Why Target CD20 and CD3 in DLBCL?

Okay, great. Just to start, as a reminder, why are we targeting CD20 and CD3 in large B-cell lymphoma?

CD20 is a marker on mature B cells, malignant B cells, but not on stem cells or plasma cells, which is helpful in terms of reducing off-target effects. By the same token, it explains why, for example, we are not using CD20-directed therapy in plasma cell disorders. We also know that CD3 is present on mature T cells. In binding CD3 lead to activation of the T cells and then cytokine released and cytotoxic activity which ultimately leads to cell death.

The thought is that dual targeting can help overcome resistance that we often see with our CD20 monoclonal antibodies, such as rituximab and obinutuzumab.

Bispecific Antibodies: Antibody With Single-Chain Variable Fragments Targeting a T-Cell and a Tumor Cell

Bispecific antibodies again are designed to recruit T cells to enhance cell killing essentially. One arm of the bispecific molecule binds to the tumor antigen, in this case, we are talking about CD20, while the other arm targets T cells, which would be via CD3.

Then once bound, you develop a synapse releasing things such as perforin, granzymes, etc., that lead to this cytokine release and cell death.

Poor Outcomes in Primary Refractory and Early Relapsed DLBCL

We do know that, in general, primary refractory and early relapsed patients with large B-cell lymphoma do poorly. The curve at the bottom is just showing some of the data from the SCHOLAR-1 study that looked at primary refractory large B-cell lymphoma and the response to salvage.

As one of the questions alluded to earlier in the polling, about 60% of patients or so do go into complete remission with their upfront treatment. However, 30% to 40% will ultimately require a second-line. Patients with primary refractory disease, which we define as persistent or recurrence in less than 12 months, have a particularly poor prognosis, as you can see in the curves on this screen.

The Shift Away From Cytotoxic Chemotherapy as the Standard of Care in R/R DLBCL

In general, we have really been trying to shift away from cytotoxic chemotherapy and lots of different hematologic malignancies, in particular large B-cell lymphoma. As many know, CAR T therapy has now become the standard of care for second-line treatment based on two different studies. So the ZUMA-7 study, which was looking at axi-cel or Yescarta compared to standard of care autologous stem cell transplant, and the TRANSFORM trial which was comparing liso-cel or now commercially known as Breyanzi to standard of care auto transplant.

Both of those showed an improvement in the CAR T arm. The overall survival benefit was seen only in the ZUMA-7 study thus far, although the TRANSFORM study did allow crossover from the standard of care to the liso-cel arms. That could be the reason we have not seen overall survival benefit.

For now, for anyone who has relapsed disease, they typically are headed to CAR T rather than the standard would be salvage chemotherapy and autologous stem cell transplant.

Which Patients Are Eligible for Bispecific Antibody Therapy?

When we are thinking about bispecific antibodies, which patients are eligible? There are patients who are not eligible for CAR T. I mean it is quite rare these days because CAR T is much better tolerated than autologous stem cell transplant. You can see in the table here some of the typical eligibility guidelines we use.

Typically for patients over 70, we are not offering an autologous transplant even before the CAR T data emerge. For CAR T and bispecific, really there is no set age limit. We have given CAR T to patients up in their upper 80s even. Performance status people, and for getting a transplant historically need to be a zero or one, whereas CAR T and bispecific patients can have a poorer performance status than that.

Then we do take into account certainly comorbidities when making decisions. Then one big difference is that when we are looking at patients for CAR T or bispecific, we take them right for those therapies without waiting for a response, typically.

Then in a very important caveat at the end, in terms of logistical, as of right now, patients who are eligible for a transplant or CAR T really need to go to a big academic center, whereas now with the advent and approval of bispecific antibodies, that is not necessary, and again, why it is really important that we are getting these out into the community.

How to Appropriately Sequence Bispecific Antibodies With Other Available Therapies for DLBCL?

How do we sequence bispecific antibodies and CAR T and whatnot? Typically, if a patient has had two or more prior lines of therapy, they get referred currently to like an academic center most commonly. Now if the patient already had CAR T that will play obviously a role in which next line of therapy they would be considered for, or if they have other comorbidities that may preclude them from getting CAR T therapy. Specifically, I mentioned that because we do have patients who are coming for us for CAR T.

I just saw a patient last week who has no caregiver at all, and so therefore was deemed ineligible for CAR T but is eligible for a bispecific antibody.

If a patient already had CAR T, of course, that would also make them ineligible for that therapy and a bispecific antibody would be a good treatment. Then when patients in general have progressed on anti-CD20 treatment such as bispecific antibody or CAR T is no longer an option, then we are going back and using some of those other salvage therapies that we have like chemoimmunotherapy options, CD19 monoclonal antibodies such as tafasitamab or CD19 antibody drug conjugates such as loncastuximab.

