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Okay, so we are going to start today by talking about the mechanism of action of the bispecific antibodies.

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[00:08:39]

CD20xCD3 Bispecific Antibodies: Mechanism of Action

So currently, bispecific antibodies bind two different targets. They target a protein or an antigen on the T-cell, in this case, and an antigen on the tumor cell or the B-cell. So the bispecific antibodies that we are going to largely talk about today target CD20 on the B-cell and CD3 on the T-cell. And this is the mechanism of action of all the currently approved bispecific antibodies in relapsed/refractory follicular lymphoma.

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[00:09:20]

CD20xCD3 Bispecific Antibodies: Structure and Function

So there are currently three approved CD20xCD3 bispecific antibodies in relapsed/refractory lymphomas. Two of them are approved in follicular lymphoma. And then there is a fourth that has been extensively studied in clinical trials and has an indication currently in Europe, but not in the U.S. right now. So mosunetuzumab was the first bispecific antibody approved. It was approved initially with an IV formulation, and actually just last week or two weeks ago, it was approved in a subcutaneous formulation as well. So this has an IV and sub-Q option. Its approval currently is in relapsed/refractory follicular lymphoma after two or more prior lines of therapy.

Epcoritamab is approved. It is also a CD20xCD3. It is approved in actually both follicular lymphoma and large cell lymphoma, and it is administered in a subcutaneous fashion. It is approved after two or more prior lines of therapy in both follicular lymphoma and large cell lymphoma.

Glofitamab is not approved in follicular lymphoma, but it is approved in relapsed/refractory large cell lymphoma or transformed follicular. It is an IV formulation, and it has a 2:1 binding, which is the only one that has this feature.

And then odronextamab is also the last CD20xCD3. This is an IV. There is currently trials that have been conducted or are ongoing, and it is approved in Europe, but it is not currently approved in the U.S. for either large cell or follicular.

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[00:11:15]

Are Bispecific Antibodies A Piece of the Puzzle in FL?

Follicular Lymphoma: A 1,000 Piece Puzzle

So we will talk about how the role of bispecific antibodies in the treatment of relapsed/refractory follicular lymphoma.

So we know that patients with follicular lymphoma tend to have very good responses to initial treatment, which is most often chemoimmunotherapy. But we also know that with each successive line of treatment that the responses lessen, and patients get less of a response and less of a progression-free survival, at least in the era of chemoimmunotherapy, leaving room for us to improve upon our available options. Because the majority of patients will be treated multiple times for their follicular lymphoma.

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How Start May Matter

There are many options of treatment for follicular lymphoma in both the frontline and the relapsed/refractory setting, and we know that what we treat a patient within their first- or second-line setting can impact our choices in later lines of setting. So the majority of patients are probably either going to be treated with single-agent rituximab for low tumor burden disease or be treated with chemoimmunotherapy in the frontline setting, although we also see the use of lenalidomide. There are multiple options at relapse, including now there is an approval for tafasitamab in combination with the R² combination. We just actually saw an approval for epcoritamab with this combination. And then multiple agents, including the bispecific antibodies, BTK inhibitors, zanubrutinib, tazemetostat, the EZH2 inhibitor, and then even the ADC Lonca has been put into the NCCN guidelines, although not approved.

We know that for patients who have early progression of disease after initial diagnosis and initial chemoimmunotherapy, that they tend to have more aggressive disease, and we are thinking about more intensive treatments, including treatments like CAR T-cell therapy or maybe even chemotherapy and transplant consolidation.

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In making these decisions, there is a lot that goes into this. If the patient is symptomatic versus asymptomatic, if they have high or low tumor burden, their comorbidities, and what treatments they previously had.

It is always important with follicular lymphoma that we re-biopsy at relapse so we know some of the disease features, and we are ruling out, especially in those early progressors, transformation to a more aggressive lymphoma.

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Armamentarium for R/R FL: It Is a Complicated Puzzle

As I mentioned, there are numerous treatments for relapsed/refractory follicular lymphoma, and at the current time, there is no ideal sequencing strategy.

