CELESTIMO: A Randomized Phase III Trial Examining the Efficacy and Safety of Mosunetuzumab in Combination With Lenalidomide Versus Rituximab in Combination With Lenalidomide in Relapsed/Refractory Follicular Lymphoma

STUDY TITLE: A Study Evaluating the Efficacy and Safety of Mosunetuzumab in Combination With Lenalidomide in Comparison to Rituximab in Combination With Lenalidomide in Patients With Follicular Lymphoma After at Least One Line of Systemic Therapy (Celestimo)

CLINICAL TRIALS.GOV IDENTIFIER: NCT04712097

PARTICIPATING CENTERS: 150 sites throughout the United States, Brazil, Asia, Europe, and Australia

ACCRUAL GOAL: 400 patients

STUDY DESIGN: CELESTIMO (NCT04712097) is a randomized, multicenter, open-label, phase III study evaluating the efficacy and safety of mosunetuzumab plus lenalidomide versus rituximab (R²) in patients with relapsed or refractory (R/R) follicular lymphoma (FL). Adult patients (≥ 18 years) with grade 1-3a FL, a performance status of 0 to 2, and at least one prior line of systemic therapy are eligible. Randomization is stratified by POD24 (progression or relapse of FL within 2 years) status, number of prior lines of therapy (1 vs. ≥ 2), and refractoriness to anti-CD20 therapy. In the mosunetuzumab-lenalidomide arm, mosunetuzumab is administered on a step-up dosing schedule (1, 2, and 30 mg) intravenously (IV) on days 1, 8, and 15 of cycle 1 (21-day cycle), and then as a fixed 30 mg dose on day 1 of cycles 2 to 12 (28-day cycles). Outpatient administration is allowed. Lenalidomide 20 mg is given orally on days 1 to 21 of cycles 2 through 12. In the R² control arm, R² (375 mg/m²) is administered IV on days 1, 8, 15, and 22 of cycle 1, then on day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Lenalidomide 20 mg is given on days 1 to 21 of cycles 1 through 12. The primary end point for this study is progression-free survival (PFS) as assessed by an independent review committee. The study began recruiting in 2021 from approximately 16 countries and 150 sites globally. With a target enrollment of approximately 400 patients, recruitment is projected to be completed in the Spring of 2023. The results of this rational randomized study with a desirable control arm are eagerly awaited.

RATIONALE: Despite favorable outcomes with frontline therapy, most patients with follicular lymphoma (FL) will relapse and eventually succumb to lymphoma or complications of therapy.¹  Therefore, there is an unmet need to develop effective, well-tolerated therapy. Mosunetuzumab is a T-cell–engaging bispecific antibody that targets CD20 present on malignant and mature B cells and CD3 present on endogenous T cells. In a pivotal, single-arm phase II trial, fixed-duration mosunetuzumab resulted in promising response rates (60% achieved a complete response) that seemed durable (median duration of response, 22.8 months) in patients with R/R FL after at least two prior systemic therapies.²  Responses were observed across all subgroups, including those refractory to prior CD20-targeted therapy and to alkylators (double refractory), and those with progression within 24 months of frontline chemoimmunotherapy (POD24) — historically poor-risk groups. Mosunetuzumab was also well tolerated, with 2 percent discontinuing therapy due to treatment-related adverse events. It is anticipated that mosunetuzumab will be approved for the treatment of R/R FL after two prior lines of systemic therapy.

Lenalidomide is an oral immunomodulatory agent that is a rational partner to be combined with anti-CD20 antibody therapy in FL, and when combined with R² in the AUGMENT study, it resulted in a significant improvement in PFS and overall survival in comparison to R² monotherapy.³  Given the T-cell–engaging properties of mosunetuzumab, a phase Ib study of mosunetuzumab in combination with lenalidomide commenced and preliminary findings suggest a manageable safety profile and promising activity.⁴  Further study was warranted and a confirmatory phase III trial desirable was used to explore whether this refined immunotherapy option for patients with R/R FL is an improvement over R².

COMMENT: Targeting CD20 and the tumor microenvironment have been effective strategies in the management of FL. T-cell–engaging bispecific antibodies that also target CD20 on the tumor surface appear to be the next generation of this approach, and it is anticipated that mosunetuzumab will be approved by the U.S. Food and Drug Administration later this year based on a single-arm phase II trial. A randomized confirmatory phase III trial will be necessary. Historically, anti-CD20 monoclonal antibody combination strategies have been more impactful than monotherapy options. The CELESTIMO study, which is exploring a novel CD20-targeting T-cell–engaging bispecific antibody (mosunetuzumab) that has a favorable toxicity profile (manageable low-grade cytokine release syndrome/outpatient delivery) combined with an oral immune modulator (lenalidomide) in comparison to R² in relapsed FL, is enrolling rapidly due to either option being very attractive. I would consider this study for any patient that has relapsed FL.