Ensuring Safe and Equitable Access to Bispecific Antibodies

While these bispecific antibodies are very promising, there is a lot of questions that remain and we will talk about some of these things. Certainly, we still do need enrolment in clinical trials, even though we have approvals for these. Certainly, we do not quite know yet which subset of patients may benefit the most. We do not know when it is best to incorporate them in the patient's treatment journey.

Currently, they are approved more in the relapsed/refractory setting, but ongoing trials that we will mention are incorporating these earlier lines of therapy. Then again, better ways to prevent and manage toxicity. Access does still remain an issue, with most of the bispecific, you still coming to larger cancer centers, albeit academic or larger community programs.

It is really important to develop safe ways to administer these therapies, monitor for toxicities and ensure equal access. So ongoing partnership with larger centers and community offices is definitely needed and is a topic at a lot of different meetings discussing these therapies.

Highlighting the Patient Voice: Patient-Reported Barriers in Treatment Decision-making

It is also important to think about what the patient wants. I am not going to read through these quotes. But you certainly have patients, in the orange that say, “Whatever you say, doc, I trust whatever you say, I will do it.” Other patients say that, “Well, I wish I had known about X, Y, Z type of side effects, maybe I would not have chosen that treatment.”

Then we often have patients who have never even heard of some of these therapies or they are sent in. But partly due to lack of education at some of our community sites, there is not as much known about them. So patients have not heard a lot about them.

On the other hand, we do have patients who are very educated, finding a lot of information on the internet and come ready with lots of questions.

InterACT Discussion Questions

Some things we will hopefully touch on given the current landscape, how do these existing unmet needs shape the trajectory of patient care and therapeutic innovations. Then certainly, how can our care teams integrate the patient goals and preferences into the treatment recommendations? Because we often are thinking about comorbidities, disease factors, but we are not always thinking about what is best for the patient, their quality of life, etc..

Centering the Patient: Effectively Integrating Key Findings for Bispecific Antibodies Into DLBCL Clinical Practice

Treatment with Bispecific Antibodies Is an Evidence-Supported Option After Failure With CAR T-Cell Therapy

Just to review some of the trial data in general. You can see there is a couple of more, I would not say traditional, but chemotherapy, chemoimmunotherapy types of options on here as well. There are Pola-BR regimen, loncastuximab as I mentioned, and tafasitamab-lenalidomide. Those are three studies that are also options certainly for patients with relapsed/refractory large cell.

Then at the bottom, you see some of the response rates and whatnot, for epcoritamab, odronextamab and glofitamab, which we will be talking about and these response rates as well.

Generally, we are seeing higher response rates with a lot of the bispecific antibodies. We still have work to do, and we will start to see higher response rates when we shift these earlier in line as well.

Bispecific Antibodies Approved or in Development for DLBCL

We will talk a little bit about each of these bispecific antibodies. Just to note, and you can see on this slide here, there are differences in the structure of these, which also leads to differences in how they are administered.

The first we will talk about is glofitamab, which is commercially known as Columvi. This is an IV infusional bispecific antibody. It is currently approved in the third or higher line setting. This is why we often see patients after they have already had CAR T.

As you can see, as we talked about, this has a CD20 binding domain and then CD3 binding domain as well.

Glofitamab in R/R DLBCL: Study Design

The first trial to mention was a single-arm phase II expansion trial. I am not going to go through the criteria, but essentially it was large B-cell patients who had two or more prior lines. All patients who get glofitamab do get a debulking dose of obinutuzumab. So a CD20 monoclonal antibody. That is really designed to decrease the circulating disease burden in preparation for the glofitamab and help to mitigate some of the toxicities such as CRS.

Then on day eight, patients get a small dose of glofitamab, and then a higher step-up dose on day 15. Then moving forward onto cycle two, the dose goes up further to 30 milligrams.

Importantly with glofitamab, it is a time-limited therapy, so patients get up to 12 cycles. Cycles are given every 21 days. For many of our patients, this is very familiar because they are used to the 21-day cycle of R-CHOP that they had in the frontline setting.

Glofitamab in R/R DLBCL: Durability of Complete Responses

When looking at responses, overall response rate is quite high. Then you can see that 40% of patients actually went into a CR. Then you can see the duration of complete remission for those who achieved complete remission in the graph on the right.

Certainly, while over half of patients did not achieve long lasting remission, these are much higher response rates than we have historically seen with our traditional therapies.

The median duration of complete remission was about 19.8 months to not evaluable.

