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Clinical

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

The FDA accepted odronextamab’s biologics license application resubmission for relapsed/refractory follicular lymphoma after phase 3 trial enrollment milestone.

FDA Accepts Odronextamab BLA in Relapsed/Refractory Follicular Lymphoma

Despite regulatory challenges from the FDA, odronextamab has received European approval for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma following 2 prior treatments.

Does Odronextamab Show Hope in FL and DLBCL Despite Regulatory Hurdles?

Advances in follicular lymphoma treatment have included the development of novel immunotherapies in relapsed and refractory disease and long-term follow-up of pivotal trials.

Exploring Bispecific Antibodies and Targeted Approaches in Follicular Lymphoma

The phase 3 inMIND trial evaluating tafasitamab in combination with lenalidomide and rituximab in relapsed or refractory follicular lymphoma showed promising progression-free survival findings, according to topline results. 

Phase 3 Trial of Tafasitamab in Follicular Lymphoma Meets Primary End Point

This FDA approval marks the first subcutaneous bispecific antibody to be approved in patients with relapsed/refractory follicular lymphoma. 

FDA Approves Epcoritamab in Relapsed/Refractory Follicular Lymphoma

Nemtabrutinib Shows Promise in Relapsed/Refractory Follicular Lymphoma

Wojciech Jurczak, MD, PhD, head of the department of oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, ​​discusses nemtabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor currently undergoing development for the treatment of patients with follicular lymphoma.

Recent data presented at the American Society of Hematology 2024 Annual Meeting and Exposition highlighted nemtabrutinib monotherapy in heavily pretreated patients with follicular lymphoma, showing a 41% objective response rate (95% CI, 24-61), including 1 complete remission, 11 partial remissions, and 6 patients with stable disease.

Additional safety and efficacy results from the phase 2 BELLWAVE-003 study (NCT04728893) showed that when nemtabrutinib was given to patients with relapsed/refractory follicular lymphoma at the recommended phase 2 dose of 65 mg once daily, the median duration of response was 5.8 months (range, 1.5-not reached [NR]) with a median time to response of 2.8 months (range, 2.6-5.4). The median progression-free survival within the as-treated population was 5.5 months (95% CI, 2.8-NR), and the median OS was NR (95% CI, 10.4-NR), with a 6-month OS rate of 100%.

Looking at safety, any-grade adverse events (AEs) were seen in 31 (86%) patients. Most of these AEs included neutropenia (28%), decreased platelet count (22%), and anemia (19%). Grade 3 or 4 AEs were observed in 13 (36%) patients. The most common grade 3 or 4 AEs included decreased platelet count (8%), thrombocytopenia (8%), neutropenia (8%), and anemia (6%).

There was no atrial fibrillation or other arrhythmia seen in the study. One patient had a dose reduction due to an AE, and 3 patients discontinued treatment due to an AE. These 3 AEs that led to discontinuation were thrombocytopenia, drug-related toxicity, and urticaria. Moreover, there were no deaths linked with AEs reported in the trial.

Findings from this study underscore the potential of newer BTK inhibitors in challenging cases, offering hope for improved outcomes in advanced lymphoma therapy.

Videos

Wojciech Jurczak, MD, PhD, ​​discusses nemtabrutinib and its development for the treatment of follicular lymphoma.

News

Balancing Risk and Efficacy in Follicular Lymphoma Treatment

Christopher R. Flowers, MD, MS, Department of Lymphoma - Myeloma, Division of Cancer Medicine at MD Anderson Cancer Center, discusses what the current treatment landscape of follicular lymphoma looks like.

According to Flowers, follicular lymphoma often affects older adults and is generally incurable with standard therapies. The current management of this disease ranges from "watch and wait" strategies for asymptomatic cases to aggressive first-line treatments like multiagent chemotherapy with antibody therapy.

Some cases, including for patients who relapse, may require advanced options such as chimeric antigen receptor (CAR)T-cell therapy or autologous stem cell transplantation. Treatment complexity has grown due to the withdrawal of certain relapsed-setting drugs, like PI3 kinase inhibitors, which were removed due to long-term toxicity concerns outweighing initial benefits. This shifting therapeutic landscape highlights the need for evolving management strategies to balance efficacy and safety in treating follicular lymphoma.

Follicular lymphoma as a disease can be quite complicated. In terms of its management strategies, I think it is a disease that is considered not to be curable with standard therapy, and a disease that typically affects older individuals, patients in their 70s and older being the average time when people are first diagnosed.

There are a variety of treatments that can be used in the first-line. Those can vary from things like just watching and waiting after someone is diagnosed until they develop signs or symptoms that require treatment, to treatments that are much more aggressive, like multiagent chemotherapy combined with antibody therapy as first-line therapies and things that are aggressive like CAR T-cell therapy and autologous stem cell transplantation when patients have relapses of their diseases. There are multiple other options that are included in between.

