I am going to review CAR T-cell therapy for lymphoma and leukemia.

[00:06:26]

FDA-Approved CAR T-Cell Therapies in NHL

Just before we get started, just to set the scene, we are fortunate in lymphoma to have a number of different settings in which we can utilize CAR T-cell therapy. Those are summarized here.

All of the existing approvals of CAR T-cell therapies target CD19, but may have differing constructs. Just to provide a brief highlight, and we will talk a little bit more about the details here. Axi-cel is approved for use in second-line or later. DLBCL in particular second-line use is restricted to those with early relapse and can also be used in third-line or later follicular lymphoma. We have brexucabtagene autoleucel, which is indicated for use in relapsed/refractory mantle cell as well as B-cell ALL, and then lisocabtagene maraleucel 4-1BB CAR T-cell, indicated across a variety of different settings, including second-line therapy for DLBCL, either in those patients with early relapse or those who are considered not fit for more intensive therapy, such as transplant in the third-line setting and beyond, and then also in the third-line setting in CLL follicular lymphoma, as well as mantle cell lymphoma with slightly different exposure requirements there, which we will review. Then lastly, tisagenlecleucel approved both in younger patients with B-cell ALL in the second-line or later, as well as in the third-line setting for both large cell lymphoma and follicular lymphoma.

[00:08:03]

FDA Eliminates REMS for CAR T-Cell Therapy

Before we get started, I just wanted to highlight a couple of important trends in the field of CAR T‑cell therapy and important updates. Many of you may have recently seen that the FDA has eliminated the REMS program for autologous CAR T-cell therapies. For those who may have followed the CAR T-cell story initially when these were approved for use, recognizing unique toxicities like CRS and ICANS, there was a requirement to have a REMS program associated with their use, as the field has really, I think, evolved consensus guidelines on management grading of these unique toxicities. I think recognizing where we have come, the FDA has removed those REMS requirements as well as has lessened some of the restrictions around how long patients need to be at a CAR T-cell site of care, as well as things like driving restrictions. We think about this as being really important to hopefully improve access further to these therapies.

[00:09:04]

Ongoing Trials Moving CAR T-Cell Therapy to Earlier Lines of Treatment

I will just highlight briefly that while a lot of what we talk about today will be data from the relapsed/refractory setting, there are ongoing trials to assess the potential use of CAR T-cell therapies in frontline treatment settings, notably highlighting ZUMA-23, which is a randomized trial of axi-cel in high-risk large cell lymphoma patients in the frontline setting compared to standard chemoimmunotherapy. Then the ALPHA3 trial was a slightly different setting here, the use of an allogeneic CAR T-cell therapy called cema-cel in patients who have MRD-positive disease in large B-cell lymphoma after frontline therapy, so as a consolidated treatment strategy. While a lot of the focus today will be on indications in the relapsed/refractory setting, note that there are efforts to assess the value of CAR T-cell therapy in the frontline.

[00:09:57]

New Directions

What is happening beyond the CD19 CAR T-cell therapy? Here are a lot of exciting things. In particular, I will highlight those CAR T-cells that are so-called dual antigen targeting CAR T-cells targeting CD19. But in addition, a second antigen, typically CD20. There are a number of these in clinical trials. Some of these have presented data at summer congresses that are very exciting, including those listed here, JNJ-4496, KITE-363, LYL314 and Zamto-cel.

We also have continued work to improve allogeneic platforms. Recognizing that collection of CAR T-cells and manufacture of autologous cells may be a barrier in certain circumstances. Aloe products have not yet quite cracked the nut, but there is continued study of these, including cema-cel and CB-010.

Then as well, rapid manufacturing platforms. There are a number of these, but a good example of this is rapcabtagene autoleucel shorten the time frame for the manufacture of autologous products. This rapid manufacturing platform also may enrich the product for certain types of naive T-cells that may be considered favorable. There are also armored CAR T-cells, so engineering in further beyond the CAR receptor itself, things like anti-cytokine or cytokine armoring that may allow these CAR T-cells to function in more hostile tumor microenvironments.

A lot happening in the space of CAR T-cell therapy.

[00:11:33]

Diffuse Large B-Cell Lymphoma

I am going to talk about each lymphoma histology slightly separately to review data from pivotal trials.

[00:11:40]

ZUMA-7: Axicabtagene Ciloleucel in R/R LBCL

We will start with diffuse large B-cell lymphoma, the most common lymphoma in which we use CAR T-cell therapy. Here we see the data from the ZUMA-7 randomized trial.

This was a study of patients with large B-cell lymphoma who had relapsed within 1 year of initial therapy or were refractory to frontline chemoimmunotherapy. As you all may know, while our long-term standard of care had been to offer patients platinum-based chemotherapy and an autologous transplant if they were fit for an intensive approach, leading to cures in, roughly speaking, around 20% of patients. This trial challenged that paradigm with the use of CD19, CAR T-cell, and ZUMA-7, specifically axi-cel.

What you see here is in this study, the overall response rate was higher for patients treated with axi-cel, including a higher rate of complete response rate. You can see that translated into long-term benefit with an improvement in event-free survival. Roughly speaking, doubling the rate of cure in the second-line by offering patients with primary refractory disease or early relapse a CD19 CAR T-cell compared to transplant. This has really led to a shift away from transplant in the second-line setting in this population, and with longer-term follow-up the ZUMA-7 study also showed an overall survival benefit in favor of axi-cel.