Glofitamab in R/R DLBCL: PFS and OS Landmark Analyses by Response at Cycle 3

In the landmark analysis based on response, and this is at cycle three. What these graphs really are just trying to illustrate is that those who go into remission early on do the best. I do not think this is surprising to anybody, but people who achieve CR by cycle three really do the best. There is a tail end of the curve here as you can see. We have about a little over 40% of patients are long-term patients in remission at the time of this data cut-off. The responses to the bispecific antibodies are quite rapid.

Glofitamab in R/R LBCL: Immune Recovery and CRS

How about immune recovery and cytokine release syndrome? With regards to immune recovery with B cells, when you are looking at end of treatment, it does take time to recover the B cells. This is not surprising given that we see the same type of thing with rituximab for example. As patients are going on through their treatment, it is important to remember this because you need to pay attention to potential risks of infection and whatnot, even when they are done with therapy. You can also see the recovery in the IgG levels as well.

In terms of CRS, which is what a lot of people are concerned about, there is certainly a risk of CRS, although the risk of high grade CRS is actually quite low. You can see in this study, only 2.6% of patients got grade 3 or higher CRS.

If you look in the bar graph down in the right, by and large, the cytokine release syndrome happens with cycle one. We do see some patients who get grade 1 CRS in cycle two, but that is quite rare. Then when you go out to cycle three and beyond, it is really rare. That is why for the most part a lot of centers have start doing the initial dosing at one of their main or larger sites. Then once patients are doing well and they are on to their subsequent cycles, they can go out to the community office to get further treatment.

STARGLO: Glofitamab + GemOx vs Rituximab + GemOx as Second-line Therapy for R/R DLBCL

Of course, after we had the single-agent data, as with anything in oncology, we are now looking at ways to combine these novel agents with other treatments. So glofitamab plus GemOx versus rituximab GemOx was this trial designed for the STARGLO study. This was for second-line treatment for relapsed/refractory large cell.

The primary endpoint in this study was overall survival.

STARGLO: Baseline Characteristics

Just to show some of the baseline characteristics. There were quite even in each group, I would say. There were a little bit of higher risk patients by stage III/IV and IPI in the R-GemOx arm, but not a big difference there.

STARGLO: PFS and OS

When you look at the progression-free and overall survival, patients who were in the glofitamab-GemOx arm did better than those in the traditional R-GemOx arm, which these were both statistically significant as well.

STARGLO: Safety; CRS and Other AEs of Interest

In terms of CRS and other adverse events of interest. Certainly, you can see in the bar graph, there were some patients who had CRS, but by and large, it was grade 1. There was some grade 2 CRS as you can see. But really low numbers of grade 3 or higher CRS, which is the CRS that we are really concerned about where patients are needing ICU, care pressors, etc..

With regards to ICANS or the neurologic adverse events, really low numbers of patients who had grade 3 or higher ICANS. We do see infections with bispecific antibodies in general. You can see that there was a higher rate of infections with the glofitamab arm than the rituximab arm. Also a higher rate of grade 3 or higher neutropenia.

Importantly, despite those differences, relatively very small numbers of patients actually had febrile neutropenia. It was more just seen on lab review.

Glofitamab: Key Ongoing Trials

Some key ongoing trials for glofitamab. There is a SKYGLO trial that is now looking at incorporation of glofitamab in the frontline setting with Pola-R-CHP versus the Pola-R-CHP regimen. Then there is ongoing studies also in relapsed/refractory setting using glofitamab alone versus glofitamab-obinutuzumab and then also glofitamab plus checkpoint blockade, so atezolizumab and polatuzumab.

There is another study in untreated large B-cell lymphoma, which is using a response adapted approach for patients.

Bispecific Antibodies Approved or in Development for DLBCL

What about epcoritamab? Glofitamab and epcoritamab have been the most commonly used thus far. Certainly, they are approved in the United States. Epcoritamab is a sub-cu formulation so different than the glofitamab.

EPCORE NHL-1: Epcoritamab in Patients With R/R B-Cell NHL

One of the key registrational trials was the EPCORE NHL-1 study. This is looking at the dose expansion phase II cohort, similar population to the glofitamab study. The step-up dosing is a little bit different for epcoritamab as you can see again, all sub-cu. There is not the debulking phase with obinutuzumab. However, throughout development of epcoritamab, there have been adjustments to help mitigate CRS, including corticosteroid prophylaxis and adjustments in how the step-up dosing has been.

You can see that with epcoritamab, the dosing starts off weekly for the first few cycles, then goes to every two weeks and then goes to every four weeks. So similar to a strategy that we use in other things such as daratumumab or darzalex for myeloma.

Now, one important difference is that epcoritamab, as of now, we continue indefinitely until progressive disease or unacceptable toxicity.