So the BTK inhibitors, the oral therapy, tazemetostat, bispecific antibodies, the CD19 antibody tafasitamab, immunomodulator therapies, CAR T-cells, are all approved for relapsed/refractory follicular, and it is really a lot of times individualized patient decision, given there is no ideal treatment sequencing.

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Where Do Bispecific Antibodies Fit in the FL Puzzle?

So where do the bispecific antibodies fit into the puzzle?

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Mosunetuzumab

First, we will talk about mosunetuzumab. Again, this is the first one approved. Approved initially as an IV formulation, and more recently, the subcutaneous formulation.

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Mosunetuzumab: IV Dosing

So the trial that led to the approval of mosunetuzumab gave this drug for relapsed/refractory follicular for patients receiving two or more prior therapies.

Bispecific antibodies do all have a ramp-up dosing schedule, and this is to help mitigate the risk of cytokine release. All of their schedules and administration is different.

So if you look at the Mosun bispecific antibody, it was given in cycle 1 at escalating doses. Day 1 gets 1 mg, day 8 gets 2 mg, and day 15 gets 60 mg. Cycle 2, day 1, so just a week later, gets 60 mg again, and then cycle 3 and beyond is 30 mg dosing. This is a four-hour infusion for the ramp-up, and then if patients tolerate it, it can go to a two-hour infusion.

Mosun is given on a set treatment schedule, but the number of cycles can range from 8-17. So for patients who achieve a complete response, treatment is discontinued after 8 cycles, and for those who achieve a partial response, they get treatment through cycle 17 unless they have disease progression or toxicity.

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Mosunetuzumab: Early Efficacy

Looking at the early efficacy of this agent, so, in the multicenter pivotal Phase I/II trial that enrolled 90 patients, the overall response rate approached 80%, so, a fairly effective agent, with 60% of those patients achieving a complete response. The median duration of response approached three years, with the median duration of complete response not reached, and the median progression-free survival was two years, with the median overall survival not reached.

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Mosunetuzumab Phase II Study in R/R FL After ≥2 PLoT 3-Yr Update

This has since been updated with a three-year follow-up of the single-agent Mosun for patients with two or more prior lines of therapy, showing median PFS of 24 months, but the 36-month PFS of 43% of patients. So as you can see, there are some currently durable responses in these patients, with median overall survival not reached in 36-month OS, a little over 80%.

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Mosunetuzumab in High-Risk Subgroups of FL

Now, we are always interested in follicular lymphoma, how patients do with therapies that are considered to have high-risk disease. So patients who have POD 24, who have early progression of disease within two years of initial diagnosis, and then patients who are double refractory, those patients are considered double refractory if they are refractory to both CD20 and alkylator therapy.

And as you can see, in terms of the progression-free survival and the duration of complete responses, it was fairly effective in the patient of populations with and without POD 24, fairly similar. For those patients who achieved a complete response with double refractory disease, the responses were similarly durable. The PFS was higher in those patients who did not have double refractory disease.

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[00:18:32]

Single-Agent Mosunetuzumab: Safety in R/R FL

So looking at safety. So by far the most common side effect with these different bispecific antibodies is cytokine release, or CRS. They do vary, though, in the frequency that CRS occurs, the grade of CRS, and then the timing of CRS.

As you can see here, this lays out the CRS by timing, and a little over half of patients, had cytokine release. The majority of these were grade 1, but there were some grade 2 and just a few grade 3 CRSs. No grade 4 CRS occurred. Most commonly with this, it occurs after the cycle 1, day 15, or the third week dosing, and that is when you hit the highest dose, so the 60 mg dose. So 36% of the patients had CRS at this time frame, with the second highest incidence occurring after the very first dose. The median time is within 24 hours of receiving the dose, and then the median duration of CRS is three days.

Treatment for CRS often involves patient monitoring. Treatment can include corticosteroids, tocilizumab, or both. Other common toxicities included fatigue, headache, neutropenia, and fever.

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MorningSun: Subcutaneous Mosunetuzumab in Patients With Previously Untreated FL

This has also been evaluated in numerous other studies, both alone and combination therapies. We will just highlight a few different studies for each of these.