[00:13:02]

Real-world Outcomes for 2L Axi-Cel for R/R LBCL

What about outcomes in the real world? This data has been around for some time now. If we look in the CIBMTR registry at outcomes for patients treated in the second-line with axi-cel, we see that the outcomes largely mirror those from the clinical trials. This is important because in the real world, we recognize there are patients that may not have been eligible for the ZUMA-7 study. Perhaps they have some comorbidities, perhaps they have some slightly different patient characteristics. But nonetheless, even in the real world where we are treating a broader population of patients, our outcomes mirror those of the ZUMA-7 trial. You see the 1-year event-free survival reported here at 54%, the 1-year OS at 74%.

[00:13:47]

Real-world Outcomes for 2L Axi-Cel for R/R LBCL: Safety

From the perspective of safety, importantly, we also see consistency in the real world with what has been reported in pivotal clinical trials. Here, looking at cytokine release syndrome, quite common with the CD28 costim CAR T-cell like axi-cel, we see that that is present in nearly all patients, but high-grade CRS, relatively uncommon, so grade 3 or greater, at 5%.

Neurologic toxicity, also expected to be higher with CD28 costim CAR like axi-cel, and we see ICANS overall rate just around 50% or slightly less than that in grade 3 or 4 in 23% or higher. This again mirrors what is seen in pivotal trials. Now, we recognize there are some late toxicities that are important for us to recognize from the experience of treating patients with CAR T-cell therapy, and these late toxicities that lead to death more often than not are due to disease progression, but can include things like infections or rare circumstances such as organ dysfunction. There is a nonrelapse mortality that we associate with the use of CAR T-cells in the case of axi-cel in the second-line setting in this study, around 5% nonrelapsed mortality at 1 year.

[00:15:03]

TRANSFORM: Lisocabtagene Maraleucel in R/R LBCL

Now, shifting gears to a different CAR T-cell but a similar setting. This is data from the TRANSFORM clinical trial looking at liso-cel or lisocabtagene maraleucel in a similar setting to what we looked at in ZUMA-7. This is a slightly different CAR T construct in the sense that we use a different costimulatory domain that may affect the kinetics of CAR T-cell expansion and potentially modulate different toxicity profile.

Also, liso-cell is given in equimolar CD4 to CD8 ratio, which is unique amongst some of the other CAR T products. Nonetheless, the bottom line from this trial is that we see a similar improvement in both response rate and progression-free survival in favor of the CAR T-cell therapy. Once again, roughly speaking, doubling curative outcomes compared to autologous transplant in the second-line setting for DLBCL. As noted here, you can see the separation of the PFS curves as early and maintained over time.

[00:16:01]

Real-world Outcomes for 2L Liso-Cel for R/R LBCL

Again, if we look at real-world outcomes again from the CIBMTR registry, slightly lower numbers here because of slightly later approval of liso-cel in this setting. What we see here is a similar trend that is consistent with the pivotal clinical trials. If we kind of overlay different trial populations, so those that would be treated in the second-line, those that might be treated with liso-cel because of ineligibility for things like transplant.

Those patients who would not have been eligible for clinical trials, we see their outcomes are almost identical here. Across a broad population, we can offer CD19, CAR T-cell therapy in the real world and expect outcomes similar to those in pivotal trials.

[00:16:46]

Real-world Outcomes for 2L Liso-Cel for R/R LBCL: Safety

Similarly, when we look at real-world evidence for liso-cel, the safety profile is consistent with that reported in clinical trials. Here, I think, distinct to axi-cel, we see a slightly different profile, less overall CRS, mostly grade 1/2, very little high grade CRS is noted. Importantly, a low rate overall of ICANS around 20% for all-comers with high-grade ICANS seen in just around 6% of patients. Again, reflecting differences in CAR manufacturer 4-1BB costim vs CD28 costim.

[00:17:23]

Retrospective CAR T vs Auto-HSCT From EBMT Group

Now, a question that often gets asked as well, based on these 2 trials, it appears there is not a role for transplantation in the second-line setting. But occasionally we do see patients who receive second-line chemotherapy and seem to be responsive to it.

As we noted in both trials, there was a proportion of patients who still did achieve reasonable outcomes with transplant. What is the role for transplant? Well, one of the data sets that we can lean on to maybe help us answer this question, if a patient has already been shown to be chemo-sensitive in the second-line, say for example, they got therapy because of rapid progression or need for palliation of symptoms and they are responding, and importantly happen to be in the CR, do we do better by taking that patient to transplant as we would have in another era or with CAR T-cell therapy?

What this analysis from the EBMT group shows is that if a patient is in the CR after second-line chemo immunotherapy, their outcomes can be just as good with an autotransplant as a CAR T-cell therapy. I would say the caveat here, again, is that we do not know how to predict chemosensitivity upfront. Those randomized trials show us that preferentially CAR T-cell therapy, if it can be delivered in a timely manner, would be a preferable therapy. But in the circumstance where a patient has already had second-line chemotherapy and is shown to be chemo-responsive and have a complete response, transplant may still have a limited role.