The other thing that has become challenging about the management for patients with follicular lymphoma is that there have been various classes of agents that were available for patients in the relapsing setting, like the PI3 kinase inhibitors, where we found toxicity over time with those drugs being on the marketplace, or that the benefits that were originally viewed for those agents no longer outweigh the risks of those agents. Those treatments have been withdrawn from the market more recently.

Christopher R. Flowers, MD, MS, discusses what the current treatment landscape of follicular lymphoma looks like.

Stephen Schuster, MD, professor of medicine at the University of Pennsylvania, discussed findings from the 3-year follow-up of the phase 2 ELARA trial (NCT03568461) of tisagenlecleucel (tisa-cel, Kymriah) for the treatment of patients with relapsed/refractory follicular lymphoma. According to the presentation at the 

, patients in this intent-to-treat group maintained durable, lasting responses 3 years after tisa-cel infusion, including patients in high-risk subgroups. 

Previously, we had done work in more aggressive lymphomas with [tisa-cel] with excellent results. It was FDA-approved, and [we] next moved on to follicular lymphoma, which is the second most common B cell lymphoma after the aggressive large cell lymphoma cohort. We had excellent results, probably even better overall than we got with the aggressive lymphomas. Not surprisingly, despite the fact that these were highly pretreated patients, very high response rate, 68% complete responses. In fact, those responses appeared very, very durable. Certainly for the patients that achieved complete response, there's been no recurrence of disease or deaths. The progression-free [survival] is very, very high, nowhere near the median, up above 70%. But for all the patients treated on the trial , in partial responders and complete responders together, I think we still haven't reached the median in 3 years, about 53%, just above. 

So some of the correlates, the immune fitness correlates, we're beginning to dive into now and not surprisingly, [we are seeing] T cells with more of a capacity to survive longer and proliferate more and differentiate to killer cells for longer periods of time. Even the patients who have the poor prognostic features and the unfit do much better than what we had before. We had to start studying it in greater detail because we want to make it better for everyone. Even as it stands in this at this point in time, it's better than what we had prior to it.

Stephen Schuster, MD, discusses findings from follow-up of the phase 2 ELARA study presented at the 2023 ASH Annual Meeting. 

Conference News

Tisa-Cel Shows Efficacy and Durability in R/R Follicular Lymphoma

Matthew Matasar, MD, discusses the development of mosunetuzumab and how it is impacting the field of follicular lymphoma.

Matasar Highlights Good News in Follicular Lymphoma

Matthew Matasar, MD, chief of the Division of Blood Disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discusses the development of mosunetuzumab (Lunsumio) and how it is serving as good news in the follicular lymphoma treatment field.

One of the biggest, most recent updates in the follicular lymphoma space has been with the development of mosunetuzumab. In December 2022, 

the FDA granted approval to mosunetuzumab

 for the treatment of adult patients with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. This approval was based on data from the phase 2 GO29781 study (NCT02500407) which enrolled 90 patients with follicular lymphoma that was grade I to IIIA. Patients must have had an ECOG performance status of 0 to 1 and received of at least 2 prior lines of therapy, including an anti-CD20 antibody and an alkylating agent.

Findings from the study showed that treatment with mosunetuzumab led to 80% of pretreated patients to have durable response rates. Additionally, the complete remission rate in the single-arm, multicenter, phase 2 study was 60%.

 For follicular lymphoma, we have important updates on the activity and durability of responses with the treatment with mosunetuzumab. Mosunetuzumab is a novel bispecific antibody targeting CD20 and CD3, creating an immune synapse with healthy T cells. This has been described in prior [meetings] and publications and clearly is an active medicine in patients with multimodal follicular lymphoma, with overall response rates of 80% and complete response [CR] rates of 60%.

The important question, however, is how durable are these responses? We now have maturing data, with a median follow-up now of 27 months. We see that the median duration of response, CR, and even median progression-free survival have not yet been reached, which for me, emphasizes the point that not only is this agent highly active in relapsed [follicular lymphoma], but the responses are quite durable.

Matthew Matasar, MD, discusses the development of mosunetuzumab and how it is a positive step forward in the field of follicular lymphoma treatment.


Matasar Highlights Good News in Follicular Lymphoma 

Christopher J. Melani, MD, assistant research physician in the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, discusses the combination regimen from the ViPOR study (NCT03223610) evaluating patients with aggressive lymphomas.

The ViPOR regimen consists of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid).

According to Melani, previously data from the ViPOR study have proven to be safe and effective in patients with relapsed/refractory aggressive B-cell lymphomas. Data for all patients with relapsed/refractory follicular lymphoma treated in the dose-escalation and expansion cohorts of the trial will be presented at the 2022 American Society of Hematology Annual Meeting.

ViPOR is a novel combination targeted therapy regimen. It was originally developed in aggressive lymphomas, mainly focusing on the ABC subtype of diffuse large B-cell lymphoma. It was originally a phase 1 study and we've now expanded into a number of different lymphoma subsets, both aggressive diffuse large B-cell lymphoma, as well as follicular lymphoma, and mantle cell lymphoma.

