Mosunetuzumab-Axgb Approved for R/R Follicular Lymphoma

R/R Follicular Lymphoma: R/R Follicular LymphomaFollicular lymphoma (FL) accounts for up to 30 percent of all cases of non-Hodgkin lymphoma. The course of this slow-growing disease is typically characterized by relapsing disease, increasing refractoriness to anti-CD20 antibodies and chemotherapy, and decreasing survival rates with each subsequent therapy. Randomized studies have demonstrated that approximately 20 percent of patients with FL experience early disease progression. Another analysis from the National LymphoCare Study in the U.S. involving patients with FL treated with first-line R-chemotherapy demonstrated that 19 percent relapsed within 2 years. Patients with refractory or early relapsing disease can have an especially poor prognosis, with a 5-year survival rate ranging from 34 to 50 percent, far more inferior to the 90 percent 5-year survival rate of those without an early progression event. Therefore, new therapeutic approaches are critically needed to overcome treatment resistance and improve outcomes for patients with relapsed or refractory FL. In December 2022, the FDA granted accelerated approval to mosunetuzumab-axgb for the treatment of adults with relapsed or refractory FL after two or more lines of systemic therapy. As a full-length, CD20-directed, CD3 T-cell bispecific monoclonal antibody, mosunetuzumab-axgb represents a new class of fixed-duration cancer immunotherapy. Instead of focusing on a singular target, bispecific antibodies are therapeutics that act on two cellular targets concurrently. For mosunetuzumab-axgb, one “arm” targets the CD3 protein on T cells, an immune cell that fights against cancer once engaged; a second “arm” binds to CD20, a protein commonly found on lymphoma cells. Mosunetuzumab-axgb was granted accelerated approval based on the positive response rate reported in the Phase II GO29781 study (Lancet Oncol 2022; https://doi.org/10.1016/S1470-2045(22)00335-7). The open-label, multi-cohort study was conducted in 49 centers in 7 countries (Australia, Canada, Germany, South Korea, Spain, U.K., and U.S.). The dose-escalation and dose-expansion trial investigated the safety, efficacy, and pharmacokinetics of fixed-duration mosunetuzumab-axgb in patients with relapsed or refractory FL. Requirements for enrollment included patients aged ≥18 years with histologically confirmed FL Grade 1-3a, and an Eastern Cooperative Oncology Group performance status of 0-1. Additionally, all patients had disease that was relapsed or refractory to at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. In total, 90 patients (median age, 60 years; age range 29-90) were enrolled between May 2, 2019, and Sept 25, 2020. The patients received intravenous mosunetuzumab-axgb administered in 21-day cycles for a minimum of 8 cycles and up to 17 cycles. Outcome measures included complete response rate (best response) by independent review facility (primary endpoint), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), safety, and tolerability (secondary endpoints). Results from the study showed high and durable response rates. Specifically, the primary analysis demonstrated an ORR of 80 percent (72/90; 95% CI: 70-88) of patients treated with mosunetuzumab-axgb and a majority of these patients (57%; 95% CI: 44-70) maintained responses for at least 18 months. Moreover, with a median follow-up of 14.9 months among responders, the estimated median DOR was 22.8 months (95% CI: 10-not reached [NR]), with complete response achieved in 60 percent of patients (54/90; 95% CI: 49-70). The median PFS and overall survival (OS) was 24 months (95% CI: 12-NR) and NR (NR-NR), respectively. The 2-year PFS and OS rates were 48 percent (95% CI: 36-60%) and 87 percent (95% CI: 80-94%), respectively. In the pooled safety population of 218 patients with hematologic malignancies who received mosunetuzumab-axgb at the recommended dose, the most common adverse event (AE) observed was cytokine release syndrome (CRS, 39%), which occurred at a median duration of 3 days (range: 1-29). Other common AEs (≥20%) were fatigue, rash, pyrexia, and headache. The most common Grade 3/4 laboratory abnormalities (≥10%) were decreased lymphocyte count, decreased phosphate, increased glucose, decreased neutrophil count, increased uric acid, decreased white blood cell count, decreased hemoglobin, and decreased platelets. Mosunetuzumab-axgb is administered as an intravenous infusion for a fixed duration, which allows for time off therapy, and can be infused in an outpatient setting. However, hospitalization may be needed upon the occurrence of select AEs, as well as during subsequent infusions following a Grade 2 CRS