[00:18:51]

Retrospective CAR T vs Auto-HSCT From EBMT Group: Relapse and Nonrelapse Mortality (NRM)

This is the nonrelapse mortality from that same EBMT analysis just to show us that relapse remains an issue both for patients with autologous transplant or CAR T-cell therapy, but it seems to taper off at around about 1.5-2 years, and nonrelapse mortality, at least in this data set, slightly numerically higher with an autotransplant compared to CAR T-cell therapy.

[00:19:16]

Retrospective CAR T vs Auto-HSCT From EBMT Group: Propensity Score Matching

This is just an analysis from the same publication looking at propensity score matching to see if we adjust for varied patient factors. Things that might be different amongst a patient who selected to get CAR T-cell therapy in this setting vs an autotransplant that largely we do not see any substantial predictors of difference and things like overall survival, PFS, relapse incidence, or nonrelapse mortality.

[00:19:42]

Rationale for Dual-Target CAR T-Cell Therapy

I mentioned that the field is very excited to be assessing the use of dual-targeted CAR T-cells in large B-cell lymphoma and other histologies. These are some of the dual-targeted CAR T-cells that are in the clinic in pivotal clinical trials currently.

I just highlight here that we can kind of mix and match varied constructs. For example, if we look at JNJ-4496, we can do dual targeting on a single CAR molecule and a so-called tandem CAR T-cell where one CAR molecule is expressed and targets both CD19 as well as CD20, and this molecule has a 4-1BB costim domain. Alternatively, we can do dual antigen targeting through the expression of 2 different CAR receptors, a so-called bicistronic CAR T-cell.

An example of this is KITE-363. Here, notably, you have 2 different CAR molecules, each independently expressed. Here in this example, they have different costimulatory domains. We may be able to mix and match CD28 and 4-1BB. Then, as a final example, Zamto-cel, which looks slightly more like JNJ-4496. A tandem CAR T-cell. These CAR T-cells may have differing properties, both in terms of expansion kinetics as well as safety profiles.

[00:21:04]

Summary of CD19/CD20 Dual-Targeting CARs

Ultimately, the focus of these dual targeting CAR T-cells is to improve upon the rate of cure from CD19 mono CARs. We recognize that loss of an antigen is one resistance mechanism to CD19 CAR T-cells. By having 2 antigen targets, we may be able to overcome some of that antigen escape that can occur under selective pressure from a single antigen-targeting CAR. So far these CAR T-cells have been studied in single-arm studies, and these data have been presented at recent summer congresses. I will just highlight them here and point out that all of them are associated with very high overall response rates, 90 plus percent, and complete response rates that are north of 70%. In contrast to CD19 mono CAR, where CR rates might be expected in the 50 to 60% range, it looks like the added antigen targeting does seem to improve the depth of response. Of course, the question is really, will these be more durable over time? That is the focus of ongoing studies. In terms of safety profile what we see is largely comparable with what we already see with CD19 CAR. But I will point out that all of these CAR T-cells seem to have a relatively low rate of high-grade toxicities, both low high-grade CRS and low high-grade ICANS, and that may reflect the inclusion of 4-1BB costimulatory domains. Importantly, some of these appear to be associated also with a very low rate of all-comer ICANS. For example, if we look at JNJ-4496, all-comer ICANS seen only in 16% of patients, and with LYL314 only in 22% of patients similar with T-cell. Again, a lots that we can kind of tweak in the CAR T-cell, including targeting a second antigen and taking forward the characteristics of the first wave of CAR T-cells that may lead to more favorable safety outcomes, including 4-1BB costimulatory domains.

[00:23:06]

Let's Revisit a Question

We will revisit a question here.

[00:23:10]

Pretest 1: How confident are you in explaining the rationale and mechanisms behind dual-targeting CAR T-cell therapy to patients and colleagues?

This question: How confident are you in explaining the rationale and mechanisms behind dual targeting CAR T-cell therapy to patients and colleagues? It looks like to some degree, everybody's confidence has improved, somewhat confident and moderately confident and very confident, and then some that are neutral.

[00:23:49]

Follicular Lymphoma

We are going to shift gears here to follicular lymphoma.

[00:23:53]

ELARA: >4 Yr Update of Tisagenlecleucel in R/R FL

Here we have 3 CAR T-cells approved, all in the third-line setting and beyond. The first that I will review is tisagenlecleucel from the ELARA trial. This is a 4-year update. I will just point out here that in follicular lymphoma, we see very high rates of overall response rates, high rates of complete response rate. Of course, the question is really about the durability of that benefit.

You see here from the ELARA trial, the 4-year PFS around 53%. This is largely driven by patients who achieve a complete response, which is shown here on the right. If we look at those patients you see in the orange line, patients with a CR have very durable, progression-free survival. Overall survival is fortunately very good for all-comers. You see in the box on the left here, that there is a marked difference in median PFS for patients who achieve a CR vs those that achieve a partial response. Fortunately, the majority are expected to achieve a CR.

[00:24:52]

ZUMA-5: 5-Yr Updated Axicabtagene Ciloleucel in FL and MZL

Looking at data from the ZUMA-5 trial, this is a 5-year update of axi-cel in follicular lymphoma. This study also did include patients with marginal zone lymphoma. I will just highlight, similar to what was seen in the ELARA trial, high rates of complete response rate, and then, high rates of relatively of ongoing response, again driven by those patients achieving a CR. Around 60% of patients with a CR maintain that CR in the median duration of complete response approaching 5 years. You can see the progression-free survival curve here. Importantly, with what looks to be the formation of an early plateau at around that 4- to 5-year mark. While we do not necessarily know that CAR T-cells are curative in follicular lymphoma, they certainly seem to be a possibility that a subset of patients may achieve curative outcomes.

