Andre H. Goy, MD, Physician in Chief Hackensack Meridian 

 Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, discusses the durability of response with brexucabtagene autoleucel (Tecartus) in mantle cell lymphoma (MCL). 

During the 2020 ASH Annual Meeting and Exposition, findings from a comparative analysis of the pharmacologic profile of brexucabtagene autoleucel and outcomes by MCL morphology and prior BTK inhibitor exposure were presented virtually. 

The analysis revealed that all subgroups defined by MCL morphology or prior BTK inhibitor exposure derived clinical benefit from brexucabtagene autoleucel, says Goy. However, patients with blastoid morphology or those who were previously treated with acalabrutinib (Calquence) monotherapy had lower post-treatment CAR T-cell expansion compared with patients with other subtypes, Goy explains. 

Notably, these findings suggest that it was not necessary for patients to have detectable, persistent CAR T cells to have a response, Goy says. Additionally, the results showed that about one-third of patients had recovered B cells after 1 year of treatment with brexucabtagene autoleucel, suggesting these responses are durable, concludes Goy.

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Andre H. Goy, MD, discusses the durability of response with brexucabtagene autoleucel in mantle cell lymphoma. 



Dr. Goy on the Durability of Response With Brexucabtagene Autoleucel in MCL 

 Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, discusses the potential utility of lisocabtagene maraleucel (liso-cel; Breyanzi) in mantle cell lymphoma (MCL). 

During the 2020 ASH Annual Meeting and Exposition, findings from the phase 1 TRANSCEND-NHL-001 trial demonstrated an objective response rate of 84% and a complete response rate of 66% with liso-cel in 32 patients with relapsed/refractory MCL. 

Moreover, compared with the results of the phase ZUMA-2 trial with brexucabtagene autoleucel (Tecartus), liso-cel appeared to demonstrate fewer cases of grade 3 or higher cytokine release syndrome and neurotoxicity, says Goy.

Although the CAR T-cell therapy is not approved to treat patients with relapsed/refractory MCL, liso-cel could provide another option that leads to durable responses in elderly patients with MCL who would otherwise have limited treatment options, concludes Goy. 

Andre H. Goy, MD, discusses the potential utility of lisocabtagene maraleucel in mantle cell lymphoma. 



Dr. Goy on the Potential Utility of Liso-Cel in MCL 

Andre Goy, MD, Physician in Chief Hackensack Meridian 

 Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, discusses the clinical implications of CAR T-cell therapy in mantle cell lymphoma (MCL). 

In July 2020, initial results of the phase 2 ZUMA-2 trial led to the FDA approval of brexucabtagene autoleucel (Tecartus) for the treatment of patients with relapsed/refractory MCL. Updated results from the study, which were presented during the 2021 Transplantation & Cellular Therapy Meetings, showed that at a median follow-up of 17.5 months, the overall response rate was 92%, with a complete response rate of 67%. 

Taken collectively, these data highlight the importance of referring patients who fail on standard therapy to clinical trials involving CAR T-cell therapy, says Goy. Currently, patients with MCL who progress on standard treatment options have poor outcomes, says Goy. CAR T-cell therapy has demonstrated high response rates that appear durable, Goy explains.

Additionally, many patients with MCL are too old for an allogeneic stem cell transplant, and the risk of developing chronic graft-versus-host disease with transplant is high, says Goy. As such, the integration of CAR T-cell therapy for this patient population with MCL that has a high risk of relapse is critical, concludes Goy. 

Andre Goy, MD, discusses the clinical implications of CAR T-cell therapy in mantle cell lymphoma.  



Dr. Goy on the Clinical Implications of CAR T-Cell Therapy in MCL 

Andre Goy, MD, Physician in Chief Hackensack Meridian Health Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, discusses the next steps with CAR T-cell therapy in mantle cell lymphoma (MCL).

