Efficacy and Safety Evaluation of Mosunetuzumab Plus Lenalidomide Versus Rituximab Plus Lenalidomide in Relapsed/Refractory Follicular Lymphoma

The primary objective of this study is to evaluate the **efficacy** of mosunetuzumab in combination with lenalidomide (M+Len) compared with rituximab in combination with lenalidomide (R+Len) in patients with relapsed/refractory follicular lymphoma. This evaluation is based on progression-free survival as determined by the independent review committee (IRC). For the non-randomized single arm extension (Arm C), the primary efficacy objective is to assess the efficacy of M+Len based on the objective response rate (ORR) as determined by the IRC. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with follicular lymphoma, a condition characterized by frequent relapses and resistance to standard therapies.

Secondary objectives include:

• Evaluating the efficacy of M+Len compared with R+Len based on progression-free survival, complete response rate, objective response rate, overall survival, duration of objective response, duration of complete response, time to deterioration in physical functioning and fatigue, time to deterioration in lymphoma symptoms, and time to next anti-lymphoma treatment.
• Assessing the safety and tolerability of M+Len compared with R+Len.
• Characterizing the pharmacokinetic (PK) profile of M+Len and R+Len.
• Evaluating the immune response to mosunetuzumab and rituximab.
• For Arm C, evaluating the efficacy and safety of M+Len, characterizing its PK profile, and assessing the immune response to mosunetuzumab.

The clinical trial involves a total of **324 participants** diagnosed with **relapsed/refractory follicular lymphoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically documented CD20+ follicular lymphoma (Grades 1-3a) and a requirement for systemic therapy as assessed by the investigator. All participants have received at least one prior systemic lymphoma therapy, which included prior immunotherapy or chemoimmunotherapy. The trial population is characterized by adequate hematologic and organ function, and participants must comply with the lenalidomide risk minimization plan, including the global pregnancy prevention program. The study also considers vulnerable populations, ensuring comprehensive evaluation and monitoring throughout the trial. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **Phase III** randomized, open-label, multicenter study designed to evaluate the efficacy and safety of mosunetuzumab in combination with lenalidomide compared to rituximab in combination with lenalidomide in patients with **relapsed/refractory follicular lymphoma**. The trial includes a non-randomized, single-arm US extension to further assess the combination of mosunetuzumab and lenalidomide. The primary objective is to evaluate progression-free survival and objective response rate as determined by an independent review committee. The trial is expected to conclude by April 2029, with recruitment having commenced in November 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented CD20+ follicular lymphoma and prior systemic therapy. Follow-up visits will be scheduled to monitor treatment efficacy and safety, with assessments including progression-free survival, complete response rate, and overall survival. The end-of-study visit will conclude the participant's involvement, with data collected on the duration of response and any adverse events experienced.

The expected length of participant involvement will vary depending on individual response to treatment and progression of the disease. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study will adhere to rigorous scientific and ethical standards, ensuring that all procedures are conducted in accordance with regulatory requirements and the trial protocol.

The clinical trial involves the evaluation of several treatments for patients with **follicular lymphoma**. The experimental medication, **mosunetuzumab**, is a protein-based therapeutic agent developed by Roche Registration GmbH (RRG). It is administered in combination with **lenalidomide**. The pharmaceutical form, dosage, route, and frequency of administration for mosunetuzumab are not specified in the provided data. However, it is known that the formulation is not pediatric and is not classified as an orphan drug. The product is identified by the sponsor product code RO 703-0816/F02-03 and RO 703-0816/F02-04.

**Lenalidomide**, a chemical substance, is provided by Bristol-Myers Squibb Pharma EEIG. It is used in combination with both mosunetuzumab and **rituximab** in the study. Lenalidomide has been re-packaged and relabeled for clinical use, and it is not a pediatric formulation. The pharmaceutical form, dosage, route, and frequency of administration for lenalidomide are not detailed in the data. The product is identified by multiple marketing authorization numbers, including EU/1/07/391/003, EU/1/07/391/009, EU/1/07/391/001, and EU/1/07/391/002.

**Rituximab**, another protein-based therapeutic agent, is also provided by Roche Registration GmbH. It is used in combination with lenalidomide as a comparator treatment in the study. Rituximab has been re-packaged and relabeled for clinical use, and it is not a pediatric formulation. The pharmaceutical form, dosage, route, and frequency of administration for rituximab are not specified in the provided data. The product is identified by the marketing authorization number EU/1/98/067/002.

Participant compliance with the dosing schedules and administration of the medications will be monitored throughout the trial. The study aims to compare the efficacy of mosunetuzumab in combination with lenalidomide against rituximab in combination with lenalidomide, with a focus on progression-free survival and objective response rate as determined by an independent review committee.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints for Arms A and B involve evaluating **progression-free survival** (PFS) as determined by the independent review committee (IRC) using the 2014 Lugano Response Criteria or death from any cause in the intent-to-treat (ITT) population. For Arm C, the primary endpoint is the **objective response rate** (ORR), defined as the proportion of patients achieving a partial response (PR) or complete response (CR) during the study, as determined by the IRC.

Secondary endpoints include several measures across all arms: PFS as determined by both the investigator and IRC, complete response rate, ORR, overall survival, duration of objective response (DOR), and duration of CR. Additional secondary endpoints focus on patient-reported outcomes, such as time to deterioration in physical functioning and fatigue, measured by the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30), and time to deterioration in lymphoma symptoms, assessed by the Functional Assessment of Cancer Therapy-Lymphoma Subscale (FACT-LymS). Other endpoints include time to next anti-lymphoma treatment (TTNALT), incidence and severity of adverse events, changes in vital signs and clinical laboratory test results, and pharmacokinetic parameters such as minimum and maximum observed concentrations (Cmin and Cmax) and area under the concentration-time curve (AUC) for both mosunetuzumab and lenalidomide.

The trial will also monitor the prevalence and incidence of anti-drug antibodies (ADAs) against mosunetuzumab and rituximab. These efficacy parameters will be measured and analyzed at various timepoints throughout the study, ensuring a comprehensive evaluation of the treatment's impact on patients with follicular lymphoma after at least one line of systemic therapy.