a monotherapy and, more significantly, in combination with an anti-PD-1 monoclonal antibody.[4] The critical role of the Fc region was confirmed through a direct comparison with BGB-A1217MF, a version of the antibody with the same variable region but a mutated Fc domain lacking

FcγR binding capabilities. BGB-A1217MF was found to be substantially less effective, indicating that the Fc effector function was necessary for optimal anti-tumor activity in these preclinical models.[4] This efficacy was associated with pharmacodynamic changes consistent with its proposed mechanism, including downregulation of TIGIT on immune cells and a reduction in Treg populations within the tumor.[4]

The preclinical package for ociperlimab was robust, presenting a compelling narrative that its Fc-competent design was a key differentiator that could translate into superior clinical efficacy. This hypothesis became central to the drug's identity and its perceived value in a competitive landscape that included Fc-silent approaches. The ultimate failure of ociperlimab in its pivotal trial directly challenges this foundational hypothesis, suggesting a more complex and context-dependent role for Fc-mediated effects in checkpoint inhibition. While preclinical models clearly demonstrated the superiority of the Fc-competent design, the clinical reality in first-line NSCLC proved otherwise. This outcome forces a critical re-evaluation, suggesting that either ADCC-mediated Treg depletion is not a dominant anti-tumor mechanism in this specific clinical setting, its benefits are insufficient to improve upon the high efficacy of PD-1 blockade, or it may have unintended negative consequences not captured by the preclinical models, such as the depletion of TIGIT-expressing effector T-cells.

Clinical Development Program: The "AdvanTIG" Trials

The clinical development of ociperlimab was pursued through a series of studies collectively named "AdvanTIG," which systematically evaluated its safety and efficacy from first-in-human dose escalation to a large-scale pivotal trial.

Phase 1/1b Foundation: The AdvanTIG-105 Study (NCT04047862)

The AdvanTIG-105 study served as the cornerstone of ociperlimab's clinical program, providing the initial safety, dosing, and efficacy data that guided its subsequent development.

Trial Design and Objectives

AdvanTIG-105 was a first-in-human, multicenter, open-label, non-randomized Phase 1/1b study.[7] The Phase 1 dose-escalation portion aimed to assess the safety and tolerability of ociperlimab in combination with the anti-PD-1 antibody tislelizumab in patients with advanced, metastatic, or unresectable solid tumors who had exhausted or were ineligible for standard therapies.[7] The primary objectives were to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to establish the recommended Phase 2 dose (RP2D).[7] The Phase 1b portion consisted of multiple disease-specific expansion cohorts designed to evaluate the preliminary antitumor activity of the combination at the RP2D, with overall response rate (ORR) as the primary objective.[13]

Dose Escalation and Safety Profile

The dose-escalation part of the study enrolled 32 patients and evaluated ociperlimab doses ranging from 50 mg to 1800 mg, administered intravenously every 3 weeks (Q3W) in combination with a fixed dose of tislelizumab (200 mg Q3W).[7] The combination demonstrated a manageable safety profile and was generally well-tolerated.[7] No dose-limiting toxicities (DLTs) were observed across the dose levels, and thus the MTD was not reached.[7] While treatment-emergent adverse events (TEAEs) were frequent (experienced by 96.9% of patients), with 62.5% experiencing Grade

≥3 TEAEs and 50.0% experiencing serious TEAEs, the safety profile was deemed consistent with that of tislelizumab monotherapy and other anti-TIGIT agents in development.[7] Based on an integrated analysis of safety, pharmacokinetics, and preliminary efficacy, the

RP2D was established as ociperlimab 900 mg IV Q3W in combination with tislelizumab 200 mg IV Q3W.[7]

Early Efficacy Signals and Expansion Cohort Results

In the heavily pre-treated, mixed-histology population of the dose-escalation cohort, the combination showed modest preliminary antitumor activity. The overall ORR was 10.0%, the median duration of response (DoR) was 3.6 months, and the disease control rate (DCR) was 50.0%.[7] The expansion cohorts, however, which focused on specific tumor types and less heavily pre-treated populations, generated more promising signals that fueled optimism for the program.