So the MorningSun study was a study conducted in previously untreated follicular lymphoma, and this used a subcutaneous mosunetuzumab. This was a multicenter Phase II study that enrolled a little over 100 patients with treatment-naive follicular lymphoma. This did cycle one step-up dosing with the sub-Q formulation. Now the sub-Q has a ramp-up as well, but the dosing is a little bit different.

So it does 5 mg day 1, 45 mg day 8, and then 45 mg day 15, and continuously same treatments as far as 8 for patients achieving a CMR, and 17 for those patients with a partial response. The primary endpoint of this trial was progression-free survival at 24 months.

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MorningSun: Baseline Characteristics of 1L FL Cohort

These are the baseline characteristics of the patients. Pretty well balanced across, or most commonly what we see for patients getting treated for follicular, most have advanced-stage disease. About half had bulky disease and half did not.

FLIPI was largely about 75% had a FLIPI of 2 or higher, with about half of patients being 3 or higher.

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MorningSun 1L FL Cohort: Response With Mosunetuzumab SC Dosing

This shows overall responses, including those across different treatments.

So as you can see, it was a fairly high overall response rate in these patients, with the majority of responses being 80% or more overall response rate, with 60% or higher complete response rate. There is a little bit lower response in patients who had some higher-risk disease factors, including high FLIPI 3-5 and elevated LDH, but fairly effective in this population in the frontline setting.

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MorningSun 1L FL Cohort: PFS With Mosunetuzumab SC Dosing

In terms of progression-free survival, the median PFS was not reached, with the 12-month PFS being a little over 80%. We need longer follow-up of this cohort of patients to determine the efficacy of this in the frontline setting.

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MorningSun 1L FL Cohort: Safety With Mosunetuzumab SC Dosing

This shows safety. As you can see, a little bit different in terms of the timing of the CRS. So any grade CRS occurred in 34% of patients, which is a little bit lower than what we saw with the IV formulation. All was grade 1-2. Largely, these were grade 1.

The median time to onset here is two days, with a median duration of 2.5 days. As you can see, the highest risk of this occurred after the cycle 1, day 1 injection, and then the rate decreased over time. So mostly all grade 1 and resolved.

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Epcoritamab

Now we will shift and talk about epcoritamab, which is the second approved CD20xCD3 bispecific antibody in relapsed/refractory follicular lymphoma.

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Epcoritamab: SC and Continuous

So epcoritamab, previously different from mosunetuzumab, is only approved in a sub-Q formulation, and it is continuous.

Mosun was IV and fixed-treatment duration. Epcoritamab subcutaneous and continuous. Epcoritamab scheduling, it also has a ramp-up in the first cycle, with a little bit different to get to the targeted dose, and then cycles for this are 28 days versus the 21 days of Mosun.

So interestingly, epcoritamab was initially approved in relapsed/refractory large cell, and there was actually a three step-up dosing, and hospitalization was recommended. But then they did an optimization cohort in follicular lymphoma and found that if you added an additional step-up and did three step-up dosing versus two step-up dosing, that you actually decreased the risk of cytokine release and do not need the hospitalization in that situation. So this again in follicular is given with a three step-up dosing, day 1, day 8, day 15, and then you hit your target dose on day 22 with 0.16 mg, 0.8 mg, 3 mg, and 48 mg being the dosing.

This continues to be given weekly for cycles two to three in the single-agent study. So it is weekly for the first three cycles at the 48 mg dose. And then cycles four through nine, it is given biweekly. And then after cycle nine, so cycle 10 and beyond, it is just given once a month. So a little more intense treatment schedule for this one.

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Epcoritamab: Early Experience

So looking at the early trial results for this.

So from the EPCORE NHL-1 study, this is a single-arm dose escalation and expansion study for patients with B-cell lymphomas. So this was enlarged B-cell lymphoma. Again, this was its first approval. So, an aggressive lymphoma had a response rate of a little over 60%, with 40% of patients achieving a CR, and median PFS of 4 months, median duration of response of 15 months, and median overall survival of 18 months.

