CD3/CD20 bispecific antibodies (BsAbs) are rapidly changing the treatment landscape for indolent B-cell lymphomas. Clinical trials among patients with relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL) have shown high complete metabolic response (CMR) rates, and two agents, epcoritamab and mosunutuzumab, have already been approved for treatment of R/R FL. As with other T-cell engaging therapies, cytokine release syndrome (CRS) is observed with these agents, but high-grade CRS is rare and neurotoxicity is very uncommon. Based on these encouraging results, investigators in Dana-Farber's Division of Lymphoma are leading multiple investigator-sponsored clinical trials testing BsAb-based therapies for patients with FL and MZL, both in the R/R setting and frontline setting.
Frontline Treatment
Chemoimmunotherapy (CIT) is a standard initial treatment for patients with FL and MZL, but it is associated with significant toxicity, including prolonged immune suppression, infections, and secondary malignancies. Patients with FL and MZL would benefit from alternative chemotherapy-free initial treatment options that are effective and well-tolerated.
At Dana-Farber, two frontline clinical trials are testing similar chemotherapy-free BsAb treatment approaches in FL and MZL. The GLOBIN trial (Dana-Farber 22-632; NCT05783596) combines the CD3/CD20 BsAb glofitamab with the CD20 monoclonal antibody (mAb) obinutuzumab for patients with high-tumor burden FL or MZL. A second trial (Dana-Farber 22-702; NCT05783609) combines rituximab and epcoritamab (R+Epco) for patients with high-tumor burden FL. In both trials, patients initially receive the CD20 mAb with the goal of reducing disease bulk and clearing circulating lymphoma cells. This design was based on the hypothesis that cytoreductive treatment with a CD20 mAb before initiation of a BsAb would lower the risk of CRS and also deepen responses based on the distinct mechanisms of action of CD20 mAbs and CD3/CD20 BsAbs. Reid Merryman, MD, presented initial results from both trials for FL cohorts at the American Society of Hematology (ASH) annual meeting in December 2025. In both trials, rates of CRS were lower than expected, suggesting that effective cytoreduction with a CD20 mAb can improve the safety profile of BsAbs in this setting. Infectious adverse events were observed in about 60% of patients but were mostly low-grade. In addition, CMR rates were very high (88% in GLOBIN trial and 94% in the R+Epco trial), on par with or better than expected with chemoimmunotherapy. Longer follow-up is needed, but so far very few patients have relapsed. For example, the 1-year progression-free survival on the R+Epco trial is 97%. Based on these encouraging results, the R+Epco trial was expanded from 35 patients to 100 patients, and the expansion cohort is open and quickly accruing patients.
Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma
While FL and MZL very often respond to frontline chemotherapy, they exhibit significantly lower response rates and remission durations with subsequent lines of therapy. Outcomes of patients with R/R disease, especially after second line therapy, are poor. Therefore there is an ongoing need for the development of novel and effective therapy for patients with R/R disease, and the optimal use of CD3/CD20 BsAbs in this setting is a key clinical question.
We are leading a third investigator-sponsored clinical trial which is testing the combination of epcoritamab, zanubrutinib, and rituximab (EZR) for patients with R/R MZL or FL (Dana-Farber 24-393; NCT06563596). Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor that is already approved as a second-line treatment in MZL and third-line treatment for patients with FL. Zanubrutinib, like other BTK inhibitors, can improve T cell fitness by reversing T cell exhaustion and inhibiting suppressor immune cells, making it a very attractive combination partner for the T-cell engager, epcoritamab. The trial, which began enrollment in early 2025, has completed accrual for its FL cohort but is still enrolling patients with R/R MZL.
Translational Science
In addition to holding great clinical promise, these new therapies present numerous novel scientific questions. All three trials include collection of tissue and blood samples for correlative analyses. The lab of Mark Murakami, MD, is leading a large translational research program to identify biomarkers associated with both toxicity (CRS, infections) and efficacy (relapse, transformation to aggressive lymphoma). Preliminary results from the two frontline trials were also presented at the 2025 ASH Annual Meeting, highlighting the favorable impact of CD20 mAb pre-treatment on not just the safety of CD3xCD20 BsAb therapy but also its anti-lymphoma immunologic activity (Figure).
We are optimistic that these studies (and many other ongoing trials of CD3/CD20 BsAbs) will lead to new and highly effective treatment options for patients with FL and MZL.