• Non-Small Cell Lung Cancer (NSCLC): In a cohort of 39 treatment-naïve patients with metastatic, PD-L1-positive NSCLC, the combination of ociperlimab and tislelizumab yielded an unconfirmed ORR of 53.8%. The response appeared to correlate with the level of PD-L1 expression; patients with a PD-L1 tumor cell score of ≥50% (n=14) had an ORR of 71.4%, compared to 44.0% for those with a score of 1-49% (n=25).[8]
• Gastric/Gastroesophageal Junction Cancer (GC/GEJC): A cohort of 60 patients with previously untreated, stage IV GC/GEJC received ociperlimab and tislelizumab plus standard chemotherapy (oxaliplatin and capecitabine or cisplatin and 5-fluorouracil).[18] As of September 2022, this triplet combination demonstrated an encouraging investigator-assessed ORR of 50.8%, a DCR of 84.7%, a median DoR of 8.1 months, and a median progression-free survival (PFS) of 8.2 months.[18]
• Esophageal Cancers: In data presented at ESMO 2023 for cohorts of patients with metastatic esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), the combination of ociperlimab, tislelizumab, and chemotherapy showed very high ORRs of 84.2% (n=19) and 80.0% (n=5), respectively.[19]

Phase 2 Investigation: The AdvanTIG-202 Study in Cervical Cancer (NCT04693234)

To explore its efficacy in other tumor types, BeiGene initiated the AdvanTIG-202 study, focusing on a population with high unmet medical need.

Trial Design and Rationale

AdvanTIG-202 was a Phase 2, randomized, multicenter, open-label study designed to evaluate the efficacy and safety of ociperlimab plus tislelizumab versus tislelizumab monotherapy.[9] The study enrolled patients with recurrent or metastatic cervical cancer (R/M CC) who had progressed after at least one line of chemotherapy.[20] A total of 178 patients were enrolled, with 138 assigned to the combination arm (Cohort 1) and 40 to the tislelizumab monotherapy arm (Cohort 2).[22] The primary endpoint was the ORR in the combination arm, as assessed by an independent review committee (IRC).[9]

Efficacy and Safety Outcomes

The primary analysis results, with a data cutoff of June 16, 2022, were presented at the ESMO 2023 congress.[21] In the combination arm, the IRC-assessed ORR was 22.5% in the all-comer population and 26.2% in patients with PD-L1-positive tumors. This result was noted to be a promising improvement over the historical ORR of approximately 15% for anti-PD-1 monotherapy in this patient population.[22] The responses were notably durable, with 76.8% of responders maintaining their response for at least 6 months. The median PFS was 3.5 months and the median overall survival (OS) was 9.0 months.[22] The combination was well-tolerated, with only 13% of patients experiencing Grade

≥3 treatment-related adverse events (TRAEs).[22] The trial is listed as completed.[20]

The Pivotal Failure: The AdvanTIG-302 Study in NSCLC (NCT04746924)

Building on the promising signals from the AdvanTIG-105 NSCLC cohort, BeiGene launched the AdvanTIG-302 study, a pivotal Phase 3 trial intended to secure regulatory approval.

Strategic Rationale and Trial Design

AdvanTIG-302 was a large-scale, global, randomized, double-blind Phase 3 clinical trial.[12] Its ambitious design aimed to establish the superiority of the ociperlimab plus tislelizumab combination over the well-established standard-of-care, pembrolizumab (Keytruda) monotherapy.[26] The study targeted the first-line treatment of patients with locally advanced, unresectable, or metastatic NSCLC whose tumors exhibited high PD-L1 expression (

≥50%) and did not have sensitizing EGFR or ALK genomic alterations.[12] The trial planned to enroll approximately 660 patients, randomized to receive either the ociperlimab/tislelizumab combination or pembrolizumab plus placebo.[12] The dual primary endpoints were PFS and OS.[12]

The Futility Analysis and Program Termination

The AdvanTIG-302 trial and the entire ociperlimab program came to an abrupt end in April 2025.[30] BeiGene announced the discontinuation of the drug's clinical development based on a recommendation from the study's IDMC.[29] This recommendation followed a pre-planned futility analysis of the trial's data. The IDMC concluded that the study was

unlikely to meet its primary endpoint of overall survival.[28] The termination was driven solely by a lack of efficacy, as no new or unexpected safety signals were identified.[29]