[00:25:44]

Marginal Zone Lymphoma

I am going to briefly talk about marginal zone lymphoma here.

[00:25:48]

TRANSCEND FL: MZL Cohort of Lisocabtagene Maraleucel

We have recent data from the TRANSCEND FL study. This was the study of lysozyme that led to the approval of follicular lymphoma. There is also a cohort of patients in this study with marginal zone lymphoma. You see the study schema here standard lymphodepletion, liso-cel standard dose given here. Then early response assessment and long-term follow-up. Primary endpoint of the study is overall response rate. These were patients who had had at least 1 prior line of therapy, including alkylating agent and CD20 therapy.

[00:26:20]

TRANSCEND FL: MZL Cohort CRS and Neurological Events

What you see for the marginal zone cohort here is a safety profile largely consistent with what is expected for liso-cel. Any grade CRS in 76% of patients, neurologic toxicity in 33% of patients. Most of this grade 1 and 2 in both settings, and at least overall the rate of grade 3 or higher ICANS or CRS is quite low. These are again reversible toxicities with a predictable onset and manageable with medicines like tocilizumab and corticosteroids.

[00:26:54]

TRANSCEND FL: MZL Cohort ORR and PFS

If we look at the efficacy endpoints for the marginal zone set, we see that the overall response rate was very high shown here 95.5%. In those who had PET-positive disease at baseline the overall response rate is 98.2% and the complete response rate is 91.1%, so a very high rate of complete responses. Median overall survival not yet reached. You see here on the right the Kaplan-Meier curve for survival with a 24-month follow-up median PFS also not reached. These very high and deep response rates lead to durable clinical benefit. That data is under priority review at the FDA for potential approval of liso-cel for use in marginal zone lymphoma, but not yet approved.

[00:27:51]

Mantle Cell Lymphoma

Just shifting gears to mantle cell lymphoma.

[00:27:54]

ZUMA-2: Brexucabtagene Autoleucel in MCL

Here we have had approval of CAR T-cell therapies for some time. The first approval was from the ZUMA-2 study. Brexucabtagene autoleucel. This is a CD28 costim domain CAR T-cell, and you see here the patients enrolled in this study heavily pretreated. Most of these patients had had prior chemotherapy as well as BTK inhibitors. There was a separate cohort reported for patients with no prior exposure to BTK inhibitors. You see, at least in the initial study, there was some dose escalation. But the overall dose of brexu-cel was 2 million cells per kilogram.

[00:28:30]

ZUMA-2 Cohort 1 and 2: ORR and DoR

If we look at cohorts 1 and 2, these were cohorts that included patients with prior BTK inhibitor exposure. You see the overall response rate is very high, complete response rates in about two thirds of patients.

[00:28:44]

ZUMA-2 Cohort 3: ORR and ORR Subgroups

Then, looking at key subgroups, we recognize that mantle cell lymphoma can be quite heterogeneous in terms of biologic risk. In these high-risk patients, perhaps those, importantly, that include patients with P53 mutations, high KI-67, that the response rate is very high even in patients who have never had a prior BTK inhibitor. That was the focus of cohort 3 of ZUMA 2.

I think this is really important because these are patient subtypes that really are not well treated with current treatment paradigms, including chemoimmunotherapy or the use of BTK monotherapy. It looks like that CAR T-cell therapy may be a very effective therapy for these traditionally high-risk mantle cell lymphoma patients, where we do not have other good treatment options.

[00:29:35]

ZUMA-2 Cohort 3: PFS and OS

Looking at specifically the cohort 3 BTK naive population, if we look at PFS that you see here, again, PFS largely seems to be driven by those patients with complete responses, albeit you can see some durability of progression-free survival in patients with PRS here as well. The 12-month PFS rate for all-comers is about 75%, 84% for those with a complete response rate.

[00:30:00]

ZUMA-2 Cohort 3: Safety

Safety for brexu-cel and mantle cell is slightly different in the sense that in mantle cell we often do see circulating disease, and that may predict slightly higher risk of grade 3 and 4 toxicities, or at least it did in the earlier cohorts in ZUMA-2. In this BTK naive population, we see high-grade CRS was fortunately uncommon high-grade ICANS still prevalent in around about 20% of patients. That is largely consistent with the experience of brexu-cel in BTK-exposed patients, but perhaps slightly less high-grade CRS.

[00:30:43]

Post-Brexu-Cel Outcomes for MCL: A Descar-T Study

Then if we look at real-world outcomes for patients treated with brexu-cel, this is a study from the French registry, the Descar-T study. Largely what we show here is that, unfortunately for patients who do progress after CD19, CAR T-cell therapy in mantle cell lymphoma outcomes are quite dismal. The majority of patients do experience rapid progression and ultimately are at high risk for death. These patients really should be patients that are considered for clinical trials and represent an area of unmet need. If we just look at response to therapy across a variety of different treatments, given we see, generally speaking, low response rates, perhaps there is a signal for bispecific antibodies in that setting. Perhaps these will emerge as a preferential treatment for patients who have had CAR T-cell therapy and progressed in mantle cell lymphoma. But more work to be done. Then lastly, from cohort 3, just showing here a PFS and OS.