EPCORE NHL-1 3-Yr Follow-up: Patient Disposition and Exposure

Looking at three-year follow-up of patients, the median number of treatment cycles was 12 in this patient population. Then in terms of those who discontinued treatment, the most common reason was for progressive disease, although there were some patients who discontinued due to adverse events.

EPCORE NHL-1 3-Yr Follow-up: PFS and OS in Patients With CR

Looking at the three-year progression-free and overall survival curves, you can see here. Patients actually did quite well, as you can see, and this was across the different subtypes. They looked at patients who just had large B-cell lymphoma, those who were transformed from follicular, etc.

The progression-free survival really was not reached in those who achieved a CR. Then similarly, those in a CR had not been reached in terms of overall survival.

EPCORE NHL-1 3-Yr Follow-up: Long-term Efficacy Outcomes

In terms of median duration of CR, 36 months. This is quite impressive for a relapsed/refractory patient population. The vast majority of these patients had not progressed and needed a new line of therapy at that time.

EPCORE NHL-1 3-Yr Follow-up: Optimization

Then there have been, as I mentioned, some approaches on ways to mitigate cytokine release syndrome and other toxicities. After this optimization strategy that was incorporated as the trials moved forward, they saw even lower rates of cytokine release syndrome. This was mainly an optimization strategy that incorporated more priming doses and intermediate step-up dosings.

Then certainly with the first full doses, when we would typically see higher rates of grade 1 and 2 CRS. When you look at the first dose in the bar graph, patients who had this optimization strategy that they employed actually had much lower rates of grade 3 and higher cytokine release syndrome.

Just in summary, there is different strategies that people can use to mitigate toxicity, knowing that if we are going to move these out into the community, that is the approach that we will have to take.

EPCORE NHL-5: SC Epcoritamab + Lenalidomide in R/R DLBCL

As with glofitamab, the latest studies are looking at incorporation of epcoritamab with other agents, so epcoritamab plus lenalidomide. In terms of this combination, overall response rates were 72% with 53% achieving complete remission. The duration of complete response was quite high, as you can see in this middle figure.

Then you can see the swimmer's plot on the right also looking at patients who did respond. As the boxes highlighting here that a number of patients went on to achieve a complete remission even like later on, so responses can deepen over time.

EPCORE NHL-2: SC Epcoritamab + GemOx in R/R DLBCL

There is also data looking at subcutaneous epcoritamab with GemOx, similar to the other data that I showed the SKYGLO that was looking at glofitamab-GemOx in relapsed/refractory large cell. Then again, very high rates of PFS and OS among complete responders. The nice thing is you can see on the graphs on the right that these patients respond very quickly.

Usually, we are reassessing response at like the three-month time point. We know already how well they are doing because most patients do respond early to these therapies. So you do not have to wait for six cycles and whatnot.

Looking at overall response in this combination was over 80%. Then roughly 60%, I would say both by Investigator Assessment and Independent Review Committee assessment achieved complete remission.

Epcoritamab: Key Ongoing Trials

There are ongoing trials with epcoritamab as well. There is epcoritamab plus lenalidomide versus R-GemOx versus epcoritamab. Then there is also an epcoritamab versus R-GemOx or BR arm. Then as with glofitamab and many of our oncology therapies, we are now using these in the frontline setting. So combining epcoritamab with some of our standards, such as R-CHOP versus R-CHOP plus rituximab, and that already includes rituximab.

Bispecific Antibodies Approved or in Development for DLBCL

Odronextamab is approved in Europe. Again, another CD20/CD3 bispecific antibody.

ELM-2: Odronextamab in R/R DLBCL

This is their phase II study that led to that approval. Primary endpoint again was overall response rate. Similar to glofitamab, this is an IV formulation. Again, as with all the bispecific antibodies, there is step-up dosing to help mitigate toxicity.

ELM-2: Responses

Overall, response rates with this were like 52% with about 30% complete responses.

ELM-2: PFS and OS

Here are the PFS and OS curves. Again, it is a theme that the patients do the best are the patients who of course achieve a complete remission. The earlier you achieve that complete remission, the better. There seems to be in general a plateauing of response. Depending on the product, that plateau can occur at a different time point, so when talking about PFS is around 40%, 50% of patients long-term progression-free survival.

Then you can also see the overall survival curve on the right based on overall response. Similar to CAR T and other therapies, those who achieve a CR certainly do the best.

ELM-2: Safety and CRS

What about safety and cytokine release syndrome? In general, there were a fairly high amount or percentage of grade 3 adverse events. However, when looking specifically at CRS, the vast majority again was grade 1 CRS with some patients also having grade 2, but very low rates of grade 3 or higher CRS.