The clinical journey of ociperlimab illustrates a critical disconnect between early-phase promise and late-stage proof. The encouraging ORR of over 50% in the small, single-arm AdvanTIG-105 NSCLC cohort provided the impetus for the large, resource-intensive AdvanTIG-302 trial. However, ORR is a surrogate endpoint that measures tumor shrinkage, which does not always translate to a survival benefit, especially when compared against a highly effective active control like pembrolizumab. The failure to demonstrate an OS benefit in the pivotal trial underscores the inherent risk of relying on early-phase ORR data to predict success in Phase 3.

Furthermore, the starkly different outcomes across tumor types—failure in first-line, PD-L1-high NSCLC versus promising signals in cervical and gastrointestinal cancers—strongly suggest that the therapeutic relevance of the TIGIT pathway is highly context-dependent. First-line PD-L1-high NSCLC is an immunologically "hot" setting where PD-1 blockade is already very effective. In this context, adding a TIGIT inhibitor may provide only marginal, non-significant benefit. Conversely, in more immunologically "cold" tumors like cervical cancer or in combination with chemotherapy, which can modulate the tumor microenvironment, TIGIT blockade may offer a more substantial contribution to the anti-tumor response. This points toward a need for more nuanced, biomarker-driven strategies for TIGIT inhibitors rather than a broad application.

Trial ID (NCT Number)	Trial Name	Phase	Brief Title/Indication(s)	Key Intervention(s)	Status / Key Outcome
NCT04047862	AdvanTIG-105	1/1b	Study of Ociperlimab + Tislelizumab in Advanced Solid Tumors	Ociperlimab, Tislelizumab, Chemotherapy	Completed. Established RP2D of 900 mg Q3W. Showed promising ORR in NSCLC, GC/GEJC, and esophageal cancer expansion cohorts.13
NCT04693234	AdvanTIG-202	2	Study of Ociperlimab + Tislelizumab in Recurrent/Metastatic Cervical Cancer	Ociperlimab, Tislelizumab	Completed. Met primary endpoint, showing promising and durable ORR (22.5%) for the combination vs. historical controls.20
NCT04746924	AdvanTIG-302	3	Study of Ociperlimab + Tislelizumab vs. Pembrolizumab in 1L PD-L1-High NSCLC	Ociperlimab, Tislelizumab, Pembrolizumab	Terminated. Failed to meet primary endpoint of OS at pre-planned futility analysis, leading to discontinuation of the entire ociperlimab program.26
NCT04866017	AdvanTIG-301	3	Study of Ociperlimab + Tislelizumab vs. Durvalumab in Stage III Unresectable NSCLC	Ociperlimab, Tislelizumab, Durvalumab	Terminated prior to failure of AdvanTIG-302.34
NCT05014815	AdvanTIG-205	2	Study of Ociperlimab + Tislelizumab + Chemotherapy in 1L NSCLC	Ociperlimab, Tislelizumab, Chemotherapy	Completed.36

Corporate Strategy and Partnership Trajectory

The corporate and strategic history of ociperlimab provides a clear narrative of the biopharmaceutical industry's initial enthusiasm for the TIGIT class, followed by a rapid recalibration as clinical data failed to meet high expectations.

The Novartis Agreement: A Peak Valuation and Validation

In December 2021, at a time of peak optimism for TIGIT inhibitors, BeiGene executed a major strategic partnership with Novartis for ociperlimab.[37] The agreement was structured as an option, collaboration, and license deal, representing a significant external validation of ociperlimab's potential from a global pharmaceutical leader.