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Epcoritamab in R/R Follicular Lymphoma

In terms of relapsed/refractory follicular lymphoma, where it has got its second indication, this showed response rates of a little over 80%. So overall response rate in the follicular population was higher, 82% ORR, with the majority of those 63% achieving a complete response and the 18-month PFS being about 50%. As you can see, similar to what we saw with mosunetuzumab for those patients who achieve a complete response, they actually have fairly durable responses with top, in blue here, being the PFS curve for those patients who achieved a CR, which again is about two-thirds of the patient population.

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[00:27:38]

Epcoritamab: CRS and ICANS in R/R FL

So now looking at the cytokine release with the epcoritamab. So this first slide looks at the DLBCL population. And again, this was with the two step-up dosing, not the three step-up dosing.

So a little over half of patients did have CRS. The majority were grade 1 and grade 2, with about a third of those being grade 1. But there were a few grade 3 events. Median onset from the first full dose was 20 hours. So right in that one-day range with the median duration of two days.

Now, if you look at this, the timing here is also when they hit with the two step-up dosing, the first highest dose. So the majority of the CRS occurred in week three when they hit the 48 mg dose with the two step-up dosing.

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Epcoritamab in R/R FL: Safety in the Pivotal vs Optimization Cohorts

Now, as I mentioned, they did this optimization cohort where they did the three step-up dosing. So they added the second intermediate dose of 3 mg to be administered on day 15. And as you can see, this improved the rate of CRS with 65% of patients in the follicular having CRS with the two step-up dosing and 49% having CRS with the optimization with the three step-up dosing.

And as you can see, all of the ones in the optimization cohort of the three step-up dosing actually were grade 1/2 and there were no grade 3 in this. And this was therefore recommended as the treatment step-up for follicular lymphoma.

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EPCORE FL-1: Trial in Patients With R/R FL

The EPCORE FL-1 study is a study in patients with relapsed/refractory follicular lymphoma. This was a randomized study that actually just recently reported out. So a global multicenter Phase III trial looking at patients with one or more prior lines of therapy with relapsed/refractory follicular lymphoma, and they were randomized to treatment with rituximab-lenalidomide based on the augment schedule or rituximab-lenalidomide with the addition of epcoritamab with primary endpoints of overall response and progression-free survival as assessed by the independent review committee.

So this trial again was just presented and did meet its primary endpoint. There was a significant improvement to adding epcoritamab to the R² regimen. And this actually has just led to an approval in the relapsed/refractory setting.

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Epcoritamab + Lenalidomide in Previously Untreated FL

So in addition to efficacy in the relapsed/refractory setting, there has been interest in moving this forward to frontline and treatment. So we saw the frontline data looking at single-agent mosunetuzumab and there are ongoing other studies evaluating that in frontline and combination.

So they have looked at epcoritamab in combination with lenalidomide and previously untreated follicular lymphoma. There is a lot of interest in trying to eliminate the use of chemotherapy in the frontline setting in follicular lymphoma. So this is a multicenter single-arm Phase II trial taking patients with treatment-naive follicular, and treating them with lenalidomide at a dose of 20 mg and then epcoritamab, and this is a defined treatment time, so this gives treatment for one year.

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[00:31:48]

Epcoritamab + Lenalidomide in Previously Untreated FL: Baseline Characteristics

These are baseline characteristics of patients treated on this trial. About half had bulky disease, similar to the last. The majority of patients had a FLIPI of 2 or higher with a over half having a FLIPI of 3-5, median age of 60. The majority of patients are advanced-stage disease.

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[00:32:18]

Epcoritamab + Lenalidomide in Previously Untreated FL: Safety

Safety. The median number of cycles given was 10 with a little under half of patients requiring a dose reduction in Len and a little under a quarter requiring a dose continuation of lenalidomide.

Most common toxicities: cytopenia, neutropenia, anemia, thrombocytopenia. You can see CRS occurred in a little over half of patients, with the majority being grade 1 or grade 2.

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[00:32:56]

Odronextamab

Now we will switch and talk about odronextamab. Again, this is not an approved bispecific antibody for follicular lymphoma or large cell lymphoma in the U.S. However, it did get an indication in the EU.

This also targets CD20xCD3.