Odronextamab: Key Ongoing Trials

There is some key ongoing trials as well in untreated large B-cell lymphoma and then also in relapsed/refractory aggressive B-cell lymphomas.

Bispecific Antibodies Approved or in Development for DLBCL

Mosunetuzumab is currently being studied in large cell. Mosunetuzumab or Lunsumio is currently approved in follicular lymphoma.

SUNMO: SC Mosunetuzumab + Polatuzumab vs R-GemOx In Relapsed/Refractory Transplant Ineligible DLBCL

The SUNMO study was looking at mosunetuzumab plus polatuzumab versus R-GemOx in patients who were transplant-eligible large B-cell lymphoma. As on the previous slide, mosunetuzumab there is different formulations as well. This particular study was using a subcutaneous formulation.

SUNMO: Response Rates

In terms of response rates, quite high. This was the combination of mosunetuzumab and polatuzumab, which is on the left-hand side with over 50% of patients achieving a CR versus you can see only 24% of patients achieved a CR in the R-GemOx arm.

SUNMO: PFS

Then here is the progression-free survival curve as well.

SUNMO: CR

Then this is just illustrating the duration of CR for patients who achieved those CR rates.

SUNMO: Safety

With regards to safety, again, really low rates of grade 3 or higher cytokine release syndrome. You could say like 0.7% of patients, one patient had grade 3 or higher. That is important to note when we are looking at which therapy we are going to choose and whatnot.

Just in general, with the bispecific antibodies, the rates of cytokine release syndrome are generally lower with regards to grade 3 or higher CRS and ICANS, which is ICANS is virtually not seen with this product. So it is just important when we are talking about moving these things out into community sites, because many of us who have been involved with a lot of the CAR T work, everyone tends to get panicked about CRS and ICANS. But the rates are certainly much lower with these agents.

Mosunetuzumab: Key Ongoing Trials

Just some ongoing trials to mention with mosunetuzumab as well.

InterACT Discussion Questions

Certainly, there is lots of impacts as we move these things forward because then the next logical question that we do not know the answer to is, “Okay, well, what if we use these upfront? Then what are we going to do when patients relapse?” That is certainly a valid question that we get a lot.

Then in terms of using evidence based data, with one particular patient, there is lots of different things that play into it. Some patients, for example, may really want a time-limited therapy. If you are talking about a CD20 bispecific antibody, glofitamab might be a better approach for them. Whereas other patients really this kind of need for an infusion versus a sub-cu dosing which can have less chair time and less time in the cancer center may move a provider to choose a sub-cu formulation such as epcoritamab.

Certainly, we will be including bispecific antibodies in the frontline setting. We are just not quite there yet in terms of approvals and whatnot. Then again, as I mentioned, it leads to other questions about what would we do later on in those particular cases.

Managing Common and Severe AEs Associated With Bispecific Antibody Therapy in Patients With DLBCL

Just shifting gears a bit to the adverse events with the bispecific antibody.

How to Consider Bispecific Abs: Have a Plan

Most importantly, you need to have a plan, especially as we are just bringing these therapies into the community, which fortunately due to the approval of IMDELLTRA in lung cancer, this has really like moved this to the forefront of cancer care and really has pushed a lot of centers to start getting a plan in place to do this.

Certainly, each patient, you need to assess their risk based on their tumor burden, look at their comorbidities, caregiver support, etc.. It is very important to educate not only the patient but also the caregiver almost more important because they are the ones who are going to be monitoring for side effects at home.

Usually, what the ideal situation is that the patients get their drug in the outpatient setting, although I know that a lot of times currently at many centers, the first step-up dosing is actually done in the inpatient setting and then shifted outpatient. There is questions about if a patient is at home, what kind of monitoring should happen? How often should we be looking at vital signs and whatnot? How do we report that to the cancer center?

Certainly that is a different scenario than if a patient is inpatient. For patients who are going to do this outpatient, including the step-up dosing, how often should they be seen? This varies by center. We are actually formulating our plan right now based on some data and plans that we have some other centers.

Typically, due to the time frame of cytokine release syndrome occurring, usually depending on the bispecific antibody, it is usually within the first 24 to 48 hours after the dose. Most centers do have patients being assessed at the 24 and 48-hour mark.

Then if they are negative, then they go on and continue therapy. Certainly, there needs to be a plan in place if a patient is having any concerning symptoms, how to direct them. There needs to be easy communication to advise patients to go to the local emergency room. Or if you have a center that is set up for it, how to treat this outpatient, whether it be with a drug such as tocilizumab or there is other strategies that people use, like having patients have some dexamethasone at home, for example. So that they can take that at home at the first sign of any symptoms and then still come in for evaluation.