In July 2020, the FDA approved the CAR T-cell therapy brexucabtagene autoleucel (Tecartus) to treat patients with relapsed/refractory MCL. The regulatory decision was based on findings from the phase 2 ZUMA-2 trial, in which a single infusion of the CAR T-cell product elicited an 87% objective response rate and a 62% complete response (CR) rate in this patient population.

The next steps with brexucabtagene autoleucel, as well as CAR T-cell therapy overall, is to improve responses for patients who do not achieve a CR, says Goy. Although the field is developing a greater understanding of how to mitigate the toxicities associated with CAR T-cell therapy, improvements in outcomes for patients with MCL, an aggressive lymphoma subtype, are still needed, Goy explains. Moreover, the concept of heavily pretreated patients and T-cell fitness as a mechanism that limits T-cell amplification could shed light on future research efforts, Goy says. Evaluating CAR T-cell therapy in a larger population of high-risk patients could highlight the widespread effect of this therapeutic modality in this setting, concludes Goy. 

Andre Goy, MD, discusses the next steps with CAR T-cell therapy in mantle cell lymphoma.  



Dr. Goy on Next Steps With CAR T-Cell Therapy in MCL 

Andre Goy, MD, MS, physician-in-chief of the Hackensack Meridian Health Oncology Care Transformation Service, chairman and executive director of John Theurer Cancer Center at Hackensack University Medical Center, Lydia Pfund chair for Lymphoma, chief of the Division of Lymphoma, professor of medicine at Georgetown University, and professor and chair of oncology at Seton Hall–Hackensack Meridian School of Medicine, discusses updates in precision medicine. 

The goal of precision medicine is to give the right intervention at the right time for the right patients, Goy says. Despite being intrinsic to a physician's work, there has also been an acceleration of precision medicine efforts given the improved understanding of cancer biology and the rapid discovery of developments in omics and novel technologies. This has made the oncology landscape very complex, especially as it relates to the sustainability and cost of cancer drugs, according to Goy. 

While some oncology professionals believe that precision medicine has not delivered, Goy argues that great strides have been made, citing developments with TKI resistances in chronic myeloid leukemia, as an example. Additionally, many other drugs are approved with a companion diagnostic, and there is a deeper understanding that some subsets of patients respond better than others to certain agents.

Given the complexity of the landscape and the number of options available, it's often times difficult for physicians to find the best treatment for patients, Goy says. This was the rationale to form the 2nd Annual Precision Medicine Symposium: An Illustrated Tumor Board. While mass information is provided at meetings by 

, the Precision Medicine Symposium aims to filter that information down.

Most if not all cancers have something to do with precision medicine, Goy asserts precision medicine will become a reality and transform into something that will help determine the best option for every patient, concludes Goy.

Andre Goy, MD, MS, discusses updates in precision medicine. 

Dr. Goy on Updates in Precision Medicine in Oncology

 R2-GDP-GOTEL is a phase 2 clinical trial that combined lenalidomide with a very well-known regimen for salvage chemotherapy, R-GDP, which consists of rituximab, cisplatin, dexamethasone, and gemcitabine. The patients were to receive lenalidomide from day 1 to day 14, in addition to the standard dose of R-GDP [rituximab, cisplatin, dexamethasone, and gemcitabine], up to 6 cycles. Patients who completed the regimen and had at least a PR [partial response] or complete remission [CR], they went on to receive lenalidomide as maintenance. They enrolled 79 patients, 78 patients were evaluated for efficacy and toxicity. The overall response rate was 59%, with a CR rate of 32%. The adverse events were mainly related to the chemotherapy, like thrombocytopenia and neutropenia, patients had rashes, also febrile neutropenia of course, reported in about 14% of patients. Further biomarker analysis showed that there was no difference in responses according to the cell of origin, and also the regimen was active in primary refractory lymphoma. Unfortunately, there were 4 toxic deaths in the study. That’s important to know when we add a new agent into our salvage regimen.