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[00:33:18]

ELM-2 Trial: Odronextamab Monotherapy in R/R B-NHL

So the ELM-2 trial, which led to its indication in the EU, odronextamab monotherapy in relapsed/refractory B-cell NHL. So relapsed/refractory after two or more prior lines of therapy. This is also given on step-up dosing to mitigate the risk of CRS. This is also IV. It is given as 0.7 mg on day 1/day 2, 4 mg on day 8/day 9, and then 20 mg on day 15 and 16 cycles 2 through 4. It is given three times in a row, three weeks in a row at 80 mg, and then it is given at 160 mg every two weeks and then every four weeks if a CR.

Primary endpoint of this trial was overall response.

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ELM-2: Baseline Characteristics

Baseline characteristics of patients on this trial: a large number of advanced-stage disease, high-risk FLIPI, about half were primary refractory, and about 40% double refractory. So a high-risk patient population.

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ELM-2: DoR and DoCR

The overall response rate of this was 80%, with a complete response rate of 74%. The median duration of response was 26 months, with a median duration of complete response of 32 months. Again, you can see patients who achieved a CR. There were some fairly durable responses with a 36-month duration of complete response in just under half of the patients.

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ELM-2: PFS and OS

This looks at the median progression-free and overall survival.

The 24-month PFS was 50%, with a 24-month OS of 70%. For those patients who achieved a complete response, they did have better outcomes, with some of these being, again, durable responses.

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Odronextamab: CRS & ICANS

So this shows the CRS in patients who received odronextamab. So this occurred in about 50% of patients. The majority were grade 1, with almost all being grade 1/2, but there were a few grade 3.

A little bit more consistent across the cycles, but the highest rate did occur at the intermediate dose of 20 mg. Median time, again, a day, and median time to resolution, two days.

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Odronextamab: Cumulative Infections

This shows the rate of cumulative infection. So we do know that infections can be a concern with bispecific antibodies, particularly viral infections because of the B-cell depletion that can occur with treatment and then for a prolonged time in some cases after treatment. So you can see, as time goes on, even past patients being treated with these, there are incidences of infection.

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A New Piece: Surovatamig (AZD-0486)

So now we are going to switch gears a little bit and talk about surovatamig, which is a bispecific antibody that actually targets CD19. So this is targeting the T and B-cell, but CD3xCD19, so different than the currently approved bispecific antibodies. We currently do not have a CD19 bispecific antibody approved. However, we do have several therapies, including CAR T-cells, tafasitamab and Lonca, which all target CD19 in different ways.

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Surovatamig (AZD-0486): Double Step-up Dosing

So this drug is also given in a step-up dosing. So they evaluated it in step-up dosing with fixed dosing, single step-up, and double step-up dosing, and found the best safety and tolerability with this double step-up dosing.

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Surovatamig (AZD-0486): Efficacy in FL

This shows efficacy in follicular lymphoma in the Phase I trial. So this has shown very high response rates and very high complete response rates, with the majority of patients with follicular lymphoma have responded to this therapy, the majority achieving a complete response, including patients who have progressed after CD20 bispecifics, and then a population of patients progressing after CD19 CAR T-cells.

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Surovatamig (AZD-0486): Efficacy in FL

So this is ongoing in numerous clinical trials, given its promising efficacy. There is an ongoing monotherapy Phase I and then Phase II trial in both relapsed/refractory follicular lymphoma and aggressive lymphoma. And then there is actually a Phase III frontline trial combining this with rituximab in follicular lymphoma.

So probably more to come on this in the future.

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Piecing Together the Administration of Bispecific Antibodies

So now, talking about the administration of these agents.

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Before You Start Bispecific Abs

So thinking about when we are going to start a bispecific antibody, very efficacious agents, but do have unique toxicities, some toxicity similar to what we see with CAR T-cells, although not usually the number of patients or the grade of like CRS and ICANS is much less common with these. But we think about this in kind of three parts.

What is the facility need for administration? What does your team need to be able to administer this? And what about resources for the patient?

In terms of facility, we want to ensure that patients, we have approval for these agents. That they have a supportive care plan, including antibiotic prophylaxis, often need IVIG, and then ensuring that there is availability of Dex and tocilizumab if they were to have CRS, requiring that. They need to either be at your facility or within a distance of a facility where they have the access to the tocilizumab, and the staff has to be trained on when and how to administer this.