The financial terms were substantial and underscored the high value placed on late-stage TIGIT assets at the time. Novartis made an upfront payment to BeiGene of $300 million. The agreement included an option for Novartis to license the asset, which, if exercised before late 2023, would trigger an additional payment of up to $700 million.[37] Upon exercising the option, Novartis would have secured the exclusive development and commercialization rights to ociperlimab in key global markets, including the United States, Canada, Mexico, the European Union, the United Kingdom, and Japan. BeiGene would retain rights in China and all other countries and would share co-detailing efforts in the U.S..[37] This deal was widely seen as a strategic move by Novartis to strengthen its immuno-oncology pipeline with a promising late-stage candidate complementary to its own development plans for tislelizumab, for which it had also licensed rights from BeiGene.[12]

The Dissolution of the Partnership: A Harbinger of Trouble

Despite the initial promise, the partnership was short-lived. In July 2023, Novartis announced its decision not to exercise its option, thereby terminating the agreement and returning all global rights for ociperlimab to BeiGene.[30] While BeiGene stated its commitment to continuing the drug's development independently, the loss of its powerhouse partner was a significant blow to the program.[30]

Novartis's rationale for the decision was based on a comprehensive review of the program. A company spokesperson stated that the decision was made after assessing "the totality of the current information, including Phase 2 data, benefit/risk, competitive space, timing, development programs, and future investments".[33] This statement, though corporate in nature, strongly implied that Novartis's internal analysis of maturing, and likely unblinded, clinical data, combined with a shifting perspective on the increasingly challenging TIGIT competitive landscape, led to the conclusion that ociperlimab's path to market and commercial success was too uncertain.

The arc of this partnership serves as a real-time barometer of the asset's perceived viability. The high-value deal in late 2021 was a clear reflection of the industry's widespread enthusiasm for the TIGIT hypothesis before major clinical setbacks had been reported for the class. Novartis's exit in mid-2023, nearly two years before the public announcement of the AdvanTIG-302 trial failure, was a critical leading indicator of trouble. A decision of this magnitude, which involved forgoing a potential blockbuster asset and a sunk cost of $300 million, suggests that Novartis's privileged access to emerging data gave them a negative outlook on the program's probability of success. For industry observers, the dissolution of such a major partnership should be interpreted not merely as a corporate realignment but as a strong, albeit indirect, negative data signal about the future prospects of the asset.

Discontinuation Analysis and Broader Implications

The termination of the ociperlimab program in April 2025 was a definitive event, driven by the failure of its lead clinical trial. This outcome has significant implications not only for BeiGene but for the entire field of TIGIT-targeted immunotherapy.

Deconstructing the AdvanTIG-302 Failure

The primary and direct cause of ociperlimab's discontinuation was the futility analysis of the AdvanTIG-302 trial, which concluded that the combination of ociperlimab and tislelizumab was unlikely to demonstrate a statistically significant improvement in Overall Survival compared to pembrolizumab monotherapy.[29] Several factors likely contributed to this failure:

• A High Efficacy Bar: Pembrolizumab monotherapy is a highly effective and deeply entrenched standard of care for first-line, PD-L1-high NSCLC. The bar for demonstrating a survival advantage over such a potent agent is exceptionally high. Any new therapy must provide not just a statistically significant but also a clinically meaningful benefit to justify its adoption, a challenge that ociperlimab could not meet.
• The Chosen Indication: The consistent failure of multiple TIGIT inhibitors in this specific patient population points toward a fundamental biological limitation. It is increasingly plausible that in this immunologically "hot" tumor setting, the PD-1/PD-L1 axis is the overwhelmingly dominant and rate-limiting immune checkpoint. Once this pathway is effectively blocked by an agent like pembrolizumab, the additional blockade of TIGIT may provide little to no incremental clinical benefit because other, non-TIGIT-related mechanisms drive primary and acquired resistance.
• Patient Selection Paradox: While selecting for patients with high PD-L1 expression enriches for a population likely to respond to immunotherapy, it also selects for the very group where pembrolizumab performs at its best. This strategy, while sound for maximizing the potential of the control arm, simultaneously makes it much more difficult for the experimental arm to demonstrate superiority.

Ociperlimab in the Context of the Troubled TIGIT Inhibitor Landscape

The failure of ociperlimab is not an outlier but rather a key event in a consistent and troubling pattern for the TIGIT drug class, particularly in NSCLC. A comparative analysis reveals a landscape littered with high-profile setbacks, suggesting a class-wide issue rather than a molecule-specific flaw in this indication. The repeated failure of four distinct anti-TIGIT antibodies from four major pharmaceutical companies in the first-line NSCLC setting—despite differences in their molecular engineering (e.g., Fc-competent vs. Fc-silent)—points overwhelmingly to a flawed biological hypothesis for this specific clinical context. The idea that "TIGIT blockade plus PD-1 blockade is superior to PD-1 blockade alone" appears to be false for first-line, PD-L1-high NSCLC.