The conclusion is that this is an active regimen, it’s a phase 2. The question is whether this is better than the standard GDP [gemcitabine, dexamethasone, cisplatin]. The reported efficacy of gemcitabine, dexamethasone, cisplatin, the overall response rate is about 45%, with CR rates in the range of 13% to 15%. Keep in mind that the earlier studies didn’t include a PET [positron emission tomography] scan as mandatory to assess for CR rates, so we don’t really know the true CR rates in the earlier studies. That’s just to keep in consideration. Also, I would say that long-term follow-up is needed to see whether that matches the long-term efficacy of this regimen in these patients. Until we know whether we need to add lenalidomide to the gemcitabine, dexamethasone, cisplatin regimen in real life, I think it’s early to say. There were some toxicities and 4 deaths in a relatively small study. I think we should be careful. Whether we need to add it, I think the decision has to be made based on a larger study, or a phase 3 randomized study.

The Smart Start study is a single-center, phase 2 clinical trial that was presented by Jason Westin, MD, and colleagues from The University of Texas MD Anderson Cancer Center. It’s a trial that consisted of 2 phases. There was a lead-in phase of rituximab, lenalidomide, and ibrutinib for 2 cycles, followed by the combination plus chemotherapy. Whether it was R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], it was physician discretion to decide which regimen the patient would go on. The overall response rate was 86%, with a CR rate of 36%, which is expected for lenalidomide and ibrutinib. There is not a high CR rate. But once the patients completed the chemotherapy part, up to 6 cycles, the overall response rate was 100%, with a CR rate of 95%. The 1-year PFS [progression-free survival]—the study has a short follow-up—was 95%.

The adverse events were expected as related to the chemotherapy agents used. There were some toxicities that we typically don’t see in patients who receive chemotherapy, like Aspergillosis. There was a patient who had CNS [central nervous system] Aspergillosis, and 1 patient who died of Aspergillosis, probably systemic Aspergillosis. That underscores the fact that adding another agent into a chemotherapy regimen could be complicated. There are descriptions of fungal infections with ibrutinib, especially in combination with steroids and cytotoxic agents, so that’s something physicians have to keep in mind.

The other interesting thing about this study is the time to initial treatment, that was about 24 days. The reason I’m pointing this out is it’s a little unusual for patients to wait 3 weeks or almost 4 weeks to start therapy, especially with an aggressive lymphoma. That tells us about a possible selection bias. You’re probably selecting the best patients, the more stable patients to do these therapies, whereas the sickest patients, the patient who was in the hospital with aggressive disease, probably is not eligible for this trial.

Overall, I think the combination showed activity in DLBCL [diffuse large B-cell lymphoma], it’s promising activity. Whether that will implicate a change in the standard of care, I think it’s early. We need to sort out this question in a randomized clinical trial, phase 3. Finally, we have to consider the cost, because you’re adding lenalidomide and ibrutinib, and that can easily be a costly therapy over 6 months. I think it’s a study that showed very interesting activity. Tolerability was acceptable. Some of the infections that we typically don’t see with the standard chemotherapy, such as Aspergillosis or fungal infections, were shown in this study, so that’s something we have to keep in mind when we decide whether to do this treatment. I wonder whether patients need to complete 6 cycles of chemotherapy. That’s something that needs to be studied. Probably fewer cycles of chemotherapy would be more convenient and may not impact efficacy. I believe there will be a follow-up study with fewer cycles of therapy to see whether that will be feasible.

Novel Therapies: R2-GDP-GOTEL and Smart Start 

The POLARGO study, as it’s called, is a large, global phase 3 trial that compares a standard chemotherapy regimen, R-GemOx, which is rituximab, gemcitabine, oxaliplatin. And the comparator arm is rituximab, gemcitabine, oxaliplatin with polatuzumab vedotin, which is an antibody-drug conjugate now approved for diffuse large B-cell lymphoma.

The purpose of this study is to demonstrate or test whether the introduction of this antibody-drug conjugate improves the outcome of patients with diffuse large B-cell lymphoma treated with rituximab, gemcitabine, oxaliplatin in the relapsed/refractory setting. This trial is ongoing, but I think there’s a fair amount of optimism that we may see a positive result here, which would improve or expand the number of treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma.