Discussing a plan for how grade 1 CRS is going to be handled and how this can be escalated. So ensuring there is a plan for when patients have fevers, what number do they call, who addresses it, how are they monitored, and what happens if they need escalation.

So training, multidisciplinary approach, the physicians, the APPs, the nurses, the triage, the emergency department, the immediate care, the inpatient teams, and even the ICUs.

And then patient resources. So making sure that the patients are able to monitor for this. They have a thermometer, some will wear devices to help with blood pressure, pulse ox, and heart rate. Ensuring that they always have the number to call when there are issues that they know where to present with any issues. And oftentimes we actually give them a prescription of steroids for them to fill and have on hand so that they can get early access after speaking with us to take that dexamethasone for symptoms.

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Consensus Recommendations on Managing Toxicities from Bispecific Antibodies for B‑Cell Lymphomas

There are consensus recommendations on managing toxicities for bispecific antibodies, including monitoring and assessing for both cytokine release, which is much more common, or neurotoxicity, which we more commonly see with the CAR T-cells, but there is a small number of patients that are reported to have this.

So we want to make sure when we are thinking about treating a patient that we are thinking about their availability of resources, their access to getting somewhere if they need to be evaluated. Do they have a caregiver, or are they able to monitor for symptoms themselves? That we are educating their patients and our teams. Again, in follicular lymphoma, these are able to be given all in the outpatient setting, but it is a consideration for higher-risk patients who are in aggressive lymphomas with inpatient administration on the doses that are at highest risk for CRS. That for patients, they have a good monitoring and a good number to call if they have any issues, how they are assessed when they do have issues.

For low grade, is there a virtual assessment by phone or video? Do patients come in? Where do they present to? We try to keep our patients out of the ER unless they are in critical need of that. And then how are they further monitored, or if their symptoms escalate?

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[00:43:20]

Bispecific Antibody Therapy-Associated Toxicity

So this just reviews, in addition to the risk of CRS or some risk of neurotoxicity, we can also see other things. Cytopenias, we get infection, particularly again, infections related to the B-cell depletion can also see neutropenia, which can lead to infection. There is a risk of tumor lysis with these agents, and there is actually a risk of tumor flare with these agents where you can see more commonly an aggressive lymphoma, but where you can actually see what appears to be progression or growth before patients start to respond.

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Cytokine-Release Syndrome

So cytokine-release syndrome, this is the grading for cytokine release with the bispecific antibodies. The majority of these are early grade, but grade 1 CRS is defined by fever. Patients can also have other constitutional symptoms.

Grade 2 CRS is defined when those patients also experience hypotension or hypoxia. So hypotension requiring fluids, hypoxia requiring oxygen, or other organ toxicity.

Grade 3 is hypoxia requiring higher doses of oxygen, hypotension or shock requiring vasopressor support, and then grade 3 organ toxicities and grade 4 requiring mechanical ventilation. Again, the large majority of CRS with these bispecific antibodies is grade 1 to grade 2 with very few cases of grade 3 CRS reported, but that can happen.

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Bispecific Antibodies-Related CRS and ICANS

So thinking about presentation, timing, and then severity. So for CRS, again, the more common thing that we see: fevers, but also can be chills, low blood pressure, hypoxia, confusion, skin rash. This most commonly occurs within about a day after the infusion, but usually can happen anywhere between a few hours after infusion to two days after administration.

So fairly not immediately after infusion, but not days or weeks either. So in that time frame. It does depend on the agent that is used. This generally resolves within 1-3 days.

This most frequently occurs and has the greatest severity during cycle one. We have seen that the step-up dosing helps in part mitigate the risk of CRS, but still is there for many of them when you reach the highest dose, but then also when patients are treated with that first day of infusion. Rarely, this is not really something we see in later cycles.

ICANS may differ from CAR T-related ICANS. Probably we would say not as well understood as the CAR T-related ICANS mechanisms. This is rare, often self-limited, but should be aware of it if a patient is coming in.