The evolving landscape also suggests a potential paradigm shift in TIGIT development. The failures of Fc-competent or Fc-active antibodies like ociperlimab and tiragolumab in NSCLC monotherapy combinations stand in contrast to the continued development of the Fc-silent antibody domvanalimab, which is showing promise in gastrointestinal cancers, notably in combination with chemotherapy. This pattern suggests a new prevailing hypothesis may be emerging: that the key to unlocking TIGIT's potential lies in either avoiding potential on-target, off-tumor toxicities or effector T-cell depletion by using an Fc-silent backbone, and/or combining it with chemotherapy to favorably modulate the tumor microenvironment. The promising data from ociperlimab's own GI cohorts, which also involved chemotherapy, further supports this notion.

Drug Name (INN)	Developer(s)	Molecular Design (Fc Function)	Lead Indication(s) for Pivotal Trials	Development Status / Key Outcome
Ociperlimab	BeiGene	Fc-competent (Human IgG1)	1L PD-L1-high NSCLC	Discontinued (April 2025). Phase 3 (AdvanTIG-302) terminated for futility (unlikely to meet OS endpoint).4
Tiragolumab	Roche / Genentech	Fc-competent (Human IgG1)	1L PD-L1-high NSCLC, SCLC, Esophageal, Liver Cancer	Multiple Phase 3 NSCLC failures (SKYSCRAPER-01, -06). Development continues in other indications like liver cancer.31
Vibostolimab	Merck & Co.	Fc-competent (Human IgG1)	1L PD-L1+ NSCLC, Melanoma	Discontinued (Dec 2024). Multiple Phase 3 trials (e.g., KeyVibe-003) failed to show benefit.31
Belrestotug	GSK / iTeos	Fc-competent (Human IgG1)	1L PD-L1-high NSCLC, HNSCC	Discontinued (May 2025). Phase 2 trials failed to meet efficacy criteria for continuation.42
Domvanalimab	Gilead / Arcus Biosciences	Fc-silent	1L NSCLC, Upper GI Cancers	Active in Phase 3. NSCLC trial (ARC-10) discontinued; focus shifted to chemo-combo trial (STAR-121) and promising Phase 2 data in upper GI cancers.35
Rilvegostomig	AstraZeneca	Bispecific (PD-1/TIGIT) with reduced Fc function	NSCLC, Biliary, Liver, Gastric Cancer	Active in Phase 3. Advancing in multiple indications.48

Regulatory Status and History

Throughout its entire development cycle, ociperlimab remained an investigational agent. It did not receive marketing approval from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or any other global regulatory authority.[10] The program was terminated before any marketing applications were submitted.

In September 2021, BeiGene received a product-specific waiver from the EMA's Paediatric Committee (PDCO) for ociperlimab.[50] This waiver exempted the company from the requirement to conduct pediatric studies for the treatment of lung cancer, breast cancer, endometrial carcinoma, and other malignancies, on the grounds that these diseases rarely or never occur in the pediatric population. This is a standard procedural step in the development of drugs for adult cancers and carries no implication regarding the drug's safety or efficacy.[50]

Concluding Assessment

Ociperlimab (BGB-A1217) represents a case study of a rationally designed, scientifically compelling therapeutic candidate that ultimately failed to demonstrate clinical superiority in its lead indication. Its development was based on a strong preclinical hypothesis, particularly the differentiated, Fc-competent design intended to enhance anti-tumor activity through Treg depletion. Early clinical data showed encouraging signs of activity across several tumor types, attracting a major partnership with Novartis and fueling optimism for the TIGIT class.

However, the program's culmination in the failure of the pivotal AdvanTIG-302 trial in first-line, PD-L1-high NSCLC delivered a sobering verdict. The inability to improve overall survival over the highly effective standard-of-care, pembrolizumab, highlights the immense challenge of developing new immunotherapies that can meaningfully add to the benefit of first-generation checkpoint inhibitors in immunologically "hot" tumors.

