Dr Shitara on the Unique Mechanisms of Action of Domvanalimab Plus Zimberelimab in GI Cancer

"Blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy; this is usually combined with an anti–PD-L1 agent to reduce the exhaustion of T cells. Domvanalimab is an Fc-silent monoclonal antibody, and because of the lack of T-cell depletion, its toxicity profile is expected to be feasible. Zimberelimab's [mechanism of action] is very similar to nivolumab and pembrolizumab, and these combinations have been tested in various clinical trials."

Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East, discussed the rationale for dual immune checkpoint inhibition using domvanalimab and zimberelimab in the treatment of patients with solid tumors, including upper gastrointestinal malignancies. 

Domvanalimab is an investigational anti–TIGIT monoclonal antibody, and zimberelimab is an anti–PD-1 monoclonal antibody. Both agents are being evaluated in combination across several clinical trials targeting cancers with high unmet need.

TIGIT is an inhibitory receptor commonly co-expressed with PD-1 and LAG-3 on exhausted CD8-positive T cells and regulatory T cells (Tregs), particularly in later stages of immune dysfunction. TIGIT blockade is hypothesized to reinvigorate effector immune cells and restore antitumor immunity. Preclinical data suggest that TIGIT inhibition is most effective when combined with PD-1/PD-L1 pathway inhibition, given the overlapping and synergistic mechanisms of T-cell exhaustion and immune evasion.

Shitara emphasized that a key distinction among TIGIT-targeting agents lies in their Fc domain engineering. Some anti-TIGIT antibodies are Fc-competent (Fc-active), retaining the ability to engage Fcγ receptors and mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. This structure allows for potential depletion of TIGIT-expressing Tregs and other immunosuppressive cells. However, this mechanism may also carry a higher risk of depleting activated effector T cells, increasing the likelihood of immune-related toxicities.

Conversely, domvanalimab is an Fc-silent IgG1 antibody, engineered to minimize Fcγ receptor engagement. Shitara noted that this design is expected to preserve effector T-cell function while mitigating immune-mediated adverse effects, making it a favorable candidate for combination immunotherapy. Zimberelimab, the PD-1 inhibitor partner in this combination, is mechanistically analogous to approved agents such as nivolumab (Opvido) and pembrolizumab (Keytruda), he stated.

Preclinical studies offer differing views on Fc domain design in TIGIT antibodies; data from one study published in 

 support the use of Fc-silent constructs for optimal T-cell activation and lower toxicity, whereas a separate 

 publication advocated for Fc-active antibodies based on their ability to deplete suppressive immune cell subsets, Shitara detailed.

Taken together, the combination of domvanalimab and zimberelimab represents a promising Fc-silent immunotherapeutic approach aimed at enhancing antitumor immunity with a favorable safety profile, he said. This strategy is currently under clinical investigation in multiple tumor types, including gastrointestinal cancers, Shitara concluded.

Videos

Kohei Shitara, MD, details the mechanisms of action of the investigational therapies domvanalimab and zimberelimab for gastrointestinal cancer. 
 

Yelena Y. Janjigian, MD, is chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center.

Dirk Arnold, MD, PhD is Director of the Asklepios Tumorzentrum Hamburg, a network cancer centre serving 7 community hospitals in Hamburg, and also Head of the department of Oncology, Haematology and Palliative Care at AK Altona, Hamburg

GI Cancer Experts on Notable Updates Shared During the 2025 ASCO Annual Meeting

We spoke with the following investigators in the field of gastrointestinal (GI) cancer to get their perspective on the most significant updates in the space shared during the 

Dirk Arnold, MD, PhD, the director of the Asklepios Tumorzentrum Hamburg and the head of the Department of Oncology, Hematology, and Palliative Care at AK Altona.

Kohei Shitara, MD, the director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East.

Yelena Y. Janjigian, MD, the chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center.

Ronan J. Kelly, MD, the chief of oncology, the W.W. Caruth, Jr. Chair in Immunology, and the founder and director of the Texas Cancer Interception Institute at Baylor Scott & White Health.

Vincent Picozzi, MD, a medical oncologist at Virginia Mason Franciscan Health.

During the meeting, there were several notable updates, including positive data with the addition of atezolizumab (Tecentriq) to chemotherapy as adjuvant treatment for patients with deficient mismatch repair colorectal cancer (CRC) in the phase 3 Alliance A021502; ATOMIC trial (NCT02912559), Arnold said. It was also impressive to see how the addition of targeted agents to chemotherapy improved outcomes for patients with CRC harboring 

Shitara and Janjigian both highlighted findings from the phase 3 MATTERHORN study (NCT04592913), which evaluated durvalumab (Imfinzi) plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) in patients with resectable gastric/gastroesophageal junction (GEJ) cancer. Findings from the study showed that patients who received the combination (n = 474) experienced a median event-free survival that was not reached (NR; 95% CI, 40.7-NR) vs 32.8 months (95% CI, 27.9-NR) among patients who received placebo plus FLOT (n = 474; HR, 0.71; 95% CI, 0.58-0.86; log-rank 

 < .001). These findings further cemented FLOT as the best systemic regimen for this patient population and it was encouraging to see investigators build on this efficacy with the addition of durvalumab, Janjigian said.