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[00:47:06]

Guideline on Toxicity Management: CRS and ICANS

So looking at then planning initiation of these. So clinical care needs clear protocols both for evaluation and management of CRS and ICANS. We know that for patients that do have ICANS, most oftentimes these are patients that have CRS as well. There are more in aggressive lymphoma, but times that you will treat the patient in the inpatient and monitor them for 24 hours after they receive the dose at which is associated with the highest risk of CRS.

We know that early intervention can prevent progression to worsening cases. And that is why that plan for the facility, the provider, and the patient is so important to identify these early and treat them early to hopefully delay progression or worsening. Again, oftentimes we provide these patients with a prescription of dexamethasone to have at home so that they can take it prior to coming in for evaluation. Sometimes they can be monitored at home, depending on the patient and the symptoms that they are having.

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[00:48:26]

CD20 Bispecifics: CRS Mitigation Strategies

As far as mitigation strategies, there are several strategies to mitigate. The step-up dosing; the pre-medications; they are given steroids before.

Epcoritamab has four days with the first month of infusions where patients get steroids with treatment and after treatment. More common in large cell is hospitalization to monitor during the high-risk period. And then, as we saw with mosunetuzumab, a subcutaneous formulation was recently approved with lower CRS and lower-grade overall of the CRS.

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[00:49:10]

Recommendations: CRS Mitigation Strategies

So this is just the specific mitigation strategies. We already talked about the dosing for these, and then this goes through premedications for each of these agents.

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Grade 1 CRS: Management

So management of CRS. So grade 1 CRS can sometimes be managed as an outpatient or at home versus coming in and being evaluated either in the inpatient or an observation center. This can depend on the patient, their comorbidities, and how close they are. There are patients that can be treated at home if they have a good ability to monitor, stay orally hydrated, and come in if they are worsening.

There is, you know, considering again early administration of steroids to mitigate worsening CRS. If grade 1 CRS persists, then that is when you may consider the use of tocilizumab.

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Grade ≥2 CRS: Management

Grade 2 CRS, it is recommended that these patients come in and are being monitored in an inpatient setting, treated with steroids, fluids, oxygen as needed, and the use of tocilizumab. And then, grade 3 and grade 4, more urgent with tocilizumab and advanced ICU-level care.

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[00:50:48]

Recommendations on Neurotoxicity Management

Neurotoxicity. This is less common, but again, we want to be cognizant that it can happen. Perform the neuro assessment on patients, including the ICE scoring and then ensuring that they are evaluated, consideration: CT, MRI, EGLP, if this is worsening or not getting better, and making sure that we are ruling out other causes of neurotoxicity or neurologic problems.

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[00:51:26]

Recommendations on Neurotoxicity Management

And steroids are the primary use and management for neurotoxicity, grade 1 and grade 2, and then, of course, escalating care for more advanced neurotoxicity.

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[00:51:46]

Practical Guidance for Late Toxicity

Then thinking about while we are treating and later toxicity. We know that patients can have this B-cell aplasia during treatment, and for some, it is prolonged. So thinking about recurrent infections, monitoring IgG levels, and IVIG replacement. GCF can be used as needed. Thinking about prophylaxis, we prophylaxis patients for both antiviral and PJP. And then consideration of vaccination, ideally before you start these agents, if you have an opportunity to do that.

Next slide.

[00:52:24]

Now, let's go back to some of our questions

Now, let us go back to the questions.

Next slide.

[00:52:30]

Posttest 1: Which of the following best describes the mechanism of action of the bispecific antibody odronextamab which leads to cytokine release and tumor cell lysis?

So we have, which of the following best describes the mechanism of action of the bispecific antibody odronextamab, which leads to cytokine release and tumor cell lysis? So this is, remember, binding to:

1. CD3 and CD19;
2. CD3 and CD20;
3. CD8 and CD19;
4. CD8 and CD20.

Speaker: And the poll is open. Please vote in just a few more seconds for incoming answers. And here are your results.

Dr. Maddocks: Okay, so this binds CD3 and CD20. So remember all the approved ones in odronextamab target CD20. The AstraZeneca compound is the only one which is not currently approved that targets CD19. They all bind to CD20 once, except glofitamab.