The failure of ociperlimab, when viewed alongside the concurrent setbacks of its peers from Roche, Merck, and GSK, has been a crucial, albeit costly, lesson for the field of immuno-oncology. It has effectively invalidated the simple hypothesis that dual TIGIT/PD-1 blockade is broadly superior to PD-1 blockade alone in NSCLC. This series of failures underscores the limitations of preclinical models in predicting clinical success in complex tumor microenvironments and reinforces the critical importance of rigorous, randomized trials with clinically meaningful endpoints.

The story of the TIGIT pathway is not necessarily over, but it has been fundamentally reshaped. The broad enthusiasm has been replaced by a more nuanced and cautious approach. The future of TIGIT-targeted therapies now appears to lie not in broad application but in carefully selected contexts: potentially in different tumor types with distinct immune biology, such as gastrointestinal cancers; in combination with other modalities like chemotherapy; or through novel molecular engineering, such as Fc-silent or bispecific antibodies. Ociperlimab will be remembered as a well-executed program that provided a definitive, if disappointing, answer to a key scientific question and, in its failure, helped to refine the future direction of immuno-oncology research.

Works cited

1. Tiragolumab and TIGIT: pioneering the next era of cancer immunotherapy - Frontiers, accessed September 29, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1568664/full
2. Next Generation Anti TIGIT Antibodies In Cancer Immunotherapy - BioSpace, accessed September 29, 2025, https://www.biospace.com/press-releases/next-generation-anti-tigit-antibodies-in-cancer-immunotherapy
3. Definition of ociperlimab - NCI Drug Dictionary, accessed September 29, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ociperlimab
4. An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models - Frontiers, accessed September 29, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.828319/full
5. Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development - MDPI, accessed September 29, 2025, https://www.mdpi.com/2227-9059/9/9/1277
6. TIGIT Inhibitors - Pipeline Insight, 2025 - Research and Markets, accessed September 29, 2025, https://www.researchandmarkets.com/reports/5526546/tigit-inhibitors-pipeline-insight-2025
7. AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT ..., accessed September 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10603446/
8. Ociperlimab Plus Tislelizumab Demonstrates Antitumor Activity in PD-L1+ NSCLC | OncLive, accessed September 29, 2025, https://www.onclive.com/view/ociperlimab-plus-tislelizumab-demonstrates-antitumor-activity-in-pd-l1-nsclc
9. Ociperlimab/Tislelizumab Combo Under Exploration in Previously Treated Recurrent or Metastatic Cervical Cancer | OncLive, accessed September 29, 2025, https://www.onclive.com/view/ociperlimab-tislelizumab-combo-under-exploration-in-previously-treated-recurrent-or-metastatic-cervical-cancer
10. Ociperlimab Clinical Naked monospecific - The Antibody Society, accessed September 29, 2025, https://db.antibodysociety.org/db0/413/
11. An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab ..., accessed September 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8902820/
12. Document - SEC.gov, accessed September 29, 2025, https://www.sec.gov/Archives/edgar/data/1651308/000165130821000116/a8-kx17june2021xexhibit991.htm
13. Study of Ociperlimab (BGB-A1217) in Combination With Tislelizumab in Advanced Solid Tumors - NCI, accessed September 29, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-07405
14. NCT04047862 | Study of Ociperlimab (BGB-A1217) in Combination With Tislelizumab in Advanced Solid Tumors | ClinicalTrials.gov, accessed September 29, 2025, https://www.clinicaltrials.gov/study/NCT04047862
15. Clinical Trial: NCT04047862 - My Cancer Genome, accessed September 29, 2025, https://www.mycancergenome.org/content/clinical_trials/NCT04047862/