Discussion: Considerations for Managing Adverse Events

This just reiterates what I said. Of course, there needs to be a lot of planning involved. As more and more centers are starting to move these out into the community, it will be important for again, to have those partnerships with the main site and the community centers. There is always going to be challenges with new therapies. Those of us who are used to using, for example, like daratumumab or darzalex, it was quite challenging when it initially got approved. Now every cancer center gives it without a problem. We will get there as well with bispecific antibodies.

Assessment and monitoring is key and really a team-based approach incorporating our nurses, our advanced practice providers, etc., and then the afterhours triage for patients as well.

Then patient-reported improvements are key as well. A lot of the studies moving forward are really looking at patient-reported outcomes while on these therapies. As time goes on, changes will occur with regards to our management, very similar to what has happened with CAR T as we get better at managing things.

Consensus-Based Recommendations for Assessing and Managing Bispecific Antibody Toxicities

Are there strategies to mitigate safety and tolerability? Certainly, yes. Most of the bispecific antibodies do include a pre-medication such as corticosteroids because just as compared to CAR T, where we are worried about steroids being lympholytic and killing lymphocytes, the corticosteroids are not as much of a concern with the bispecific antibodies.

As I mentioned, just about all of the bispecific antibodies do have a priming or step-up dosing schedule, hospitalization certainly for CRS or toxicity monitoring. That occurs at a lot of centers. The step-up dosing is currently being done inpatient, although that is really shifting away now that there is just too many patients and hospital systems cannot incorporate that.

Monitoring patients very closely, especially those with a high tumor burden who are at higher risk for toxicity. Then depending on the severity, you need to make sure you have on hand strategies to target CRS. So specifically Tylenol and fluids, steroids. Tocilizumab is the big one that it is important that outlying centers and whatnot have on hand, which currently is not always the case, not even the cancer centers, but local hospitals and whatnot need to know how to treat patients.

Summary of Management of Bispecific Antibody-Based Adverse Events

For specific toxicity. For CRS, we have already mentioned supportive care, fluids for low grade CRS. Then with higher grade CRS, we are thinking about things like tocilizumab which targets IL-6. Then there is other strategies we use for higher grade CRS as well.

For neurologic toxicity, which can present anywhere from like a headache or tremor to aphasia, word finding difficulties, etc., certainly steroids are a mainstay. Then in patients who have refractory neurologic toxicity, anakinra which targets IL-1 and siltuximab is another IL-6 targeting agent. Then consideration of anti-epileptics as well.

Now again these toxicities are less common with the bispecific antibody. So it is just important. But it is important to have a strategy in place and some key players who really know how to manage the toxicity.

Cardiac toxicity can occur, with regards to like hypotension, etc.. Patients need to have availability of pressors if needed if they develop grade 3 or higher CRS. Then there are hem toxicities, in particular, cytopenias, etc., that may need to be managed as well.

CD20 Bispecific-Related CRS and ICANS

Just some bispecific-related CRS and ICANS. It can be any number of things how patients can present. Typically, CRS always starts with a fever. That is the first sign that you need to be thinking of CRS. Now at times there may be a patient who also might have an infection. Certainly you would want to consider that as well.

Usually CRS does happen within 12 hours to 48 hours after the administration of the dose. That is very important in terms of outpatient monitoring and determining who may be having CRS and not. Most frequently, the greatest severity is during cycle one, as I mentioned.

A lot of times the current approach for many places is that the initial step-up dosing, if you will, happens at one of the main, if not the main cancer center, a larger cancer center that has access to a hospital nearby, etc.. Rarely does it persist beyond cycle two.

Then with ICANS again, it can be a spectrum of side effects, although these are much less common and severe as we see with CAR T. Now the mechanism is a little bit unclear as well because these bispecific antibodies are not expected to cross the blood-brain barrier versus like CAR T cells, which can. So the mechanism may be very distinct, but that is why we are not seeing it as much.

Improving Management of CRS in Patients Treated With BsAbs

Again, this slide just speaks to the importance of education. Really developing a partnership approach where you have some key players that you know at a larger center who are very familiar with treating. That way there is somebody always ready to help for a community site, and that is what we are trying to do even at our own center, it is have some champions, if you will.

We have a very large network of cancer centers here. Our approach has been, and we are working on now starting to do outpatient step-up dosing at a few of our larger sites. That way we can iron out all of the wrinkles, if you will. Then we can more broadly integrate outpatient step-up dosing to our other sites as well, which is really important because patients do not want to drive three hours to get this treatment. Honestly, they should not have to. We really need to make sure that there is access for patients no matter where they live.