[00:31:44]

Chronic Lymphocytic Leukemia

I am going to skip forward to talk about CLL.

[00:31:47]

TRANSCEND CLL 004: Lisocabtagene Maraleucel in Relapsed/Refractory CLL/SLL

We do have a CAR T-cell therapy approved here. Lisocabtagene maraleucel. Based on the transcend CLL study, this is the study design here. All of these patients were quite late line. You see the inclusion/exclusion on the left here. These were patients that had to either be ineligible to receive a BTK inhibitor or had progressed on a BTK inhibitor. Many of these patients, as we will show you, had a substantial adverse biologic characteristics.

[00:32:17]

TRANSCEND CLL 004: Efficacy Outcomes in DL2

The median lines of prior therapy was 5. If we separate out the outcomes in the study population to those who had progressed on so-called novel therapies, either a covalent BTK inhibitor or venetoclax or had exposure to both, you see here that the response was consistent across subgroups. We see a response rate just around 50% or so in those who had progressed on either BTK or venetoclax and in those who had maybe had exposure, perhaps these might be patients that received a fixed duration exposure of one or the other drug or were venetoclax naive.

We see a slightly higher response rate there. In terms of depth of response, around 20% of all patients treated in the study did achieve a CR. Around about 2 thirds of patients achieved uMRD-negative state by 10^-4 in the blood at least. The depth of response is important in CLL. As we see this really correlates with durable outcome as it is shown here.

[00:33:20]

TRANSCEND CLL 004: DoR and PFS in DL2

If we look at that population of patients that achieves very deep responses, those with CRS or CRIs, you see that as represented by the green line here. These are the patients that really seem to have very impressive progression-free survival in a very late-line setting. Those patients who achieve a partial response still certainly can have some durability of benefit, but their median PFS is around 26 months.

Unfortunately for patients that are refractory to therapy, these patients have very poor outcomes. I think the take home point for this study is that this is a really late-line population, perhaps not what we are seeing today in the real world. Most of these patients had had prior chemoimmunotherapy for CLL, which is relatively rare these days. Perhaps these outcomes may be different in patients who have started therapy with novel agents like BTK inhibitors and venetoclax. There are ongoing trials to help assess that.

[00:34:13]

TRANSCEND CLL 004: Safety in Full Study Population

In terms of safety, again, with circulating disease, we see most patients do experience CRS. Fortunately for most, this is grade 1/2. There is a small subset of patients that did have high-grade CRS. Neurologic toxicities do seem to be higher in this population than in others in which liso-cel has been studied. Namely, again, perhaps due to this presence of circulating disease, we see about 18% of patients with high-grade ICANS. CLL patients certainly are at risk for things like infections and secondary malignancies. We do see that represented in the long-term follow-up here as well.

[00:34:52

Summary of CAR T-Cell Therapy Data in Lymphomas

Just summarizing where we are with CAR T-cell therapy in lymphomas, I am not going to go through all these bullet points. But just to show you, in large B-cell lymphoma, we have really paradigm-changing trial results from ZUMA-7 and TRANSFORM leaving the curative outcomes in the second-line and beyond.

We have, building upon that dual antigen-targeting CAR T-cells targeting CD19 and CD20 in the clinic, coming in follicular lymphoma in late line patients who typically have short progression-free survival, very durable responses with high complete response rates similar in marginal zone. We may see here an approval for the first CAR T-cell in that setting based on the TRANSCEND FL study. Then in mantle cell lymphoma, we see the ability to overcome high-risk disease biology in patients that are both progressed after BTK inhibitors and BTK naive but poor outcomes in those who progress after CAR T-cell therapy. Then in CLL, similarly in very late line patients, the potential for durable responses in those patients who achieve very deep responses to the CAR T-cells.

[00:35:55]

Let's Revisit a Question

I am just going to revisit a question here, and then we will briefly touch on ALL.

[00:36:00]

Posttest 2

When counseling a patient with marginal zone lymphoma about liso-cel, what would you tell them was the primary result of the MZL cohort?

It looks like the polling results, the majority answered overall response rate of 95%, which is the correct answer. Just to remind you, that was the main efficacy endpoint presented from the TRANSCEND FL study. This is again under priority review for the FDA for 2 or more lines of therapy.

[00:36:54]

Acute Lymphoblastic Leukemia

I am just going to briefly touch on ALL.

[00:36:56]

FDA-Approved CAR T-Cell Therapies in ALL

We have 3 CAR T-cells approved here in these settings.

[00:37:00]

FELIX: Obecabtagene Autoleucel in ALL

The newest one, being obe-cel, based on the FELIX trial, slightly different here in the sense that patients receive different CAR T dosing based on the quantification of blasts at baseline. If you had a lower blast count, higher CAR T-cell dose upfront, and then a second split dose at day 10. You had a higher blast count upfront, a lower dose of CAR T-cells to help mitigate safety events, then the higher dose at day 10.

[00:37:30]

FELIX: Remissions and Survival

What you see here is complete response rates in 78% of patients. Not all patients ultimately underwent any consolidation. Around 40% of patients are in an ongoing remission without a consolidative transplant. Those patients who had a consolidative transplant and an MRD-negative remission, around 18% of patients. If we look at outcomes based on receipt of stem cell transplant consolidation or not, you can see overall here for relapsed/refractory ALL good outcomes overall, with about 2 thirds of patients alive at 1 year post therapy.

