Zimberelimab

iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.

“We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Gilead Sciences\' Dietmar Berger, M.D., Ph.D., told Fierce.\n Dietmar Berger, M.D., Ph.D., joined Gilead Sciences as chief medical officer at the start of this year after the company’s oncology department suffered some prominent setbacks. The run of bad luck included two back-to-back phase 3 flops of Trodelvy in non-small cell lung cancer and bladder cancer as well as the demise of the anti-CD47 drug magrolimab from a $4.9 billion acquisition.But Berger, who boasts a deep background in cancer drug development, still believes the virology giant made the right move to branch out into oncology and immunology.“I am a strong believer that diversification for Gilead is the right decision,” Berger told Fierce in an interview on the sidelines of the 2025 American Society of Clinical Oncology (ASCO) annual meeting.“I also think that oncology and immunology are the right areas for Gilead, because of the emerging science … and because we can apply a lot of the strength that Gilead has—for example in chemistry, in protein design and deep understanding of biology—very strongly to oncology and immunology.”As a new head of development joining a biopharma company, it’s natural to think about ways to improve the portfolio, he said. “We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Berger added.The CMO said he’s trying to build a “balanced” and “partially derisked portfolio” by combining direct cytotoxic mechanisms with immuno-oncology. Again, diversification is key here. At ASCO, Gilead’s cell therapy unit Kite Pharma reported some early positive data for its anti-CD19/CD20 bicistronic CAR-T therapy in advanced B-cell lymphoma. Another bivalent CAR-T candidate partnered with the University of Pennsylvania targeting EGFR and interleukin-13 receptor alpha 2 recorded notable tumor shrinkage in eight (62%) of 13 patients with recurrent glioblastoma, a notoriously aggressive and hard-to-treat brain cancer.Trodelvy also had a positive story to tell at this year’s ASCO, courtesy of two positive phase 3 readouts in first-line triple-negative breast cancer (TNBC). In a potentially practice-changing data set, Trodelvy and Merck & Co.’s Keytruda significantly reduced the risk of progression or death by 35% versus Keytruda and chemotherapy in first-line PD-L1-positive TNBC.In immuno-oncology, Berger highlighted GS-1811, an anti-CCR8 antibody Gilead obtained from Jounce Therapeutics. The drug, designed to remove immunosuppressive tumor-infiltrating T regulatory cells, is still in early-stage development.All told, Gilead has 58 projects across virology, oncology and immunology in its portfolio, the largest and most diverse pipeline in the biopharma\'s history. Challenges in ADC and immuno-oncologyFor Trodelvy, new TROP2 competition has arrived in the form of AstraZeneca and Daiichi Sankyo’s Datroway and Merck and Kelun-Biotech’s sac-TMT.In Trodelvy’s home base of second-line TNBC, the Gilead drug is the only one that has demonstrated an overall survival benefit. Parallel data that could help experts compare these drugs side by side in a cross-trial fashion have not yet read out, Berger explained.Besides first-line TNBC, Trodelvy is also being tested in earlier-line HR-positive, HER2-negative breast cancer, which could represent a bigger patient population than TNBC. Following the Evoke-01 flop, the Evoke-03 study for Trodelvy and Keytruda in first-line PD-L1-high NSCLC remains ongoing.Since Gilead’s $21 billion acquisition of Immunomedics in 2020, the company still has only one antibody-drug conjugate asset, whereas other players in the space such as AstraZeneca and Pfizer have developed multiple products.The Immunomedics deal was a strategic acquisition designed to give Gilead an anchor in its diversification into solid tumors, and the company then built R&D capabilities around that, Berger noted.“That bit of a time lag is largely based on: How do you build an oncology organization?” Berger said.New oncology molecules are now coming out of Gilead’s internal research capabilities, and the company will also “focus strongly” on external opportunities, he said. Berger wouldn’t name specific ADC projects outside of Gilead that he’s interested in. Toward the end of 2024, before Berger officially moved across from Sanofi, Gilead penned a deal with Tubulis to develop a topoisomerase I inhibitor-based ADC.“There’s usually the question, do you combine different mechanisms, or do you double down on a specific pathway,” Berger said of target selection for ADCs.Choosing the linker is dependent on whether a bystander effect—in which the cytotoxic payload from the ADC kills cells surrounding the target cell—is desired, and the toxin needs to be carefully evaluated because these payloads hit different tumor types differently, Berger noted.Meanwhile, things don’t look too promising for Gilead’s late-stage immuno-oncology program, the Arcus Biosciences-partnered domvanalimab. The drug is one of the few remaining anti-TIGIT antibodies still in development after companies such as Merck, Bristol Myers Squibb, GSK and BeOne (formerly BeiGene) walked away from the field. Roche’s Genentech, where Berger used to lead oncology clinical development, has all but abandoned tiragolumab after several disappointing studies, and the pharma is now only waiting for two fully enrolled phase 3 trials to read out.Berger argued that domvanalimab may still stand a chance. The TIGIT molecules that have failed so far are mostly Fc-competent antibodies, whereas domvanalimab is Fc-silent.Fc-enabled anti-TIGIT antibodies theoretically have enhanced tumor-killing effects because they can bind to FcγRs and activate immune cells. But they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses. Before nixing its TIGIT candidate vibostolimab, Merck had noted a higher rate of immune-related adverse events in at least two failed phase 3 trials. Only data will tell whether Fc-competence is the key. Gilead and Arcus are running two phase 3 trials that combine domvanalimab with Arcus’ PD-1 drug zimberelimab and chemotherapy in first-line NSCLC and gastric, gastroesophageal junction and esophageal adenocarcinoma.Gilead has a stated goal to have 30% of its revenue from oncology products by 2030. Berger acknowledged that the huge clinical success—and potential imminent approval—of twice-yearly lenacapavir for HIV prevention could make achieving that goal harder but said the company remains committed to a target of 30% of revenue from outside virology.“It does place a stronger focus on oncology,” Berger said. “But don’t get me wrong, I think we are in a good spot now.”