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Advances in FL

CE / CME

Current and Emerging Therapeutic Advances in Follicular Lymphoma: A Class in Session

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: March 06, 2023

Expiration: March 05, 2024

CME/CE Information

Activity

Progress
1
Course Completed

Comparison of Mechanism of Action of Bispecific Antibodies and CAR T-Cell Therapies

John M. Burke, MD:
Mosunetuzumab-axgb is the first bispecific antibody approved for adults with R/R FL after ≥2 lines of systemic therapy.14 In terms of mechanisms, both bispecific antibodies and CAR T-cell therapies use antibody variable fragments to direct cytotoxic T-cell lymphocytes to cancer cells, but this is accomplished in different ways. The Bispecific antibodies mosunetuzumab-axgb, odronextamab, and epcoritamab, have been engineered to bind both an antigen (CD20) on the targeted malignant B-cells and an antigen (CD3) on the immune effector T-cells.15

Bispecific antibodies are available “off the shelf” with no waiting time to treat a patient. By contrast, CAR T-cell manufacturing can take up to 3‑4 weeks. In terms of dosing, bispecific antibodies are given repetitively over time, whereas CAR T-cell therapy is provided as a single dose following a lymphodepleting chemotherapy regimen. CAR T-cell therapy may be more immunogenic and appears to be associated with a greater incidence of CRS.

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Phase II Study of Mosunetuzumab Monotherapy in R/R FL

John M. Burke, MD:
Mosunetuzumab was evaluated in adults with R/R FL after ≥2 prior systemic therapies in a single-arm phase II expansion study with 90 patients.16 A step-up dosing protocol was instituted with the administration of premedications for the first 2 cycles with continuation until cycle 8 with CR. For those with PR or stable disease, mosunetuzumab was continued as tolerated for 17 cycles. It was reported after a median of 18.3 months of follow-up that the primary endpoint was met with a CR in 60% of participants, compared with 14% in a historic control group (P <.0001).16

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Phase II Study of Mosunetuzumab in R/R FL: Baseline Characteristics

John M. Burke, MD:
At baseline, the median age of the patients (N= 90) was 60 years. They had received a median of 3 prior lines of therapy. Some (21%) had received a prior autologous HSCT. More than one half (52.2%) of the participants had progressed within 24 months of their initial therapy. The median follow-up in the most recent report was 28.3 months.17 Most patients (59%) received 8 cycles of mosunetuzumab, though 12% received 17 cycles.

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Phase II Study of Mosunetuzumab in R/R FL: Response

John M. Burke, MD:
In these patients with heavily pretreated FL, mosunetuzumab achieved an ORR of 78% and CR rate of 60% after 28 months of follow-up, which was consistent with the 18.3-month follow-up report.

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Phase II Study of Mosunetuzumab in R/R FL: Duration of CR and PFS

John M. Burke, MD:
The estimated median duration of CR with mosunetuzumab was not reached, compared with 15 months for the last therapy. Estimated median PFS with mosunetuzumab was double that of the last therapy (24 vs 12 months).

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Phase II Study of Mosunetuzumab in R/R FL: Safety

John M. Burke, MD:
Only 2 patients discontinued mosunetuzumab due to related toxicities. The most common AEs were CRS, fatigue, and headache. No new serious AEs have emerged since the last report of this study. Very rare tumor flares and occasional cytopenias may occur at random times. Like any B-cell–targeting agent, mosunetuzumab can increase susceptibility to infections. Hypophosphatemia has also been observed with mosunetuzumab.

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Phase II Study of Mosunetuzumab in R/R FL: CRS

John M. Burke, MD:
As noted previously, CRS typically refers to a syndrome of fever and flu-like symptoms but can progress to more serious symptoms, including hypotension, hypoxia, and multiorgan failure. Fortunately, for most patients treated with mosunetuzumab, the CRS is relatively low grade. They experience only fever, and most patients do not develop significant hypotension or hypoxia. Premedications with corticosteroids, antihistamines, and an antipyretic are recommended with the initial administration of mosunetuzumab and with subsequent doses if CRS is experienced.14 It is recommended to administer mosunetuzumab with a weekly ramp-up dosing schedule during the first cycle to help reduce risk of higher-grade CRS. Hospitalization is not mandatory.14 The CRS tends to occur within the first month during the ramp-up phase of treatment, and then it tends to go away. Only a minority of patients required corticosteroids (11%) or tocilizumab (8%) beyond the corticosteroid premedication. Although the CRS is fairly frequent, it is usually minor; these minor cases can be managed as an outpatient.