event. Additionally, hospitalization is recommended during subsequent infusions following a Grade 3 CRS event. The recommended mosunetuzumab-axgb dose is 1 mg on Cycle 1 Day 1, 2 mg on Cycle 1 Day 8, 60 mg on Cycle 1 Day 15, 60 mg on Cycle 2 Day 1, and 30 mg on Day 1 in subsequent cycles. A treatment cycle is 21 days. Mosunetuzumab-axgb should be administered for 8 cycles unless patients experience unacceptable toxicity or disease progression. After 8 cycles, patients with a complete response should discontinue therapy. Patients with a partial response or stable disease should continue treatment up to 17 cycles unless they experience progressive disease or unacceptable toxicity. This indication's continued approval may remain contingent on the verification of clinical benefit in a confirmatory trial. For further insights into the impact of mosunetuzumab-axgb in FL, Oncology Times reached out to study authors, Nancy Bartlett, MD, and Elizabeth Budde, MD, PhD. Bartlett is the Koman Chair in Medical Oncology at Washington University School of Medicine and Budde is Associate Professor in the Department of Hematologic Oncology & Hematopoietic Cell Transplantation at City of Hope. Oncology Times: What are some of the treatment challenges for patients with relapsed or refractory FL? Bartlett: “Although the first- and second-line therapies for FL such as rituximab/bendamustine and rituximab/lenalidomide are well-tolerated, they still carry a modest risk of bone marrow suppression and serious late effects, including prolonged immunosuppression or second cancers. Earlier lines of therapy may affect tolerance of later lines of therapy, so having well-tolerated treatments available at the time of relapse is important. Many patients with FL are older and are more likely to have comorbidities, potentially limiting their treatment options.” Oncology Times: How does the approval of mosunetuzumab-axgb change the treatment paradigm for adults with relapsed or refractory FL? How does mosunetuzumab-axgb avoid many of the logistical obstacles associated with other current therapies with this patient class? Bartlett: “Given the efficacy and safety of mosunetuzumab-axgb, this will likely be the first choice for third-line therapy. The advantages of mosunetuzumab-axgb over other options in this setting include a complete response rate of 60 percent; very low incidence of serious side effects, including late effects; administration once every 3 weeks; and the fixed duration of treatment. For patients who achieve a complete remission, treatment would be complete in approximately 6 months. Other agents approved in this setting have lower response rates and are administered until progression and some require weekly administration. Although CAR T-cell therapy is approved in third line or later, excluding transformed FL, I do not think there is a scenario where that would be prescribed before mosunetuzumab-axgb for FL.” Budde: “It provides a highly efficacious and safe treatment option for these patients. Its clinical efficacy does not differ with regards to age. Patients with advanced age can also derive similar clinical benefits. It is readily available and given in the outpatient setting. There is also no Risk Evaluation and Mitigation Strategy (REMS) requirement by the FDA, a strong endorsement of its favorable safety profile. It can be given in the community setting instead of a certified treatment center, which is required for CAR T-cell therapy. This is particularly important for patients who live far from an academic center and have limited social support.” Oncology Times: Are there any studies evaluating mosunetuzumab-axgb in other formulations, in combination with other therapies, or its impact in earlier lines of treatment? Budde: “Given the high efficacy and favorable side effect profile, mosunetuzumab-axgb is now under active clinical testing in combination with other anti-lymphoma drugs, such as lenalidomide and polatuzumab. Clinical trials are also underway to evaluate the use of mosunetuzumab-axgb in patients with newly diagnosed FL, marginal zone lymphoma, and elderly patients with newly diagnosed aggressive large B-cell lymphoma. “To further improve its convenience in the outpatient setting, subcutaneous injection formulation was developed, and the recommended Phase II dose has been identified. A pivotal Phase II study treating FL using this formulation is near completion. Subcutaneous injection formulation also has the advantage of reducing infusion room chair and staff time. A win-win to both the patients and the treatment center if the efficacy is demonstrated to be the same.” Dibash Kumar Das is a contributing writer.

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