A Pilot Trial of Low Dose-Mosunetuzumab for Low-Tumor Burden Indolent B-Cell Lymphoma: Trial in Progress

Background:

Advanced stage indolent B-cell lymphoma is incurable but progresses slowly, allowing patients with low-tumor burden to adopt a “watch-and-wait” strategy until symptoms develop or the disease progresses. First-line treatments for high-tumor burden follicular lymphoma (FL) typically involves chemoimmunotherapy or rituximab plus lenalidomide. However, these treatments are associated with significant toxicities, including fatigue, alopecia, myelosuppression, infections, and the long-term risk of secondary malignancies. Given the indolent nature of FL and marginal zone lymphoma (MZL), the low-tumor burden setting, prior to development of critical symptoms, presents an opportunity to study novel, low-toxicity therapies. Treatment with rituximab monotherapy has been shown in various studies to delay the need for chemotherapy. While it does not improve survival compared to a “watch-and-wait” approach, the ability to delay more toxic therapies may be highly beneficial to patients.

Mosunetuzumab (mosun) is a CD20-directed CD3⁺ T-cell engager that has shown promising results in relapsed/refractory FL with an overall response rate (ORR) of 80% and a complete response (CR) rate of 60% (Budde Lancet Oncology 2022). Step-up dosing was utilized to mitigate cytokine release syndrome (CRS), and doses were escalated from 1 to 60 mg. However, there is mounting evidence that a clear dose-response relationship is not always seen with immunotherapeutic drugs. This provides an opportunity to investigate the potential of lower drug doses in mitigating adverse events (AEs) and costs.

Given these data, our pilot clinical trial aims to study the safety and efficacy of low-dose mosun in untreated low-tumor burden indolent NHL. We hypothesize that this low-dose and low-toxicity treatment will be well-tolerated and may delay the need for more toxic chemoimmunotherapy.

Study Design and Methods: This is a single-center, single-arm, pilot trial, conducted at Fred Hutchinson Cancer Center, in Seattle, WA, and registered on clinicaltrials.gov as NCT06442475.

Major Inclusion Criteria: Adults (≥18 years) with histologically confirmed indolent B-cell lymphoma (FL grades 1-3A, or MZL) with low-tumor burden defined by GELF criteria, ECOG 0-2, and no prior therapy for lymphoma. Patients must have measurable disease on CT or FDG-PET.

Major Exclusion Criteria: Uncontrolled systemic infection, another active malignancy requiring systemic treatment, or an autoimmune condition requiring immunosuppression.

Treatment: Patients will receive IV mosunetuzumab in 4 weekly doses: 1 mg on D1, 2 mg on D8, 1 mg on D15, 1 mg on D21, for a total of 5 mg. Patients will be seen in clinic weekly on treatment for assessment of labs and adverse events (AEs). Response assessment will occur with PET/CT during week 13 and categorized per Lugano criteria. Patients will be followed for 6 months on trial, then per standard-of-care for up to 5 years, until death, withdrawing consent, or becoming lost to follow-up, whichever comes first.

Endpoints:

• Primary: best overall response (CR, PR) by PET/CT

• Secondary: progression-free survival, duration of response, time to next lymphoma treatment, time to cytotoxic treatment, all grades toxicity, grade >3 CRS

• Exploratory: health-related quality of life (HRQoL) as measured by PROMIS29+2, PRO-CTCAE, and the Cancer Therapy Satisfaction Questionnaire (CTSQ). Additionally, changes in the gut microbiome, cytokine profiling, and T-cell subsets will be assessed and correlated with clinical responses and toxicities.

Statistics: We plan accrual of 20 patients and aim to demonstrate an ORR > 70% (benchmark from RESORT trial of rituximab). With 20 patients, if the true response rate is 70%, the 95% CI will be 52%-88%. We will plan for an initial efficacy analysis after 10 patients: if the ORR < 50% (< 4 responses among the 10), we will consider early trial termination for lack of efficacy.

Summary: This pilot trial examines low-dose mosun in patients with low-tumor burden indolent B-cell lymphomas. If successful, this trial will lay the groundwork for larger studies confirming the role of low-dose mosun in frontline treatment. Moreover, it will provide a strategy that minimizes costs and improves access to care for patients in resource-limited settings.

Di:BeiGene: Consultancy, Research Funding; Schrodinger, Inc.: Research Funding. Lynch:SeaGen, Foresight Diagnostics, Abbvie, Janssen: Consultancy; Merck: Honoraria; TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt, Merck, Janssen: Research Funding. Poh:Incyte: Research Funding; Seagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dren Bio: Research Funding; Acrotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding. Shadman:Koi Biotherapeutics: Current holder of stock options in a privately-held company; Vincerx, Janssen: Research Funding; Bristol Myers Squibb (spouse): Current Employment; Merck, Nurix, Fate Therapeutics, Eli Lilly, Kite Pharma, Bristol Myers Squibb: Consultancy; Morphosys/Incyte, Beigene, Genmab, AstraZeneca, Genentech, Abbvie: Consultancy, Research Funding. Smith:ADC therapeutics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Ignyta (spouse): Research Funding; Coherus Biosciences (spouse): Consultancy; Millenium/Takeda: Consultancy; abbvie: Consultancy; BMS (spouse): Research Funding; AstraZeneca: Consultancy, Research Funding; Bayer: Research Funding; Incyte: Consultancy, Research Funding; Enterome: Research Funding; KITE pharma: Consultancy; Lumanity: Consultancy; Kymera Therapeutics: Research Funding; Karyopharm: Consultancy; Merck Sharp and Dohme Corp: Research Funding; Genentech: Consultancy, Research Funding; Epizyme: Consultancy; De Novo Biopharma: Research Funding. Till:Mustang Bio: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Research Funding. Ujjani:AbbVie, Astrazeneca, Lilly, PCYC: Research Funding; Abbvie, Astrazeneca, Beigene, Genentech, Jansen, Lilly, Pharmacyclics: Honoraria. Gopal:Merck: Consultancy, Honoraria, Research Funding; I-Mab bio: Research Funding; IgM Bio: Research Funding; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; SeaGen: Research Funding; Teva: Research Funding; Genmab: Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys/Incyte: Consultancy, Honoraria; ADCT: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Compliment: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; Fresenius-Kabi: Consultancy, Honoraria; Scitek: Consultancy, Honoraria; Sana: Consultancy, Honoraria.

Mosunetuzumab is a CD20xCD3 bispecific antibody approved by the FDA for use in patients with follicular lymphoma after 2 or more lines of systemic therapy. Frontline use of low-dose mosunetuzumab in frontline indolent B-cell lymphoma is experimental.