[00:38:07]

FELIX: Event-Free Survival and Overall Survival

This is shown here in the Kaplan-Meier curve.

[00:38:14]

ZUMA-3: Brexucabtagene Autoleucel in ALL

I will just briefly touch on data from ZUMA-3 for brexu-cel. This was an approval for brexu-cel in relapsed/refractory ALL, and similar to what we see in other settings, good overall survival, again, primarily what appears to be driven by those patients with deep responses.

[00:38:33]

ZUMA 3: 5-Yr Updated OS

You can see for all-comers, median OS is 25 months. But for those who have a complete response or CRI, nearing a 5-year median overall survival, which is remarkable.

[00:38:44]

Panel Discussion and Q&A Session

I think we are going to skip through the questions in the interest of time here, so that we can get to Dr. Krishnan's presentation. I will then turn it off to Dr. Krishnan. Thank you.

[00:38:57]

CAR T-Cell Therapy for Multiple Myeloma

Dr. Amrita Krishnan (City of Hope): Thank you, Dr. Patel. I listened to that. I would say the good thing for myeloma doctors is we only have 2 CAR Ts to talk about. It seems like we will get into the data. We have a lot less high-grade ICANS. The bad thing is, you did not mention MNTs, which, therefore, it leads me to assume it is more of a myeloma-focused problem. But we can talk about that in the discussion and also talk a little bit about the new black box warning for cilta-cel with IEC colitis.

[00:39:33]

FDA-Approved Autologous CAR T Therapy for R/R MM

To get into this, then, as I noted, we have 2 CAR Ts approved in myeloma. There are slightly different indications for the approval. They were, of course, initially approved in very advanced disease for prior or more prior lines of therapy. Basically, the major classes of drugs, iMiD, PI, CD38.

Last year in April was a huge step forward for the myeloma world that they got approved in earlier lines of therapy. But there is a little distinction. Ide-cel was approved after 2 or more prior lines of therapy. A PI and iMiD and an anti-CD38 antibody, whereas cilta-cel was approved after 1 or more prior lines of therapy. You do not, in fact, have to have had a CD38 antibody. That is a pretty significant distinction. The major part of the cilta approval was being refractory to lenalidomide.

[00:40:36]

Let's Revisit a Question

Now, let us go back to the first question here.

[00:40:40]

Patient Case: 62-Yr-Old Woman With R/R MM

The 62-year-old woman, newly diagnosed, had quad induction CD38 PI and an iMiD has a relapse on len maintenance.

[00:40:54]

Pretest 3: Based on current indications and clinical evidence, which CAR T-cell therapy would be an appropriate treatment option for this patient?

Based on the current evidence, which CAR T would be appropriate? All right. Wonderful. I think people picked up on the cilta after 1 prior line, which would be this patient and len refractory. All right.

Let us go to our next question. We kind of just said this, that cilta is the right answer because it is 1 prior line PI image. This patient actually had a CD38 antibody, so that may have thrown off some of the other people who picked ide-cel. Ide-cel is off to 2 or more prior lines. Then, of course, axi-cel and liso-cel are not approved in myeloma.

[00:42:02]

Ongoing Phase III Trials Moving CAR T-Cell Therapy to Earlier Lines of Treatment

I think the biggest push in myeloma, and I would argue maybe even quicker than lymphoma, perhaps not, is once we get something approved fourth line, then we try to move it earlier. As you can see, second- and third-line. Of course it becomes the question of frontline.

If you do a frontline CAR T therapy when you have fitter T-cells, will you ultimately, frankly, be able to cure myeloma is, of course, the goal. The other question for us is the role of stem cell transplantation, which in myeloma still really remains a huge backbone of myeloma therapy. We have had 2 trials that have completed accrual, and we are waiting for readout very excitedly.

The first is CARTITUDE-5, which this was for patients who for transplant is not intended as upfront therapy. This was VRd plus cilta-cel vs VRd followed by rebdex maintenance. The other trial, CARTITUDE-6, which I would argue is probably the one that is the most relevant in the US. This was quad induction, followed by cilta-cel as consolidation or quad induction, followed by transplant as consolidation. Then actually there are 2 years of lenalidomide maintenance in both arms. That trial completed accrual earlier this year. Of course, though, we are waiting many years for a readout on that.

We have some other CAR T constructs that are not FDA approved, but we, again, are testing them. They have been tested in phase I and phase II trials and now are in phase III. First is the GPRC CAR T arlo-cel. That is being compared to standard of care for patients with 1-3 prior lines. Then we have another BCMA construct, anito-cel, also being compared against standard of care in patients with 1-3 prior lines. These trials are ongoing and still accruing. We certainly are very interested in their outcomes.

[00:44:10]

New Directions

As I mentioned, therefore, these are the new directions, new targets. GPRC being a big target of both CAR T as well as bispecific antibodies. Arlo-cel is really the one with the most data right now. We are waiting for the phase III data on that. There are other targets. It is much earlier data in the CAR T setting, but we have a lot more data in the bispecific antibody setting. For example, FcRH5. There is a CAR T, but it is in very, very early phases, and SLAMF7 is CS1. As one knows, there is an antibody-approved elotuzumab, but also there are CAR Ts in this space as well in phase I.

