Domvanalimab-Based Combo Aims to Leverage Anti-TIGIT Mechanism in Upper GI Cancers

Sam Klempner, MD

After displaying promising results in patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma in the phase 2 EDGE-Gastric trial (NCT05329766), the combination of the investigational anti-TIGIT agent domvanalimab, the PD-1 inhibitor zimberelimab (Sepalizumab), and FOLFOX (leucovorin, fluorouracil, and oxaliplatin) is being further evaluated in this patient population in the phase 3 STAR-221 trial (NCT05568095). Findings from the phase 3 study could further support the integration of TIGIT blockade into the management of upper gastrointestinal (GI) cancers, according to Sam Klempner, MD.

“There have been preceding data that [showed] some activity, both with FOLFOX plus domvanalimab and zimberelimab, as well as with other TIGIT antibodies in [patients with] esophageal cancers. We have seen some preliminary activity that justifies the need for a phase 3 trial,” Klempner, a medical oncologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School in Boston, said in an interview with OncLive®.

Updated fingings from arm A1 of the EDGE-Gastric presented at the 2024 ASCO Annual Meeting showed that patients who received the combination (n = 41) achieved a median progression-free survival (PFS) of 12.9 months (95% CI, 9.8-13.8) and a 12-month PFS rate of 57.6% (95% CI, 41.7%-73.5%).1,2 The confirmed objective response rate (ORR) was 58.5% (95% CI, 42.1%-73.7%), including a complete response rate of 7.3%. The median duration of response was 12.4 months (95% CI, 9.9-not evaluable).

In the interview, Klempner discussed the rationale for investigating TIGIT blockade in combination with chemotherapy and anti–PD-1 therapy for patients with upper GI cancers;, the design of STAR-221; and the potential effect on the clinical landscape that positive results from the phase 3 study could have.

OncLive: How do domvanalimab and zimberelimab work alongside chemotherapy to elicit antitumor responses?

Klempner: Domvanalimab plus zimberelimab is a combination geared toward providing additional stimulation to T and natural killer [cell] populations, which are important for an antitumor immune response.

Chemotherapy itself [leads to] some immunogenic cell death, which may promote an antitumor immune response. We have a long track record and [data from] multiple phase 3 trials supporting the combination of chemotherapy plus anti–PD-1 [therapy in upper GI cancers]. The question of whether we can further push on the T-cell axis with TIGIT blockade is an open one, and that’s the question that STAR-221 is seeking to answer.

Theoretically, the addition of anti-TIGIT [therapy] may help expand a particularly important immune cell subset—progenitor exhausted T cells—that are important for persistent immune responses. The hope is that PD-1 and TIGIT dual blockade will extend the benefit of immunotherapy to more patients and enhance the durability of response.

Why may TIGIT blockade have a role in upper GI cancers?

It’s certainly an open question, and one that STAR-221 will hopefully answer. We’ve seen some data across tumor types with TIGIT [blockade], and [the history] has been checkered. We’ve seen multiple negative studies in lung cancer, for example; however, upper GI cancers are a different beast. They have inherently different tumor microenvironments and intrinsic immune resistance properties. It’s certainly a concern whether this [approach] will [be effective] in patients with upper GI cancers, but we’re going to get the answer soon.

What data show that this combination could surpass the limitations of SOC agents in the frontline setting for patients with upper GI cancers?

EDGE-Gastric was trying to support the idea of…a phase 3 trial [with an anti-TIGIT approach]. There was no control arm [in EDGE-Gastric], and every patient got the same therapy. We saw a good ORR, but the PFS [data] were even more promising, with a [median] of 12.9 months. This was a significant numerical improvement vs historical controls using FOLFOX plus anti–PD-1 [therapy]. [The results] were promising and—if they hold true—the addition of the anti-TIGIT on top of anti–PD-1 [therapy] might extend [treatment] benefit, but all of the caveats need to be considered.

This was a single-arm, phase 2 trial of 41 patients, but [the data] are certainly supportive of the idea that there is promise to the strategy of combining FOLFOX with anti–PD-1 and -TIGIT [therapies] in STAR-221.

Are there any notable design characteristics of STAR-221?

It’s a straightforward phase 3 design. Over the last several years, chemotherapy plus immunotherapy has been the standard of care for the vast majority of our patients [with advanced upper GI cancers]. The question is: can we build upon our best standard by adding anti-TIGIT [therapy]? STAR-221 will compare our standard of care, FOLFOX plus nivolumab [Opdivo], with FOLFOX plus domvanalimab and zimberelimab. It is a 1:1 random assignment of approximately 1000 patients.

This is a large phase 3 trial powered to detect a difference and improvement in overall survival, which is the primary end point. There are some prespecified subgroups [based on] what we’ve learned from other phase 3 trials, [which will be] centered around particular PD-L1 strata.

Across the phase 3 trials that have been published, we’ve seen [populations of patients with] a PD-L1 [combined positive score] of greater than 1 and greater than 5 emerge as the main [subgroups] that we need to understand. Those subgroups will help place the data [from STAR-221] in the context of other phase 3 trials.

Were there any barriers to enrollment for STAR-221, given the criteria and existing FDA-approved options in this setting?

The comparator arm is an active combination, and it’s probably our best standard for this patient population. I don’t believe there is a more active control arm that could have been [selected], so that was not a barrier to accrual. The trial is fully accrued, and we’re awaiting the readout.

It accrued quickly because there weren’t a lot of other phase 3 trials in this patient population following the establishment of the chemotherapy plus anti–PD-1 [therapy] as a standard. There was a strong appetite for this trial globally, and now we just need to wait for enough [survival] events to trigger the analyses so we get an understanding of the outcomes, which hopefully we’ll see in the not-too-distant future.

How could positive results from STAR-221 affect the development of domvanalimab and its potential placement among current chemoimmunotherapy regimens in the HER2-negative population?

When we see new patients with stage IV disease, we look at our panel of biomarkers, and we assign them therapies based on that. Patients with microsatellite instability–high disease should clearly receive immunotherapy. Patients with HER2-positive disease get HER2-directed therapies. [Patients in the] HER2-negative population have the option of Claudin-18.2–[directed therapy] if they have Claudin-18.2–positive [disease]. However, for a sizable proportion of these patients, the current standard is chemotherapy plus anti–PD-1 [therapy].

If this STAR-221 is positive, the standard for that population could become chemotherapy plus PD-1 and TIGIT blockade. That would be wonderful for our patients if we’re able to improve the survival even further. I suspect if the trial is positive, it is possible that [this regimen] would change the current standard of chemotherapy plus anti–PD-1 [therapy] to chemotherapy plus anti–PD-1 and -TIGIT [therapy].

References

1. Janjigian Y, Oh D, Pelster M, et al. Updates on abstract 433248: EDGE-Gastric arm a1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL.
2. 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. News release. Gilead. June 1, 2024. Accessed June 27, 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