Anti–Gremlin-1 Therapy Plus Chemo Makes Waves in GI Malignancies

The potentially first-in-class gremlin-1–directed monoclonal antibody ginisortamab (UCB6114) in combination with chemotherapy has demonstrated early-phase efficacy signals that warrant further study in patients with advanced solid tumors, particularly those with gastrointestinal (GI) malignancies.

“There is a signal that this drug is safe and can be easily combined with these 2 chemotherapy regimens and we saw responses in both [arms] of this early clinical trial,” Heinz-Josef Lenz, MD, said of the phase 1/2 ONC001 trial (NCT04393298) in an interview with OncLive®. “The data suggest that there may be good evidence and rationale to further evaluate this [agent] in disease-specific phase 1b or phase 2 studies.”

Lenz is a professor of medicine and cancer biology, the J. Terrence Lanni Chair in Gastrointestinal Cancer Research, codirector of the University of Southern California (USC) Center for Molecular Pathway and Drug Discovery, and codirector of the USC Norris Center for Cancer Drug Development at the Keck School of Medicine of USC in Los Angeles.

Data from the combination cohorts of ONC001 demonstrate the potential for gremlin-1 to evolve as a therapeutic target across advanced solid tumor treatment paradigms.

What was the design of the ONC001 study?

“Usually, we try to target cancer cells with receptors, and not targets in the tumor microenvironment [TME],” Lenz explained. “But we have learned over the [past couple] years that cancer-associated fibroblasts play an incredibly important role in cancer development, progression, and the development of resistance. They [use] a communication network with cancer cells and other compartments in the tumor, including immune cell trafficking and inflammation and metabolic pathways.”

Gremlin-1 is a high-affinity bone morphogenetic protein (BMP) antagonist that plays a role in tumor development and progression.¹ Preclinical research in human colorectal cancer (CRC) cell lines has shown that ginisortamab blocks binding between gremlin-1 and BMP, restores the BMP signaling pathway, and activates the downstream SMAD pathway.

“This is an unusual target, because gremlin-1 is produced by cancer-associated fibroblasts, and this protein binds to an important oncogenic signaling [pathway],” Lenz added. “[High levels of cancer-associated fibroblasts] inhibit some of this pathway, which leads to tumor initiation and progression. This expression level is associated with poor outcomes in CRC.”

The first-in-human, nonrandomized, open-label ONC001 trial evaluated ginisortamab as monotherapy and in combination with standard-of-care (SOC) regimens in patients at least 18 years of age with advanced solid tumors.² Part A enrolled patients with colorectal adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, stomach adenocarcinoma, urothelial carcinoma, or invasive breast carcinoma. Part A1, the dose-optimization portion, enrolled patients with colorectal, gastric, and gastroesophageal junction (GEJ) adenocarcinoma; as well as pancreatic cancer.

Part B enrolled patients with unresectable locally advanced or metastatic colorectal, gastric, or GEJ adenocarcinoma who had previously received or were deemed unsuitable for treatment with at least 2 anticancer treatments. These patients received intravenous (IV) ginisortamab at 500 mg (n = 9), 1000 mg (n = 4), or 2000 mg (n = 8) every 2 weeks, along with oral trifluridine/tipiracil (TAS-102; Lonsurf) at 35 mg/m² twice daily on days 1 through 5 and 8 through 12 of each 28-day cycle.³

Part C enrolled patients with advanced GI cancers who had previously received or were deemed unsuitable for treatment with a maximum of 1 or anticancer regimen.⁴ These patients received IV ginisortamab at 500 mg (n = 5), 1000 mg (n = 3), or 2000 mg (n = 7) in combination with mFOLFOX6 (modified leucovorin, 5-fluorouracil [5-FU], and oxaliplatin) every 2 weeks in 28-day cycles.

Safety was the primary end point across all parts of the trial. Secondary end points included pharmacokinetics (PK), biomarker analyses, and efficacy.^2,3,4

How has ginisortamab monotherapy performed in advanced solid tumors?

Part A of ONC001 showed ginisortamab to have a favorable safety profile and PK characteristics at the maximum dose, which was 2000 mg every 2 weeks.^3,4

“It was important to see, [with] an antibody targeting gremlin-1, some single-agent activity,” Lenz noted of the data from part A. “We have data [showing] that you can shrink tumors with this antibody alone, which is not a cytotoxic [agent] in the classical sense, but inhibits proliferation pathways linked to BMP and downstream to the SMAD pathway. [However], alone, this antibody may not be effective enough, which we have learned with many other antibodies in CRC.”

What safety and efficacy findings have been reported with ginisortamab plus TAS-102 in patients with advanced solid tumors?

