Pharmacist's Application to Practice: Mosunetuzumab

Pharmacist’s Application to Practice

Mosunetuzumab for relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of therapy. Corresponding FDA Drug Update: FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma

What is the potential role for mosunetuzumab in the treatment of R/R FL?

• Mosunetuzumab is a full-length, IgG1-based CD20xCD3 T-cell engaging bispecific antibody that directs T cells to eliminate malignant CD20+ lymphoma cells.1 This bispecific antibody is produced using “knobs-into-holes” technology, targets the same epitope on CD20 as rituximab, and has an Fc silencing mutation to prevent FcɣR binding.2
• Mosunetuzumab is a National Comprehensive Cancer Network (NCCN) category 2A recommendation for 3rd line and subsequent therapy in FL. Other therapies that may be considered in this line of therapy include the PI3K inhibitors (e.g., copanlisib), the EZH2 inhibitor tazemetostat, and anti-CD19 CAR-T cell therapy (e.g., axicabtagene ciloleucel and tisagenlecleucel).3
• The efficacy and safety of mosunetuzumab was demonstrated in several phase I and II clinical trials in R/R non-hodgkin lymphoma (NHL), including FL. The FDA approval was based on a single-arm, multicenter, phase II study in adult patients with grade 1-3a FL1,4,5:
  • Patients (n=90) had R/R disease to 2 or more lines of therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. Key baseline characteristics included a median age of 60, 77% having stage III/IV disease, 31% having more than 3 prior lines of therapy, including 69% who were refractory to the last line of therapy.
    • IV mosunetuzumab was given in 21 day cycles with cycle 1 involving step-up dosing (1 mg day 1, 2 mg day 8, 60 mg day 15), 60 mg cycle 2, then 30 mg in cycle 3 onward.
    • Patients who achieve a complete response (CR) completed treatment after 8 cycles, and those who achieved a partial response (PR) or stable disease continued treatment for up to 17 cycles
  • Per independent review committee (IRC), the primary outcome of CR rate was 60%, and the objective response rate (CR+PR) per IRC was 80%. Median time to first response was 1.4 months and median time to first CR was 3 months.
  • Median PFS was 17.9 months and median OS was not reached.
  • Most common adverse effects included cytokine release syndrome (CRS) in 44% of patients, fatigue in 37%, and headache in 31%. Most common grade 3/4 adverse effects included neutropenia in 27%, hypophosphatemia in 17%, hyperglycemia in 8%, and anemia in 8%.
    • CRS was primarily low-grade in nature – 26% had grade 1, 17% had grade 2, and 2% had grade 3/4 CRS; the majority of CRS events occurred in cycle 1 during ramp up dosing.
    • Few (5%) instances of immune effector cell-associated neurotoxicity (ICANS) occurred that were primarily low-grade in nature (e.g., confusion, attention disturbance).
• The response rates and safety profile compares favorably to other novel therapy options in the 3rd line or later setting3,6:
  • PI3K inhibitors, such as copanlisib, umbralisib, and idelalisib, have objective response rates in the 40-60% range, but CR is uncommon. Use is limited by immune-mediated toxicities (diarrhea/colitis, hepatitis, pneumonitis) and opportunistic infections (e.g., PJP and viral reactivations).
  • Tazemetostat has an overall response rate of 69% (13% CR rate) in EZH2 mutated FL R/R to 2 or more prior therapies. EZH2 inhibitors are generally well-tolerated with mild GI adverse effects being most common.
  • CAR-T cells have higher response rates (ORR 94% for axicabtagene ciloleucel, 86.2% with tisagenlecleucel), but cross-trial comparisons to bispecific antibodies are challenging due to differences in patient characteristics and no head-to-head data exists. In general, CRS and ICANS occur more frequently with CAR-T cell therapy than with bispecific antibodies.
  • Other bispecific antibodies have been studied in R/R FL (e.g., glofitamab, epcoritamab, etc.), with similar response rates and toxicity profile.
• Mosunetuzumab has also been studied in other R/R B-cell NHL (mainly DLBCL), demonstrating a 34.9% overall response rate (19.4% CR rate), regardless of prior CAR-T therapy (36.8% ORR in this population).5

What role can the pharmacist play in the management of patients on mosunetuzumab?

• Pharmacists can help select appropriate patients for mosunetuzumab. Advantages include the higher response rates (compared to other oral targeted options) and favorable safety profile compared to CAR-T cell therapy. The fixed duration of therapy for mosunetuzumab is also appealing compared to other indefinite treatment strategies.
• Ensure patients have adequate pre-medication prior to step up doses in cycle 1, and for the cycle 2 dose.
• Pharmacists play a vital role in grading and management of toxicities of mosunetuzumab, including CRS and ICANS.
• Patients should be counseled on the signs and symptoms of CRS and ICANS, including fever, chills, hypotension, tachycardia, hypoxia, headache, confusion, peripheral neuropathy, or dizziness. Patients should seek immediate attention if signs or symptoms occur.

Clinical Pearls

• CRS with mosunetuzumab is generally low-grade in nature; thus, from a stewardship perspective, consider the use of dexamethasone rather than tocilizumab, which may not be required for CRS management. Dexamethasone also represents an easier on-demand treatment option for any CRS symptoms that occur at home during the dose ramp-up phase.
• There are no dose adjustments for renal or hepatic impairment. For gaps in therapy, an abbreviated dose ramp-up may need to be repeated – the prescribing information has a helpful chart for each cycle.4
• Premedications should be given with cycle 1 and cycle 2, including a corticosteroid (dexamethasone 20 mg or methylprednisolone 80 mg IV), an antihistamine (diphenhydramine 50 – 100 mg or equivalent), and an antipyretic (e.g., oral acetaminophen 500-1000 mg). In those who experience any grade CRS with a previous dose, premedications should be given for the next cycle.4
• An in-line filter should not be used to administer mosunetuzumab.4
• Tumor-flare occurred in 4% of patients, given the immune-activating nature of bispecific antibodies such as mosunetuzumab. Monitor patients carefully who have bulky disease or disease in close proximity to vital organs.4

References

1.Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022 Aug;23(8):1055-1065.

2.Falchi L, Vardhana SA, Salles GA. Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities. Blood. 2023 Feb 2;141(5):467-480.

3.National Comprehensive Cancer Network. B-Cell Lymphomas (Version .4.2023). https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 30, 2023.

4.Mosunetuzumab (Lunsumio). [prescribing information]. San Francisco, CA: Genentech, Inc; 2022.

5.Budde LE, Assouline S, Sehn LH, et al. Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: phase I dose-escalation study. J Clin Oncol. 2022 Feb 10;40(5):481-491.

6.Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol. 2022 Dec;97(12):1638-1651. doi: 10.1002/ajh.26737.