Mosunetuzumab 1mg/1ml solution for infusion vials

Follicular lymphoma is the most common indolent non-Hodgkin's lymphoma, and because of the incurable nature of this disorder, new therapies are constantly needed. The recently approved T-cell-dependent bispecific antibody mosunetuzumab showed promising results and manageable toxicities for patients with relapsed or refractory follicular lymphoma. Namely, as opposed to cellular immunotherapy options, this agent has the potential of being effective in patients with unfavorable features with a tolerable rate and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity, and infectious complications. Given the recent withdrawal from the market of PI3K inhibitors and the practical challenges in utilizing with chimeric antigen receptor T-cells (CAR-T) for some patients, mosunetuzumab represents a "breath of fresh air" for both patients and hemato-oncologists. More data are required to better define the real potential of this molecule, either alone or in combination with other agents, including antibody drug conjugates, immunomodulators, and checkpoint inhibitors. Future studies will also shed light on the efficacy of mosunetuzumab compared with CAR-T, in well-designed registries or ideally in randomized controlled trials.

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Despite advancements in treatment for B-cell non-Hodgkin lymphoma (B-NHL) in recent decades, many patients still relapse or are refractory to treatment, which represents a high unmet medical need. Novel CD20 × CD3 T-cell-engaging bispecific antibodies (bsAbs) have created a new paradigm for the treatment of B-NHL. Pivotal studies of four CD20 × CD3 bsAbs, mosunetuzumab, glofitamab, epcoritamab, and odronextamab, as monotherapy, have demonstrated robust responses with generally manageable safety profiles in patients with relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma after ≥ 2 lines of systemic therapy. These agents have presented unique challenges (e.g., cytokine release syndrome [CRS]), which have required different strategies to overcome. This review provides a comprehensive overview of the clinical development of these four CD20 × CD3 bsAbs that have been investigated for the treatment of B-NHL, with a specific focus on translational assessments to select starting doses in first-in-human studies, management of CRS, application of modeling and simulation approaches to aid dose escalation and optimization/selection, and strategies used in the design of phase I-III clinical trials. By highlighting learnings and experiences from these four bsAbs assessed, which have not been summarized collectively elsewhere, we aim to promote more efficient study design for novel bsAbs in B-NHL in the future.

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ABSTRACT: Mosunetuzumab, a CD20×CD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7 to not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of CR was not reached (NR; 95% CI, 33.0 to NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE to NE). Median progression-free survival was 24.0 months (95% CI, 12.0 to NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) after 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions, and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe, and effective treatment for patients with R/R FL, including those with high-risk disease. This trial was registered at www.clinicaltrials.gov as #NCT02500407.

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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mosunetuzumab is a CD20xCD3 T-cell–engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407 ). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

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PURPOSE Prognosis for patients with refractory/relapsed large B-cell lymphoma (LBCL) considered ineligible for curative-intent therapy is poor. The combination of mosunetuzumab, a T-cell–engaging bispecific antibody, and polatuzumab vedotin, an antibody-drug conjugate (Mosun-Pola), represents a novel fixed-duration outpatient therapy. METHODS In the phase III SUNMO trial, patients with refractory/relapsed LBCL who were ineligible for autologous stem-cell transplant were randomly assigned (2:1) to receive Mosun-Pola or rituximab, gemcitabine, and oxaliplatin (R-GemOx). Dual primary end points were centrally assessed overall response rate (ORR) and progression-free survival (PFS). Overall survival was a key secondary end point. RESULTS A total of 208 patients were randomly assigned to receive Mosun-Pola (n = 138) or R-GemOx (n = 70). At a median follow-up of 23.2 months, the primary analysis of SUNMO demonstrated that the median PFS was significantly longer with Mosun-Pola than with R-GemOx (11.5 months [95% CI, 5.6 to 18] v 3.8 months [95% CI, 2.9 to 4.1]; hazard ratio for progression or death, 0.41 [95% CI, 0.3 to 0.6]; P < .0001). ORR was significantly greater with Mosun-Pola versus R-GemOx (70% v 40%; P < .0001), with complete response rates of 51% and 24%, respectively. In the Mosun-Pola group, the rate of grade ≥2 cytokine release syndrome (CRS) and usage of tocilizumab occurred in <5% of patients and patient-reported outcomes were improved compared with R-GemOx. CONCLUSION Mosun-Pola demonstrated superior efficacy versus R-GemOx, with significant improvements in both ORR and PFS, and infrequent CRS events with a manageable safety profile.

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ABSTRACT: This phase 2 study evaluated mosunetuzumab plus cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin (Pola-M-CHP) vs Pola-rituximab (R)-CHP for first-line treatment of diffuse large B-cell lymphoma. Patients were randomized 2:1 to receive 6 cycles of Pola-M-CHP or Pola-R-CHP on day 1 of each 21-day cycle. Mosunetuzumab was administered intravenously via step-up dosing during cycle 1 and at 30 mg on day 1 of subsequent cycles. The primary end point was independent review committee-assessed complete response (CR) rate by positron emission tomography-computed tomography. Overall, 62 patients were enrolled and received Pola-M-CHP (n = 40) or Pola-R-CHP (n = 22). CR rates were similar in both arms (72.5% with Pola-M-CHP vs 77.3% with Pola-R-CHP); the 24-month investigator-assessed progression-free survival rate was 70.8% (95% confidence interval [CI], 55.6-86.1) with Pola-M-CHP vs 81.8% (95% CI, 65.7-97.9) with Pola-R-CHP. The most common adverse event (AE) was cytokine release syndrome (68.4%; mostly grade 1 [52.6%], and primarily confined to cycle 1) with Pola-M-CHP and neutropenia/neutrophil count decreased (54.5%) with Pola-R-CHP. Neutropenia/neutrophil count decreased was the most frequently observed grade ≥3 AE in both arms (Pola-M-CHP, 36.8%; Pola-R-CHP, 22.7%). Rates of grade ≥3 AEs (86.8% vs 59.1%), serious AEs (63.2% vs 13.6%), and AEs leading to treatment discontinuation (13.2% vs 0%) were higher with Pola-M-CHP than Pola-R-CHP, respectively. Pharmacodynamic changes were supportive of mosunetuzumab's mechanism of action and its addition to the Pola-CHP combination. Pola-M-CHP, although an active combination, did not demonstrate a clinical benefit over Pola-R-CHP in this small study. This trial was registered at www.clinicaltrials.gov as #NCT03677141.

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Bispecific antibodies are emerging as a promising new immunotherapy modality and are actively being evaluated in clinical trials for patients with lymphoma. As the first BsAb to receive regulatory approval for lymphoma, mosunetuzumab, an antiCD20/anti-CD3 BsAb, is an exciting new option for patients with relapsed or refractory (R/R) follicular lymphoma. The approval was based on results from an international, multicenter, phase 2 trial in patients with relapsed or refractory (R/R) follicular lymphoma following at least 2 prior lines of systemic therapy. Mosunetuzumab demonstrated remarkable efficacy with an overall response rate of 80% and complete response rate of 60%. Here we provided an overview of the latest clinical data on mosunetuzumab in lymphoma presented at the 2022 ASH Annual Meeting.

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