Dual targeting, a similar concept to the lymphoma that Dr. Patel talked about. Perhaps dual targeting one will increase response rates, but more importantly, perhaps improve progression-free survival by reducing the risk of antigen escape. We have several dual targeting constructs listed here that you can see, both are in Phase I/II trials. Then, of course, the myeloma.

If you have one good thing, maybe you add on more. In this case, the concept of adding on bispecifics following a CAR T as a sort of maintenance. We have the aMMbition study, which used quad induction and then used a GPRC-targeting bispecific talquetamab followed by cilta-cel or quad induction, followed by cilta-cel, and then using the talquetamab. Both of these approaches are being studied. These trials are very small studies and really just proof of concept. These also completed accrual, and we are waiting for readouts.

[00:46:04]

Arlocabtagene Autoleucel for R/R MM: Study Design

Let us talk about arlo-cel. As I mentioned, it is in phase III now. But there was some phase I, phase II data. Advanced relapsed disease. The most important thing to notice on the arlo-cel data, which is why we are so interested in it, is, it allowed patients who had had prior BCMA therapy. That remains a huge unmet need for us because, unfortunately, unlike lymphoma, we do not really still see a plateau in the curve for patients treated with BCMA CAR T. We need to find effective treatments for them after relapse.

[00:46:44]

Arlo-cel for R/R MM: Extended Follow-up

Arlo-cel as you can see here, was given, and it was gratifying that the response rate was quite high, 87 to 91%. Also exciting to us was the PFS in patients who had had prior BCMA therapy at around 19 months, and it seemed comparable to those. In fact, it had no prior anti-BCMA therapy. This again was very exciting for us.

[00:47:11]

Arlo-cel for R/R MM: TEAEs (>=30% of Treated Patients)

If we look at toxicities, you can see again heme toxicity infection. GPRC is a very unique molecule. If you have not used talquetamab, you may not be as familiar, but it can affect the taste buds. GPRC is expressed, and also keratinized tissue. Dysgeusia is something we always think about. Indeed, you saw it in about a third of patients, though relatively mild. To be honest, it tended to be more transient than what we saw with the bispecifics.

[00:47:47]

Arlo-cel for R/R MM: Select TRAEs

In terms of neurologic toxicity, so, I mentioned in most of the myeloma CARs, the ICANS are early neurologic toxicity tends to be low. But these other later neurologic toxicities are things that we are starting to see. Most notably this idea of cerebellar toxicity because GPRC is also expressed in the cerebellum. Dizziness, ataxia, dysarthria. We saw that a median of 30 days, really up to 6 months, in patients with varying degrees of resolution. This is important as a late toxicity. Often, once patients have returned back to their primary oncologist. Something to certainly be aware of.

[00:48:38]

iMMagine-1: Phase II Study of Anitocabtagene Autoleucel in R/R MM

Then anito-cel. This is a BCMA construct that has also been under study. Again, same kind of idea. They did not in the original trial allow patients with prior anti-BCMA therapies, but it was the traditional PI iMiD anti-CD38.

[00:49:03]

iMMagine-1: Updated Efficacy Results

Response rates appear extremely high with the imagined ones, or at least with early data, 97%, including depth of response, 93% of patients MRD-negative. Again, follow-up relatively short in this trial. I do not want to make too much of the fact that the median PFS has not been reached yet. We are waiting for longer readouts, but at least the 12-month PFS seems very promising.

[00:49:31]

iMMagine-1: CRS and ICANS

I think, again, ICANS tends to be relatively low incidence, and certainly very low high grade ICANS with this construct.

[00:49:46]

iMMagine-1: Treatment-Emergent AEs

In terms of other late toxicities, so far, no SPMs have been reported. One could argue that just because follow-up has been still very short, and, so far, no late neurologic toxicities. Again, that is something we continue to monitor. It is of great interest to us.

[00:50:08]

GC012F: Dual-Targeting BCMA/CD19 CAR T-Cell Therapy

Now, just to talk about dual targeting, we have this at City of Hope. Again, may increase the depth of response as well as durability of those responses, as well as the idea of a faster manufacturing time.

[00:50:25]

GC012F: Phase I Study in R/R MM

This was based on the grey cell phase I trial, which showed response rates approaching 100% in this small group of patients.

[00:50:41]

GC012F: Phase I Study in Newly Diagnosed MM

A median duration of PFS not reached with a median follow-up of about 2 years. This was very exciting. This is a trial certainly ongoing now in the US.

[00:50:55]

GC012F: Safety

Again, safety seems good. Very little in terms of a high-grade CRS. That certainly was of interest to us as well.

[00:51:11]

Real-world Cilta-cel: Efficacy Outcomes

All right. Just to look at cilta-cel real-world outcomes, just to see again high response rates. I am going to speed up a little here in the interest of time. Again, encourage the real-world mirrors what we saw in the trial.

[00:51:26]

Real-world Cilta-cel: Safety Outcomes

In regard to response as well as in terms of toxicity with ICANS in about 14% of patients, but most of it being low-grade and CRS in the majority of patients, but again, most of it being grade 1/2.