In part B, 2 patients experienced dose-limiting toxicities (DLTs): 1 patient with grade 4 neutropenia who received ginisortamab at 500 mg, and 1 patient with a grade 3 non–site-specific embolism who received ginisortamab at 2000 mg.³ However, no treatment-emergent adverse effects (TEAEs) led to study discontinuation or death.

The PK and circulating gremlin-1 concentration findings were consistent with those seen in the dose-escalation portion of part A. Notably, the concentrations of ginisortamab and circulating gremlin-1 were found to be dose dependent and were not affected by co-administrating the agent with TAS-102.

One patient with metastatic CRC who received ginisortamab at 1000 mg achieved a confirmed partial response (PR), with a duration of response (DOR) of approximately 5.7 months and a progression-free survival (PFS) of approximately 9.5 months. Overall, 7 patients achieved disease control; all had CRC. The median PFS was approximately 1.9 months (95% CI, 1.7-4.0). Notably, 1 patient, who received ginisortamab at 500 mg, achieved a PFS of approximately 15 months.

What safety and efficacy findings have been reported with ginisortamab plus mFOLFOX6 in patients with GI tumors?

In part C, no DLTs were reported.⁴ TEAEs led to death in 2 patients but were deemed unrelated to study treatment. Furthermore, no grade 3 or higher TEAEs were attributed to ginisortamab only.

Two patients achieved a confirmed PR; both had metastatic GEJ adenocarcinoma and had received ginisortamab at 500 mg. The DORs in these patients were approximately 5.6 months and approximately 8.9 months. Overall, 9 patients had disease control. The median PFS was approximately 4.0 months (95% CI, 1.8-5.7).

“There have been no safety signals,” Lenz contextualized. “[Ginisortamab is] a safe drug to give in the monotherapy arm, as well as in the combination arms. The combination [regimens] did not add AEs to [ginisortamab], and there was no interaction with the pharmacokinetics of either of these combination chemotherapeutic regimens.”

What are the next steps for evaluating ginisortamab in patients with GI cancers?

Following positive findings from ONC001, the ongoing phase 2 CRUK trial (NCT04393298) is investigating ginisortamab across populations of patients with metastatic pancreatic ductal adenocarcinoma.⁵ In module A, patients will receive the agent as first-line therapy in combination with SOC gemcitabine plus nab-paclitaxel (Abraxane). This module will evaluate disease control rate and PFS.

In module B, patients will receive ginisortamab in combination with the MEK inhibitor cobimetinib (Cotellic) as maintenance therapy after disease stabilization or response following at least 16 weeks of SOC therapy. PFS will serve as the primary end point.

Module A opened in April 2024 and is ongoing in the UK, Norway, Spain, and Germany. Module B is planned to begin enrollment in the first quarter of 2026.

“Targets in the TME will become much more important, particularly with combinations [containing] immunotherapy or anti-VEGF treatment, which are all already in the TME,” Lenz concluded. “We have seen the significant role of cancer-associated fibroblasts in modulating and changing the TME and changing the sensitivity of chemotherapeutic agents, as well as targeted agents. I’m excited about this target, and hopefully we will see more efficacy in phase 1 and phase 2 clinical trials.”

References

1. Davies GCG, Dedi N, Jones PS, et al. Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer. MAbs. 2023;15(1):2289681. doi:10.1080/19420862.2023.2289681
2. A study to assess the safety, pharmacokinetics and anti tumor activity of UCB6114 administered intravenously to participants with advanced solid tumors. ClinicalTrials.gov. Updated May 29, 2025. Accessed January 27, 2026. https://clinicaltrials.gov/study/NCT04393298
3. Sarker D, Banerji U, Blagden SP, et al. Phase I/II dose-escalation study evaluating ginisortamab (UCB6114), an anti-gremlin-1 monoclonal antibody (mAb) with first-in-class potential, in combination with trifluridine/tipiracil (TFD/TPI) in advanced solid tumours. Ann Oncol. 2025;36(suppl 2):S529-S530. doi:10.1016/j.annonc.2025.08.1411
4. Lenz HJ, Banerji U, Evans TRJ, et al. Phase I/II dose-escalation study evaluating ginisortamab (UCB6114), an anti-gremlin-1 monoclonal antibody (mAb) with first-in-class potential, in combination with 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in advanced solid tumours. Ann Oncol. 2025;36(suppl 2):S531-S532. doi:10.1016/j.annonc.2025.08.1414
5. Evans TRJ, Guren TK, Baxter M, et al. CRUK: phase II trial of ginisortamab with (1) 1st-line gemcitabine + nab-paclitaxel (AG) or (2) MEK inhibitor as maintenance therapy in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol. 2026;44(suppl 2)TPS793. doi:10.1200/JCO.2026.44.2_suppl.TPS793