I think you’re referring to the LYSA trial presented at ASCO [the American Society of Clinical Oncology annual meeting], which was atezolizumab, a checkpoint inhibitor, with obinutuzumab and venetoclax in relapsed/refractory large cell lymphoma. This was a small number of patients.

I think 80%-plus of patients had at least 2 lines of therapy, and two-thirds of them were refractory to the last regimen. I don’t remember the exact number of patients, but the trial was reported with an overall metabolic response at the end of treatment of 24%, and an 18% complete metabolic response. It’s early for the follow-up, but this is again one of these combinations, a biological agent plus immunotherapy. That might bring an opportunity to the unmet need of patients who are not eligible for high-dose therapy, transplant, or potentially CAR [chimeric antigen receptor] T-cell therapy. It’s another example of the impact of immunotherapy as well.

I would like to summarize and say that this is a very exciting time in the field of medicine, particularly in lymphoma where we have been, for decades, doing R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], which remained as the standard of care default. But we definitely should be aware that this is not sufficient in a high-risk IPI [International Prognostic Index] patient, double hit, double expresser, and non-GC [germinal center] subtype, and other high-grade lymphoma that I alluded to previously. And I think that these patients should be recommended for clinical trials and probably more intensive therapy and maybe cell therapy consolidation, like the ZUMA-6 trial looking at CAR [chimeric antigen receptor] T-cell therapy as consolidation in patients who have double-hit lymphoma, high-grade lymphomas.

It is really not altered, but probably underestimated. But the future is the biological classification of lymphoma and trying to improve this curve that we see, to identify truly the high grade. And to do this, we need to have a baseline signature that is usable in routine and actionable. I think cell-free DNA, or circulating tumor DNA, is likely to be more usable and used in the future. As I mentioned, immunotherapy is more and more part of the induction or pre-phase consolidation. And again, given all the opportunities that I just mentioned tonight, it reflects on the fact that it is really important to encourage physicians to go to clinical trials, to participate. The reason being is that when you look, the impression is that large cell lymphoma now is a clinical result, the outcome is so great. But when you look at real-world data in high-risk patients, the outcome particularly in a high-risk patient is still very poor. So I would encourage physicians to look at clinical trials in this population as well. Thank you.

Novel Treatment Combinations for R/R DLBCL

We still have unmet needs for patients with diffuse large B-cell lymphoma. As I mentioned, for older patients in their 80s and above, even standard therapy with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is very difficult to receive. And in those cases after failure of less intense regimens, such as mini R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], or bendamustine, or others, there is a significant unmet need for patients to be treated with targeted agents. Tafasitamab with lenalidomide is likely to be an option for those patients in the future, as well as selinexor, and polatuzumab vedotin, which is approved in combination with bendamustine/rituximab.

 I think overall in cancer, immunotherapy will continue to expand dramatically. I think more and more we’re going to try to combine small molecules, biological agents as sort of an induction with or without immunotherapy, and immunotherapy afterward as a consolidation. That’s 1 model. But there’s also lymphoma—more and more we see that we can, as I mentioned for example, the R-squared, ibrutinib window-type trials in the patients who are particularly non-GC [germinal center] subtype and frail patients can respond really well to this and have a shortened version of chemotherapy. And then there are ongoing trials looking at checkpoint inhibitors in combination with chemotherapy. BiTE [bispecific T-cell engager], as I mentioned, combination with trastuzumab, in combination with chemotherapy. More and more we’re going to integrate that.

And the third piece that is important is the role of immunotherapy as an immuno-consolidation post-induction. We know that cell-free DNA might help us with the depth of response in those patients. But we know that the patient’s immune status post-chemotherapy—although we don’t have a great way to quantify it, but based on the ratio data from the Mayo Clinic, for example, the ratio of lymphocytes to monocytes, across the board in a number of diseases and many subtypes of lymphoma—shows that it has a dramatic impact on the outcome. We don’t exactly know yet how to tackle this, but that’s an opportunity as a consolidation eventually. Definitely the question is more novel therapy, more immunotherapy, either in addition or to replace chemotherapy.