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Adverse Events and Management With Mosunetuzumab-axgb

John M. Burke, MD:
When managing patients with mosunetuzumab-axgb, education about frequently monitoring vital signs for CRS at home and having a caregiver available to assist with close monitoring are necessary. It is not advisable to have people living on their own without good social support. Advise patients and caregivers to report any fevers and other vital sign abnormalities to the provider.

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In addition to premedication with corticosteroids, antihistamine, and an antipyretic, which of the following is the recommended strategy to reduce CRS risk when treating a patient with R/R FL with the bispecific antibody mosunetuzumab-axgb?

ELM-2: Phase II Study of Odronextamab in R/R FL

John M. Burke, MD:
Several other bispecific antibodies are under investigation in FL. Findings from a phase II trial of odronextamab, a human CD20 x CD3 bispecific antibody, which included patients with R/R FL, were recently reported.18 Adults with grades 1-3a FL after ≥2 prior systemic therapies received odronextamab with a step-up dosing schedule. The primary outcome was ORR.

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ELM-2: Phase II Study of Odronextamab in R/R FL Baseline Characteristics

John M. Burke, MD:
The median age of the patients was 61 years. They had received a median of 3 prior lines of therapy. Some (30.5%) had received a transplant, and many (74.8%) were refractory to prior CD20 antibody therapy. Approximately one half (48.1%) experienced POD24, which indicates higher-risk FL.

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ELM-2: Phase II Study of Odronextamab in R/R FL Response

John M. Burke, MD:
The ORR reported by odronextamab was 81.8% and a CR of 75.2%. Among responders, 92% achieved a CR. The results approached the response rates seen with CAR T-cell therapy in R/R FL.

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ELM-2: Phase II Study of Odronextamab in R/R FL CRS

John M. Burke, MD:
Any-grade CRS with odronextamab occurred in approximately 50% of patients. Events were mostly grade 1 with no grade ≥4 events. The modification of step-up dosing helped mitigate the incidence of grade 2/3 CRS from 23.5% to 12.7%. No patients needed ICU admission or mechanical ventilation.

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EPCORE NHL-2: Epcoritamab Plus R2 in R/R FL Study Design

John M. Burke, MD:
Another investigational CD20 x CD3 bispecific antibody epcoritamab was studied in combination with R2 in patients with R/R FL. Different doses were being explored in this phase Ib/II trial with a primary endpoint of ORR.19 Adults with grades 1-3a, stage II-IV FL with measurable disease were administered epcoritamab with continuation every 4 weeks for ≤2 years.

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EPCORE NHL-2: Epcoritamab Plus R2 in R/R FL Updated Response

John M. Burke, MD:
In this combination of epcoritamab and R2 in patients with relapsed disease, after 5.6 months of follow-up, they reported an ORR of 96.2% and a complete metabolic response of 83.5%. Results of arm 6 from the trial evaluating the regimen in the frontline setting (n = 36) demonstrated an ORR of 94% and a complete metabolic response of 83.5%.20 In comparison with R2 in R/R FL, the ORR is approximately 76%, and CR rates are approximately 40%.21

With the approval of mosunetuzumab-axgb and encouraging data with odronextamab and epcoritamab, there is great interest in the potential of the bispecific antibodies as a novel treatment for our patients. Patients with FL do not have curable disease in most circumstances, and the treatment goal in the R/R setting is to prolong life without causing much toxicity. The majority of patients are probably older (70 years of age or older), and these patients may be less willing to tolerate all the logistics and toxicities with CAR T-cell therapy. For this reason, bispecific antibodies like mosunetuzumab-axgb may play a significant role in the management of FL, at least in the near term. Another scenario in which bispecific antibody therapy may have an important role is the patients who have an aggressive FL where a quick response is desired to obtain symptom relief. For doctors in community practice like me, it takes a couple of months until our patients travel to see a CAR T-cell specialist to obtain the insurance authorization. Within a week or two, the same patient may receive mosunetuzumab-axgb treatment in the office, which is an advantage in terms of being able to deliver the treatment quickly for symptom relief.

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