[00:51:43]

Prophylactic Dexamethasone in Early Post-CAR Period

These are the things, just touching upon a little bit. The issue with cilta-cel has been this question of delayed neurologic toxicity. The Parkinson's-like toxicities. How do we prevent it? Some of the things we have done have increased effectiveness of bridging therapy in patient selection. Some interest has been placed on this idea of the peak ALC because we think the question has become is it the expansion of the CAR or is it the persistence, or perhaps both, that is leading to these delayed neurologic toxicities.

There was a small study of 7 patients who were treated with dexamethasone prophylactically if their ALC around between Day 10 and Day 20 went over 5000. It seemed to drop down, that a peak expansion and those patients did not develop late neurologic toxicity.

[00:52:40]

Immune Effector Cell-Associated Enterocolitis

Again, very small number of patients. But based on that study and based on the fact that that is a very devastating complication, many centers have adopted some degree of dexamethasone based on an ALC by the 5000 or 3000 during those first 2 weeks post-CAR T.

[00:52:59]

New FDA Boxed Warning for Cilta-Cel: IEC-EC

The other thing, and this is important to note, this was just added to the cilta-cel label as a black box warning was IEC colitis. The incidence was about 2% post cilta-cel. It is something to be aware of in patients who present with late-onset nonbloody diarrhea. You could see here some of the risk factors postulated to be this, including a high CAR-TOX score, high serum ferritin before. But something to be aware of when the patients return to care in the community, that this can be a complication.

In patients who are presenting with diarrhea, it is of course, rule out infection. GI evaluation as well, because we also want to rule out T-cell lymphoma of the GI tract. That has also been reported in patients who presented with IEC colitis. This is something to have a high degree of suspicion and also just awareness, as we are also learning more and more about this.

[00:54:13]

Let's Revisit a Question

Let us go back to a question here.

[00:54:16]

Pretest 4: When counseling a patient who is considering cilta-cel, which boxed warning adverse event should you make sure to discuss with them and their caregiver?

When counseling a patient considering cilta-cel which boxed or black box warning should you make sure to discuss with them and their caregiver?

Perfect. All right. Absolutely. It is not wrong to say infection, but that is just not listed as a black box warning.

Amber, do you take these, or do we?

Amber Williams: I can take it, and then we will go to the Q&A session.

[00:55:13]

Poll 3: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No;
3. Uncertain.

All right. We will move on.

[00:55:30]

Poll 4: Please take a moment to text in one key change that you plan to make in your clinical practice based on this education.

We will leave this up while our faculty answer some audience questions. Please feel free to put those in the Q&A box as well.

Q&A

Amber Williams: Dr. Patel, actually, I think there is a question for you on CLL.

Dr. Patel: Yeah. Happy to answer that. The question looks like for a CLL patient who progressed on BTK inhibitor and venetoclax, do you wait for them to progress on pirtobrutinib prior to collecting cells for CAR T? This is a great question. Generally we think about pirtobrutinib as being a good bridging strategy. I think for patients that perhaps are good candidates for CAR T-cell, often I may start the pirtobrutinib and then discuss with the patient the CAR T-cell process and try to ultimately deliver that therapy as early as we might be able to. There are, of course, maybe some patients for whom a pirtobrutinib may be more of a destination therapy. But I think anytime you are starting the pirtobrutinib is a good time to consider a referral or evaluation by a CAR T specialist.

Dr. Krishnan: Oh, there is another answer. Why is anito-cel expected to work differently? That is a great question. It is a different construct. I cannot really speak to that portion of it. It is not so much the response rate. It is the question of the side effect profile and is it going to be more favorable. Because the response rate with cilta-cel is actually extremely high, and it is really just delayed toxicities. Is there going to be a different profile of that? It may have to do also with cell dose. The peak ALK expansion, etc. I think all those things may play into it. We are still waiting to see.

Amber Williams: Then if there are any questions on that slide that you think are worth answering or discussing, you can go ahead and do that.

Dr. Patel: Sure. Made me a little bit different in different disease settings. Maybe I can speak to the first and second question in the lymphoma setting. Our most common sequence because of second-line CAR T availability in DLBCL is bispecific after CAR. There, fortunately, we do not seem to see a substantial difference in CRS or ICANS in patients who are getting a bispecific who have had a CAR vs not, albeit in, I think, very, very rare circumstances you could, I suppose, theoretically drive CAR T re-expansion with bispecific. In patients where you may have unusual CRS profile or refractory CRS, that might be something to consider, but it seems to be a very rare circumstance in lymphoma, at least. In this question around revaccination, is it the same as post-auto transplant. This is an area where I think, especially in the lymphoma world, we need to do more research. I think certainly memory B-cells and plasma cells are not expected to be wiped out by all CAR T-cell therapy. But there may be certain populations where because of the disease itself, there is some need to revaccinate.

CLL is the one I think about where there is immune dysfunction long before we ever give CAR T-cell therapy to patients. This may vary across different lymphoma histologies and is an area of ongoing work in our field. Dr. Krishnan's right. We are fortunate not to have these delayed neurotoxicities in lymphoma. That seems to be something that is more specific to anti-BCMA CAR T-cells, at least.

Dr. Krishnan: The only comment I have to say in the myeloma for the bispecifics is we have a lot of data suggesting that if you give a bispecific before a CAR the response rate of the CAR is lower and the PFS is significantly lower. We really try not to do that, and we really try to do CAR first if at all possible.