 With the new therapies coming to the clinic, how does cost affect your patients’ access to treatment? I’m sure that cost and access impact a patient’s and oncologist’s decision and, hence, care for therapies, especially for an aggressive disease like diffuse large B-cell lymphoma. Not only the cost of the drug itself, but also the cost of the logistics, such as in CAR [chimeric antigen receptor] T-cell therapy. There is a lot of cost implicated in treating the adverse effects, admission to the hospital, admission to the ICU [intensive care unit], the use of a caregiver, the caregiver has to be off work, the patients cannot drive for 2 months. There is cost in relation to that.

When you talk about the combination of tafasitamab and lenalidomide, I would think that it will be a top price for tafasitamab. But then you have to add the cost of lenalidomide, and whether insurance can cover part of the cost of lenalidomide, there may be a copay for patients. That should be considered in terms of the cost. Tafasitamab is a treatment that is given indefinitely. Patients get treatment for as long as they respond or for as long as they tolerate the medication. So that’s a cost because patients have to keep coming to an infusion center, they have to maintain a line. If they have complications related to the line, like infections or thrombosis, that adds to the cost because we have to treat those conditions. It’s important to consider those.

In the case of selinexor, which is a single oral agent, it will have definitely a top price. It doesn’t have the cost of hospitalization, it doesn’t have the cost of having an IV [intravenous] line. It’s an indefinite treatment, so if there is a patient who had a response, those patients have to remain on the drug for a long time. As far as I remember, in the trial some patients went on treatment for up to 3 years. That should be a consideration in regard to the cost. However, there are other costs that should be considered for selinexor. It’s a novel agent, has specific adverse effects that need to be taken care of, such as diarrhea, nausea, adding the medications to treat the nausea, adding the medications to treat the diarrhea. There are issues with cytopenias as well as thrombocytopenia. There are recommendations in the trial about using growth factors, they also have costs. So it is important to keep in mind when we use the novel therapies available, the other costs that are outside of the specific medications.

Relapsed/Refractory DLBCL: Unmet Needs

There is a potential for tafasitamab in combination with lenalidomide to significantly impact the treatment landscape for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting.

As I mentioned, the standard approach really should still be CAR [chimeric antigen receptor] T-cell therapy for patients who are young and fit enough to receive this therapy. But for patients who relapse after CAR T cell, or who are unable to make it to an authorized treatment center for CAR T, or are of significantly advanced age or with poor performance status, in those cases more traditional pharmacologic therapies are likely to be needed. And they will probably cycle through on an ongoing basis as the patients will likely eventually lose their response to these agents.

In the case of tafasitamab, this is an anti-CD19 monoclonal antibody, which was studied in a phase 2 trial in combination with lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. And what was reported and recently published was that a high proportion of patients, somewhere in the 40% to 50% range, achieved reasonably long-term remission with an impressive overall response rate of this combination.

With the anticipated approval of tafasitamab, in combination with lenalidomide for diffuse large B-cell lymphoma, I think we’re going to have more in our armamentarium and more options for patients with this disease.

The Re-MIND study was presented at the ASCO [American Society of Clinical Oncology] annual meeting. It’s an interesting study looking at lenalidomide as a single agent in the relapsed large cell lymphoma and to use it as real-world evidence to compare with the L-MIND trial, which was tafasitamab plus lenalidomide, where I mentioned the results were very impressive. This was to try to compare the outcome of this population with a combination versus a single agent. I think this was an important work because the awareness of the importance of real-world data is increasing rapidly. And these real-world data can confirm the clinical benefits of a new trial but also give you, if we can see a control group, although this was not completely matched as a control group, to suggest that the combination was really beneficial, with the anti-CD19 in addition to lenalidomide.