Then just with regards to the training, it is important that we often think about the nurses and the APPs and the physicians being trained, but oftentimes where we run into issues is if a patient presents to an outside hospital who is not familiar with these types of therapies. Again, that speaks to the education of the caregiver and patient so that they know to tell that on-call physician or APP, “Hey, I am getting this therapy. You need to think about these things.” And has a phone number for somebody for them to call to get some input on how to manage this toxicity.

Then it is also good to have ICU staff trained neurologists and whatnot. Most of your larger centers will have that who are doing like CAR T therapy. As we move out into our community hospitals, that is not always the case. It is very important that you develop your own plan and educational program with your larger partnering site.

BsAbs Management Strategies: Neurotoxicity/ICANS

As I mentioned, this is again just to review, because we get a lot of questions on anxiety, about neurologic toxicity or ICANS. This is definitely much higher incidence with the CAR T cells. It typically does develop concurrently or shortly after CRS, although we do see it sometimes independently. I will say with the bispecifics, by and large what we see is a headache, tremor, maybe a little bit of word finding difficulty. But patients’ symptoms resolve very quickly after steroids.

We do step-up dosing and premedication. Patients get dexamethasone. Oftentimes we will have them have dexamethasone at home. That way, even if they are planning on coming in for evaluation at the earliest sign that something might be brewing, we have them take a dose of dexamethasone. If patients have CRS, we also give tocilizumab. There is no role for tocilizumab if the patient does not have CRS as well.

Then if we are concerned about more severe neurologic toxicity, we typically start an anti-epileptic such as keppra.

Monitoring and Managing Cytopenias

Then just importantly, not to forget, we all talk about CRS and ICANS, but there are other risks with bispecific antibodies, specifically infection risks. Certainly you need to monitor for cytopenias. Then also we sometimes do give G-CSF, if needed.

Infection Prophylaxis and Vaccinations

Then another important point is antibacterial prophylaxis. This varies center-to-center. For certain bispecific antibodies, we are a bit more aggressive with IVIG, for example. Certainly in the lymphoma population, typically, if patients are less than 400 with their IgG level, we usually at our center give IVIG.

Now for the myeloma bispecifics, which I know is not the topic today, it is often recommended just to standardly give it monthly because of the high risk of infections in these heavily pre-treated patients.

Then we do continue prophylaxis typically for up to six months. It has not really been established, but I usually have patients all on acyclovir or similar for HSV prophylaxis. We often use PJP prophylaxis as well in these patients.

Managing Infections Associated With Bispecific Antibodies

Then typically if a patient is having a significant infection, of course, we hold the bispecific antibody, consider discontinuing for a grade 4 infection. Oftentimes, we are having our infectious disease colleagues help us. Then if a patient does come in with typical neutropenic fever type of things where we are using broad spectrum antibiotics and whatnot.

Then we just also think about other things like CMV, EBV and whatnot that you might not think of in your typical oncology population. Unless you do a lot of hem malignancies, then we are used to these looking for these things, especially in the BMT and CAR T world, but just something to keep in mind as well.

Coordinating Referrals/Transition and Follow-up Care

It is also important when incorporating bispecific antibodies to have a very streamlined process for referrals and also a really important follow-up plan. Typically, even after patients are back out in the community after their step-up dosing here, we do periodically check in with patients, whether it be every three months just to make sure everything is going smoothly. Then certainly creating patient and care team informational materials that more clearly outline symptoms to look out for management and then also to the patient piece really creating clear, easy phone numbers, etc. on who to call if something happens, especially for the caregiver.

Then more and more health systems are starting to incorporate telehealth to provide some of the follow-up care and also for remote vital sign monitoring, because that is going to be really key in order to get these agents broadly distributed to all the patients that are eligible.

Information Required for Safe Outpatient Transition

Then typically, if we are sending a patient back out into the community, it is always good to include a plan. What infection prophylaxis are they on? How long should that continue to give specifics of what products they are getting and whatnot. Not only for the providers, but also for the patient. Then also to suggest things to follow-up on in terms of labs.

I usually say, “Make sure you are checking IgG levels, for example.” That is a very important piece as well. Of course, provider contact information, whether it be the physician who sees the patient or if you have some champions at your cancer center who are very familiar with the use of bispecifics as key point people.

Bringing Bispecific Antibodies Into Community Practice

Just to reiterate, community practices can deliver bispecifics with proper training and protocols, but they do have to be educated because there can be serious toxicities, albeit rare with the bispecifics. Shared care models have really been effective. Step-up dosing at the tertiary center and then transitioning back out to the community care, although that is not necessarily going to be that sustainable as the number of these bispecific antibodies is increasing across diseases and we are moving them into earlier lines of therapy, for example, even in the second-line setting for a disease like multiple myeloma.