16. Study of Ociperlimab in Combination With Tislelizumab in Advanced Solid Tumors, accessed September 29, 2025, https://www.mayo.edu/research/clinical-trials/cls-20523442
17. AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors - PubMed, accessed September 29, 2025, https://pubmed.ncbi.nlm.nih.gov/37857528/
18. AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC). - ASCO, accessed September 29, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT426528
19. ESMO 2023 AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS), accessed September 29, 2025, https://www.beonemedinfo.com/CongressDocuments/Sun_BGB-900-105_ESMO_Abstract_2023.pdf
20. AdvanTIG-202: Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB ..., accessed September 29, 2025, https://beonemedicines.com/clinical-trials/advantig-202-anti-pd-1-monoclonal-antibody-tislelizumab-bgb-a317-combined-with-or-without-anti-tigit-monoclonal-antibody-ociperlimab-bgb-a1217-in-participants-with-previously-treated-recurrent-or/
21. AdvanTIG-202: Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) Combined With or Without Anti-TIGIT Monoclonal Antibody Ociperlimab (BGB-A1217) in Participants With Previously Treated Recurrent or Metastatic Cervical Cancer - larvol clin, accessed September 29, 2025, https://clin.larvol.com/trial-detail/NCT04693234
22. ESMO 2023 AdvanTIG-202: Phase 2 Randomized, Multicenter, Open-Label Study of Tislelizumab (TIS) With or Without Ociperlimab (OCI, accessed September 29, 2025, https://www.beonemedinfo.com/CongressDocuments/Lee_BGB-A317-A1217-202_ESMO_Abstract_2023.pdf
23. Clinical Trial for Patients With Previously Treated Recurrent or Metastatic Cervical Cancer Is Exploring Ociperlimab Plus Tislelizumab Combo, accessed September 29, 2025, https://www.cancernetwork.com/view/clinical-trial-for-patients-with-previously-treated-recurrent-or-metastatic-cervical-cancer-exploring-ociperlimab-plus-tislelizumab-combo
24. Ociperlimab - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 29, 2025, https://synapse.patsnap.com/drug/1b2275c846cd4870b8c0836c049bb997
25. Ociperlimab Completed Phase 2 Trials for Cervical Cancer Treatment | DrugBank Online, accessed September 29, 2025, https://go.drugbank.com/drugs/DB18947/clinical_trials?conditions=DBCOND0028450&phase=2&purpose=treatment&status=completed
26. NCT04746924 | A Study of Ociperlimab With Tislelizumab Compared to Pembrolizumab in Participants With Untreated Lung Cancer | ClinicalTrials.gov, accessed September 29, 2025, https://www.clinicaltrials.gov/study/NCT04746924
27. AdvanTIG-302: Anti-TIGIT monoclonal antibody ociperlimab+tislelizumab in non-small cell lung cancer, accessed September 29, 2025, https://www.beonemedinfo.com/CongressDocuments/Quantin_AdvanTIG-302_CPLF_Poster_2024.pdf
28. A Study of Ociperlimab With Tislelizumab Compared to Pembrolizumab in Participants With Untreated Lung Cancer - larvol clin, accessed September 29, 2025, https://clin.larvol.com/trial-detail/NCT04746924
29. Developers Terminate Clinical Program for Ociperlimab in Lung Cancer - CancerNetwork, accessed September 29, 2025, https://www.cancernetwork.com/view/developers-terminate-clinical-program-for-ociperlimab-in-lung-cancer
30. BeiGene bins TIGIT drug after pivotal lung cancer study failure - FirstWord Pharma, accessed September 29, 2025, https://firstwordpharma.com/story/5947200
31. BeiGene abandons TIGIT antibody after lung cancer flop - pharmaphorum, accessed September 29, 2025, https://pharmaphorum.com/news/beigene-abandons-tigit-antibody-after-lung-cancer-flop
32. Phase III Lung Cancer Trial Terminated Due to Futility - EMJ, accessed September 29, 2025, https://www.emjreviews.com/oncology/news/phase-iii-lung-cancer-trial-terminated-due-to-futility/
33. BeiGene Scraps TIGIT Candidate After Underwhelming Lung Cancer Data - BioSpace, accessed September 29, 2025, https://www.biospace.com/business/beigene-scraps-tigit-candidate-after-underwhelming-lung-cancer-data