Emerging Treatments for Relapsed/Refractory DLBCL

The FDA approval for selinexor is anticipated this summer, and it is likely to be approved for relapsed or refractory diffuse large B-cell lymphoma [DLBCL].

The treatment landscape for diffuse large B-cell lymphoma is changing now that we have CAR [chimeric antigen receptor] T-cell therapy. It’s important to know that although a proportion of patients with CAR T cells may be cured, as I mentioned previously, with this therapy, 60% or more of the patients will not enter durable remission and will relapse.

For those patients, there are limited treatment options. Polatuzumab vedotin is a treatment option for those patients in combination with bendamustine and rituximab, which is approved in this setting. It’s anticipated that selinexor will also be approved in this setting.

This is an oral agent that can be used as a single agent in third-line therapy, as I mentioned, it was just approved. But I think the real benefit will be when we start to combine this with other agents, and hopefully have better disease control.

In my opinion, what I look at more is efficacy, how efficacious is a drug or a regimen. For patients with DLBCL, what I typically do is ask them what are their goals, if their goals are to cure the disease, or to maintain the disease in some type of remission, but no cure. If they want to achieve a cure and they’re healthy enough to do it and they don’t have a lot of significant comorbidities, I offer what is the standard of care, which is CAR T-cell therapy. That’s the main thing. I would say with all the CAR T-cell drugs available, essentially, the majority of patients could get CAR T-cell therapy. Age is not a limitation. Our oldest patient was 84 years old, he was in good shape, he was able to get treatment and he’s in remission. I think that’s a reason we have to offer what is the best care and best option, which is a curative option.

If the patient prefers not to undergo CAR T-cell therapy, not only because of the adverse effects, but also because of the logistics—traveling, leaving home, staying in a different place—that’s definitely a factor in deciding whether to pursue CAR T-cell therapy. In those cases in which CAR T cell is not possible for all those reasons, the patient is too weak, too sick, or logistic reasons, then oral agents such as selinexor play a role. Also other agents can be given closer to home, like monoclonal antibodies such as tafasitamab or polatuzumab. Those are viable options in the community.

When you have all these options, you have to choose the option that is more efficacious, but at the same time, less toxic. As I mentioned before, the monoclonal antibodies are used commonly by community oncologists, so they’re familiar with it. I wouldn’t see a problem in using tafasitamab orpolatuzumab. So there are options for those patients and they know how to use them. Selinexor is a novel agent, so you have to try to learn how to manage the adverse effects. Also the activity is modest. I don’t deny there is activity, but it’s not probably the greatest clinical activity, if you compare it to tafasitamab with lenalidomide, or polatuzumab/bendamustine/rituximab.

Finally, the other aspect is the maintenance of an IV [intravenous] line. So far, selinexor is the only oral agent approved for diffuse large B-cell lymphoma in the relapsed/refractory setting as a single agent. That’s definitely convenient because patients just take 1 pill. But again, it’s probably the less important factor in my opinion.

One of the things that has come up recently, one of the concerns, is that we’re experiencing the global pandemic of COVID-19 [coronavirus disease 2019]. This has led to some concern about intensive treatment regimens that are highly immunosuppressive, including autologous stem-cell transplantation, and potentially CAR T-cell therapy.

In my mind, the risks and benefits of using immunosuppressive therapy have to be weighed against the risk of infections, including COVID-19. But for a treatment for a disease such as relapsed diffuse large B-cell lymphoma, I think the benefits of the therapies that we discussed, including transplant and CAR T, still outweigh those risks.

There may be patients who are presented with the option of continuing to receive IV therapy as opposed to an oral agent like selinexor that can be taken at home. And it’s possible that an oral agent may be safer because of less exposure to the patient, but it also has to be taken into account that some of these agents can cause neutropenia and even if they’re oral, and that can predispose patients to infection.

Andre Goy, MD, John Theurer Cancer Center

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