It is just not going to be possible to have everybody go to a tertiary center. Additionally, patients do not want to, so they live far away and they should be able to get this locally as long as folks are properly trained.

InterACT Discussion Question

Institutional protocols are very important. Certainly, we can all go to a website for a particular product and look at strategies, but sometimes there is an easier way to do it if your center can develop protocols and approaches to management that are more user friendly, that then can be used across the board often. There are big national societies too, such as the ASTCT, for example, that has strategies to treat CRS, for example, with CAR T patients. There is actually a consensus about approaching CRS as well in bispecific antibodies.

Those more general guidelines are becoming more commonplace just because as more and more approvals for these immune therapies have occurred, it just gets overwhelming to know what to do with what specific product.

Posttest 1

That is all I have. We have some post-test questions. Then if anyone has any questions for me, I am happy to answer those as well.

Speaker: Perfect. Post-test question number one, I will go ahead and launch this polling question. That poll is open. Give everybody a few seconds to submit the response to that. Here are your results. If you go to the next slide, Dr. Dorritie.

Posttest 2

Dr. Dorritie: This is again asking, which can be given in the third-line setting with an ECOG of one.

Speaker: That poll is open. Just a few more seconds for the incoming answers on this one. Here are your results for that. The next slide. Post-test three. Just a few more seconds for incoming answers on this one. Here are your results.

Then we have one more post question and a couple of poll questions after that. But one more post-test question. That poll is open. Here your results for this question.

Poll 4

Just asking here, if you plan on making any changes in your practice based on today's discussion. Here are the results for that.

Poll 5

Then lastly, again, this is a QR code for you to respond to and let us know what changes you would make in your practice. Again, I will leave this open for just a few moments. You can scan that QR code and submit your response where you can type in your response in the Q&A section for us. I will leave that open for a few moments. And Lisa, if you will go ahead and close this out.

Speaker: Great. First I wanted to check with the local group there in Washington to make sure there were not any questions from the in-person learners. We do have a few questions that have come through the Q&A. Dr. Dorritie, are you able to see those?

Q&A

Dr. Dorritie: Let me see, if I can.

Speaker: I can read those out to you if I need to.

Dr. Dorritie: Wait a sec maybe.

Speaker: While you are looking at those. There are two QR codes on the screen. I have also placed links in the chat panel. One will lead to the downloadable slide deck from today's presentation, and the other will lead to the program evaluation link. To complete and claim your credit, you will need to log in to or sign up for a DCE account, and we would encourage you to claim your credit within 30 days as credit for today's program will expire after that time frame.

We can jump to those questions that are in Q&A now. If there are any further questions, please feel free to enter those into the Q&A panel.

Dr. Dorritie: Let me see. In patients with early relapse less than 12 months, where do you position bispecifics relative to CAR T?

Currently, bispecifics are not approved for early relapse. You have to have two or more lines of prior therapy. CAR T would be the way to go. In general, thus far the CAR T response rates have been higher and longer. We have more data in terms of long-term follow-up. So I would say CAR T is still my choice in this setting, although again, this may change as we are moving these earlier.

How should frailty and comorbidity profiles alter frontline versus relapse treatment? That is a great question.

I do think in general, we do need to be using a more objective approach to frailty. There is certainly frailty indices and whatnot that a lot of times many of us are just using like the eyeball test. Do they look fit or unfit? As time moves on, patients get more frail with subsequent therapy. That plays a role in what we are choosing in terms of our strategy at that point.

Should bispecific antibodies be considered before transplant in high-risk patients?

In certain patients, yes. I guess it depends on what you find is high risk. A lot of these novel therapies, both bispecifics and CAR T are being looked at, for example, in our patients with large B-cell lymphoma who have multiple gene mutations or double hits, because we just know that these highest risk patients do not do well long term. That is really a big area of focus.

The problem is that we do not have that many of those patients in terms of a large group to look at. But yes, I agree because we historically know that patients do not do that great with our standard therapies, which includes transplant.

Then what patient characteristics argue against bispecific antibodies?

In general, most patients are candidates for bispecific antibody. That being said, there are some patients who I have not been able to give a bispecific mostly, I would say for social reasons, like caregiver issues, because even though these rates of CRS and ICANS are much lower, you still do need to have somebody like some kind of a caregiver checking in on you and whatnot. I would think more than disease related factors. In my practice, that is what I have seen be the biggest issue.

That could potentially be more of an issue, even as we are talking about using these out in the community where really, right now, if you are getting step-up dosing in the hospital, it is really rare to have these severe toxicities with subsequent cycles. If we are talking about moving these out into local sites, patients are going to have to have somebody helping them at home. Those are the factors that may argue against using these in across broad swaths of patients.