34. Ociperlimab: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 29, 2025, https://go.drugbank.com/drugs/DB18947
35. BeiGene bows out of TIGIT | ApexOnco - Clinical Trials news and analysis, accessed September 29, 2025, https://www.oncologypipeline.com/apexonco/beigene-bows-out-tigit
36. Study Details | NCT05014815 | Ociperlimab With Tislelizumab and Chemotherapy in Participants With Untreated Metastatic Non-Small Cell Lung Cancer | ClinicalTrials.gov, accessed September 29, 2025, https://www.clinicaltrials.gov/study/NCT05014815
37. Novartis strengthens immunotherapy pipeline with option, collaboration and license agreement with BeiGene for TIGIT inhibitor ociperlimab, accessed September 29, 2025, https://www.novartis.com/news/media-releases/novartis-strengthens-immunotherapy-pipeline-option-collaboration-and-license-agreement-beigene-tigit-inhibitor-ociperlimab
38. BeiGene abandons ociperlimab over poor phase 3 prospects in latest blow to TIGITs, accessed September 29, 2025, https://www.fiercebiotech.com/biotech/beigene-abandons-ociperlimab-over-poor-phase-3-prospects-latest-blow-tigits
39. Tiragolumab - Wikipedia, accessed September 29, 2025, https://en.wikipedia.org/wiki/Tiragolumab
40. Genentech Provides Update on Phase II/III Skyscraper-06 Study in Metastatic Non-Squamous Non-Small Cell Lung Cancer, accessed September 29, 2025, https://www.gene.com/media/press-releases/15029/2024-07-03/genentech-provides-update-on-phase-iiiii
41. Roche reports update on Phase III SKYSCRAPER-01 study results, accessed September 29, 2025, https://www.roche.com/media/releases/med-cor-2024-11-26
42. GSK provides update on belrestotug development programme, accessed September 29, 2025, https://www.gsk.com/media/t4wfvvjr/sea-belrestotug-programme-update.pdf
43. Belrestotug Program Terminated After Mixed Phase 2 Results in NSCLC | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways, accessed September 29, 2025, https://www.targetedonc.com/view/belrestotug-program-terminated-after-mixed-phase-2-results-in-nsclc
44. GSK, iTeos Abandon TIGIT Therapy, Adding to Long List of Recent Class Failures, accessed September 29, 2025, https://www.biospace.com/drug-development/gsk-iteos-abandon-tigit-therapy-adding-to-long-list-of-recent-failures
45. Domvanalimab | Mechanism of Action - Arcus Biosciences, accessed September 29, 2025, https://arcusbio.com/our-science/clinical-candidates/domvanalimab/
46. Domvanalimab Plus Zimberelimab and Chemo Set for Phase 3 Study After Showing Efficacy in Untreated Upper GI Cancers | OncLive, accessed September 29, 2025, https://www.onclive.com/view/domvanalimab-plus-zimberelimab-and-chemo-set-for-phase-3-study-after-showing-efficacy-in-untreated-upper-gi-cancers
47. Gilead and Arcus Announce Anti TIGIT Domvanalimab Plus Zimberelimab and Chemotherapy Exceeded One Year of Median Progression Free Survival as a First Line Treatment for Upper GI Cancers, accessed September 29, 2025, https://www.gilead.com/news/news-details/2024/gilead-and-arcus-announce-anti-tigit-domvanalimab-plus-zimberelimab-and-chemotherapy-exceeded-one-year-of-median-progression-free-survival-as-a-first-line-treatment-for-upper-gi-cancers
48. Rilvegostomig - Astrazeneca - AdisInsight - Springer, accessed September 29, 2025, https://adisinsight.springer.com/drugs/800064909
49. Rilvegostomig, AstraZeneca's Bi-specific Antibody Derived from Compugen's COM902, Expected to Progress into Phase 3 - PR Newswire, accessed September 29, 2025, https://www.prnewswire.com/news-releases/rilvegostomig-astrazenecas-bi-specific-antibody-derived-from-compugens-com902-expected-to-progress-into-phase-3-301746238.html
50. European Medicines Agency decision P/0354/2021 of 8 September 2021 on the granting of a product specific waiver for ociperlimab, accessed September 29, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-0354-2021-ema-decision-8-september-2021-granting-product-specific-waiver-ociperlimab-emea-003028-pip01-21_en.pdf