[00:53:50]

Next slide.

[00:54:02[

Posttest 2: A 70-yr-old man was diagnosed with follicular lymphoma. He achieved a remission with rituximab + bendamustine, but 18 months later, he relapsed. He then achieved partial remission with rituximab + lenalidomide. He relapsed again after 12 more mo. His ECOG PS is 1 and has no other comorbidities. What bispecific antibody would you recommend that is FDA approved for use in FL?

So a 70-year-old, this is our gentleman who got BR and relapsed and got R² and then relapsed again. And we are asking what bispecific antibody we would want to use to treat his follicular lymphoma in the third line.

1. Glofitamab;
2. Mosun;
3. Odronextamab; or
4. Tafasitamab.

Speaker: And this poll is open. Please vote. And we will give everybody a few more seconds to submit their response. And here are your results.

Dr. Maddocks: Okay, everybody said mosunetuzumab.

[00:54:58]

So this is the agent that is FDA-approved for relapsed/refractory follicular lymphoma. Remember, glofitamab is only for a large cell lymphoma. Odronextamab is approved in the EU. And tafasitamab is a CD19 antibody, not bispecific antibody.

[00:55:12]

Posttest 3: In talking with a patient with R/R FL, which of the following would you tell them is the typical timing of cytokine-release syndrome onset after the first infusion of a bispecific engaging therapy?

And our last posttest question. This is related to the timing of cytokine release. So what is the typical timing of CRS after the first infusion of a bispecific engaging therapy?

1. One hour;
2. 1-2 days;
3. One week; or
4. One month.

Speaker: And this poll is open. Please vote. And just a few more seconds for incoming responses. And here are your results.

Dr. Maddocks: Okay. 100% of people said within 1-2 days, which is the correct answer.

[00:56:00]

The CRS onset usually happens within 1-2 days after the initial or highest-risk infusion with all of these agents.

So great. Everybody got that right.

[00:56:13]

Poll: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Speaker: And the poll is open. Please vote. We will give everybody a few more seconds on this response. And here are your results.

Dr. Maddocks: Okay. Half yes and half uncertain. Okay.

Speaker: And our last question.

[00:56:53]

Poll: Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

Dr. Maddocks: Please take a moment to enter one key change that you plan to make in your clinical practice based on this education.

Speaker: And again, this is the opportunity to scan this QR code to submit your response for us, or you can type in your response in this text box. And due to the fact that we are right at the top of the hour, I will go ahead and collect that information on the back end, and Dr. Maddocks, I am going to send you on to the next slide.

[00:57:20]

Thank You For Attending Our Program!

Dr. Maddocks: Okay. So thank you for attending our program. Scan this QR code to get the online evaluation and claim your credit.

Additional resources are available. There is an email if you are having any issues. And I think it looks like there is a few questions in the chat.

Speaker: There are. Can you see those?

Q&A

Dr. Maddocks: Yes. So the first is, how should we counsel patients regarding ICANS risk with bispecifics? So typically what I do is just talk to the patients that there are reported risk of different kinds of neurological toxicities and counsel them and their support, which essentially can be any neurological side effect. Make sure that if they notice anything off in the patient that they are immediately calling our on-call number for instructions and evaluation.

The other question is, are there patient comorbidity profiles that make bispecifics preferable over other regimens? When I think about this, in general, they are fairly well tolerated agents. I think we used to use probably more CAR T-cell therapy in follicular lymphoma when it was first approved for those patients with higher-risk disease features or earlier progression. I think when we think about patients, these can be given in patients who have more comorbidities. So I am thinking about using these probably earlier than that in other lines.

Considerations, you know, you do have to think about are there patients that have cardiac toxicity or will have a problem tolerating CRS if they have CRS. I think about, again, infectious risk and making sure I am giving appropriate prophylaxis in all patients. And then I would say another big thing which can often get missed is the IVIG.

So I frequently am giving IVIG in these patients through treatment or after treatment because of the risk of infection. But I think managing with CRS being the biggest risk, just thinking about their ability to tolerate that, those fevers, changes in blood pressure or oxygenation, and what support they need if those side effects do occur.