Data from the phase 3 DESTINY-Gastric04 trial (NCT04704934) firmly position fam-trastuzumab deruxtecan (T-DXd; Enhertu) as a standard-of-care option in the second line for patients with unresectable or metastatic HER2-positive gastric/GEJ adenocarcinoma. Findings from the study showed that patients who received T-DXd experienced a significant overall survival benefit compared with those treated with ramucirumab (Cyramza) plus paclitaxel (HR, 0.70; 95% CI, 0.55-0.90; 

During the meeting, there were several presentations that examined artificial intelligence–supported approaches, which was notable, Picozzi said. Pancreatic cancer research is also attracting a lot of attention from investigators across the world, he added.

Expert investigators in GI cancers share their perspectives on the most significant updates in the space shared during the 2025 ASCO Annual Meeting.

Dr Shitara on the Background of the CheckMate 649 Trial in GEJ Adenocarcinoma

Kohei Shitara, MD, medical oncologist, chief, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, discusses 

the background of the phase 3 CheckMate 649 study

 (NCT02872116) investigating nivolumab (Opdivo) plus chemotherapy vs chemotherapy alone in the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma.

The CheckMate 649 study was a global trial that established chemotherapy plus nivolumab as the standard treatment for patients with untreated HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinomas. The study successfully met its primary end points of progression-free survival and overall survival benefits with this combination therapy vs chemotherapy alone, as demonstrated in the first interim analysis conducted at a median follow-up of 13.1 months (IQR, 6.7-19.1) for the combination arm vs 11.1 months (IQR, 5.8-16.1) for the chemotherapy alone arm. These findings were published in 

 in 2021 and subsequently led to regulatory approval of the regimen in numerous countries. Subsequent analyses, including a 2-year follow-up published in 

 and a 3-year follow-up published in the 

, have further validated the efficacy of the treatment.

The patient population evaluated in the study consisted of patients in the first-line setting who had not received prior chemotherapy and had confirmed HER2-negative disease, Shitara begins. It is important to note that patients with HER2-positive disease were excluded from the trial, according to Shitara. Beyond this criterion, the trial targeted the usual first-line population for gastric or GEJ adenocarcinomas, he explains. Although a subgroup analysis based on PD-L1 combined positive score was conducted, knowledge of PD-L1 status was not required for inclusion in the all-comer population, Shitara reports.

Overall, the CheckMate 649 study data represent a significant advancement in the treatment paradigm for HER2-negative gastric or GEJ adenocarcinomas, he emphasizes. By establishing the efficacy of chemotherapy plus nivolumab in the first-line setting, the study has provided a new standard of care for patients with this type of cancer, Shitara notes. The inclusion of diverse patient populations and comprehensive follow-up analyses further strengthen the validity and generalizability of the findings, underscoring the importance of this landmark trial in improving patient outcomes, he concludes.

Kohei Shitara, MD, discusses the background of the phase 3 CheckMate 649 study in advanced gastric cancer, GEJ cancer, and esophageal adenocarcinoma.

Kohei Shitara, MD, medical oncologist and the chief of the Department of Gastrointestinal Oncology of the National Cancer Center Hospital East in Kashiwa, Japan, discusses the evaluation of the combination of zolbetuximab plus mFOLFOX6 in patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The phase 3 SPOTLIGHT trial (NCT03504397) randomly assigned patients to receive the combination of zolbetuximab and mFOLFOX6 (n = 283) or placebo and mFOLFOX6 (n = 282).

Findings presented at the 2023 ASCO Gastrointestinal Cancers Symposium

 showed that patients treated with the combination experienced a statistically significant improvement in progression-free survival (PFS), meeting the primary end point of the trial, Shitara says. Those treated with zolbetuximab and mFOLFOX6 experienced a median PFS of 10.61 months, compared with 8.67 months for those administered mFOLFOX6 plus placebo (HR, 0.751; 95% CI, 0.589-0.942; 

 = .0066). Additionally, zolbetuximab plus mFOLFOX6 elicited 12- and 24-month PFS rates of 49% and 24%, respectively, compared with 35% and 15% for mFOLFOX6 plus placebo.

Zolbetuximab plus mFOLFOX6 also produced a statistically significant improvement in overall survival (OS), Shitara explains. The median OS was 18.23 months with zolbetuximab/mFOLFOX6 and 15.54 months with placebo/mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; 

 = .0053). Notably, as part of the study design, OS was only tested if the PFS benefit with zolbetuximab plus mFOLFOX6 was found to be significant, Shitara says.

To be eligible for enrollment, patients were required to have moderate-to-strong CLDN18 staining in at least 75% of tumor cells, and they needed to have HER2-negative disease. Over the course of the trial, investigators screened more than 2700 patients for CLDN18.2 positivity, and 565 patients were enrolled and randomly assigned to treatment during the study, Shitara says.

Along with the primary end point of PFS, key secondary end points included OS, objective response rate, duration of response, and safety.

Kohei Shitara, MD, discusses the evaluation of the combination of zolbetuximab plus mFOLFOX6 in patients with CLDN18.2–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

Dr. Shitara on Zolbetuximab Plus mFOLFOX6 in CLDN18.2+, HER2– Gastric/GEJ Adenocarcinoma

Kohei Shitara, MD, chief, Department of Gastrointestinal Oncology, the National Cancer Center Hospital East, in Kashiwa, Japan, discusses the rationale for the phase 3 DESTINY-Gastric04 trial (NCT04704934) in patients with HER2-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma.

The randomized, open-label study will evaluate the efficacy and safety of fam-trastuzumab deruxtecan-nxki (Enhertu) compared with the standard of care in patients who have progressed on a trastuzumab (Herceptin)-containing regimen.

Based on the phase 2 DESTINY-Gastric01 trial (NCT03329690), in both 2020 and 2021, trastuzumab deruxtecan was approved for the treatment of metastatic HER2-positive gastric cancer in the Japan and in the United States, respectively, Shitara says. However, the approval in Japan only covered an indication for patients with unresectable advanced or recurrent gastric cancer that has progressed following chemotherapy, Shitara adds. Though the FDA approval covered treatment in the second-line setting, there is currently no direct comparison between trastuzumab deruxtecan and standard of care, Shitara explains.

A confirmatory DESTINY-Gastric04 trial will compare trastuzumab deruxtecan to the current standard of care, and the trial is currently enrolling, Shitara concludes.

Kohei Shitara, MD, discusses the rationale for the phase 3 DESTINY-Gastric04 trial in patients with HER2-positive gastric cancer or gastro-esophageal junction adenocarcinoma.


Dr. Shitara on the Rationale for the DESTINY-Gastric04 Trial in HER2+ Gastric Cancers

Kohei Shitara, MD, chief, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, discusses the rationale to analyze the effects of prior therapy on outcomes with TAS-102 (trifluridine/tipiracil; Lonsurf) in patients with metastatic gastric/gastroesophageal junction (GEJ) cancer.

, findings from an analysis of the phase 3 TAGS trial were presented in a virtual poster. The results showed that TAS-102, administered as third- or later-line treatment in patients with metastatic gastric/GEJ cancer, improved survival outcomes compared with placebo irrespective of prior therapy.

TAS-102 is an oral combination that was approved in February 2019 for the treatment of patients with metastatic gastric/GEJ cancer who have received at least 2 prior lines of chemotherapy based on data from the TAGS trial. The regimen is also approved in the European Union and Japan for use in this patient population, concludes Shitara.

Kohei Shitara, MD, discusses the rationale to analyze the effects of prior therapy on outcomes with TAS-102 in patients with metastatic gastric/gastroesophageal junction cancer.  



Dr. Shitara on Analyzing the Effects of Prior Therapy on TAS-102 in Gastric/GEJ Cancer 

Kohei Shitara, MD, chief, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, discusses the FDA approval of fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-positive metastatic gastric/gastroesophageal junction (GEJ) cancer.

On January 15, 2021, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric/GEJ adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen. The regulatory decision was based on data from the phase 2 DESTINY-Gastric01 trial in which trastuzumab deruxtecan induced a higher objective response rate compared with chemotherapy in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed following a trastuzumab-based treatment.

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) that utilizes a topoisomerase payload, Shitara explains. Moreover, the payload has good permeability that can elicit a bystander effect on HER2-negative cancer cells surrounding the target. As such, patients with heterogenous cancers, such as gastric cancer, may derive benefit from this agent, Shitara says.

Previously, in September 2020, the Japanese Ministry of Health, Labor, and Welfare approved trastuzumab deruxtecan for the treatment of patients with HER2-positive unresectable advanced or recurrent gastric cancer that has progressed following chemotherapy. The FDA approval is a welcome addition to the limited armamentarium for patients with metastatic gastric cancer and should become a standard of care in the space, concludes Shitara.

Kohei Shitara, MD, discusses the FDA approval of fam-trastuzumab deruxtecan-nxki in HER2-positive metastatic gastric/gastroesophageal junction cancer. 

Kohei Shitara, MD, National Cancer Center Hospital East

Articles