At the National Cancer Institute. We used our preclinical models to show synergy between a number of agents and BTK inhibitors, mainly ibrutinib. Three of the most synergistic agents in killing are leading to cytotoxicity. In diffuse large B-cell lymphoma included the BTK inhibitor ibrutinib, with venetoclax, an inhibitor of BCL2, as well as the immunomodulatory agent lenalidomide, which has multiple effects on DLBCL cell lines, reducing NF-kappa B activation and promoting cell mediated death. Based on those preclinical synergy studies, we combine them with the glucocorticoid prednisone as another mechanism of cytotoxic stress or genotoxic stress to the lymphoma, as well as the novel type 2 CD20 antibody obinutuzumab to develop the ViPOR regimen.

Christopher J. Melani, MD, discusses the combination regimen from the ViPOR study evaluating patients with aggressive lymphomas. 


About the ViPOR Regimen in Aggressive Lymphomas

Mark J. Roschewski, MD, a senior clinician and the clinical director of the Lymphoid Malignancies Branch of the Center for Cancer Research at the National Cancer Institute, discusses standard of care options for the treatment of follicular lymphoma.

According to Roschewski, there are several options for a patient with newly diagnosed follicular lymphoma. One option is to actually ‘watch and wait’ until the patient needs therapy. If the patient is at the point where therapy is needed, the most common option is chemotherapy or a combination chemotherapy such as rituximab (Rituxan), cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone (R-CHOP). Another option is bendamustine in combination with rituximab. 

Additionally, according to Roschewski, rituximab can be used with lenalidomide (Revlimid). Rituximab and lenalidomide can also be given as monotherapy. 

 [The] first thing that happens after diagnosis is one has to make a decision if they need treatment or not. So, one management strategy actually is to do 'watch and wait' until you think a patient has gotten to the point where they need treatment. So, all the patients on this study will have met that criteria. They either have some symptoms or their diseases is threatening an organ system. And then when you need treatment, the most common thing to do would be to give chemotherapy, combination chemotherapy, such as R-CHOP or bendamustine/rituximab. Or another good option is lenalidomide {Revlimid] with rituximab. And a fourth option would be to give rituximab or lenalidomide by itself. So, there's a lot of different options.

Mark J. Roschewski, MD, discusses standard of care options for the treatment of follicular lymphoma.









Treatment Options for Newly Diagnosed Follicular Lymphoma 

Sattva S. Neelapu, MD, a professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, discusses the challenges surrounding chimeric antigen receptor (CAR) T-cell therapy for the treatment of follicular lymphoma and other lymphomas.

According to Neelapu, while the response rate stands at around 80%, only about 35% to 40% of patients will have a long-term remission. This may be for multiple reasons, including the dysfunctionality of the CAR T cells or due to previous chemotherapies received by the patient.

However, CAR T cells from a healthy donor could help overcome some of these concerns as the fitness of the cells will be much higher than those from the patient. According to Neelapu, an over-the-counter product offers other benefits. For example, a product would not need to be manufactured, meaning the turnaround time would be quicker. Patients would not need to spend lengthy periods of time at one of the country’s few CAR T-cell centers. In addition to improving efficacy, an over-the-counter product could help expand access. 

 | Autologous CAR T-cell therapy, so there are at least 2 CAR T autologous CAR T products that are currently FDA approved for relapsed refractory large B-cell lymphoma. This option does not impressive efficacy here with response rates up to 80%, but only about 35% to 40% of his patients have long term remission. So, if we look at why the 60% of patients relapse or progress after autologous CAR T-cell therapy, there appears to be multiple reasons. So, one of the reasons obviously, is because the CAR T cells are dysfunctional because the T cells in the patient could be affected either because of the disease, the lymphoma itself, or because of the chemotherapies that these patients receive. So, if we were to take CAR T cells from a healthy donor that could potentially be overcome, because the fitness of the T cells would be much better compared to autologous CAR T.

 | But besides that, there are other challenges with autologous CAR T-cell therapy because the logistics of manufacturing come. It is a patient specific CAR T product. So, it takes on an average of at least 3 to 4 weeks turnaround time from the time we collect the pieces from the patient to when we can actually administer the CAR T cells to the patient. This could potentially be overcome by off-the- shelf CAR T-cell therapy approach from a healthy donor.

 | In addition, when we look at what percentage of the patients we actually get referred to autologous CAR T therapy, who actually received the product, we see that at least at our center, somewhere in the range of 10% to 15% of those patients who get referred to our center for commercial CAR T don't end up getting that CAR T product. The main reason for that is because of the delays in the manufacturing, the 3 to 4-week turnaround time. Besides that, if we look at the numbers of patients who are treated with autologous CAR T in 2019 across the US, for example, the estimates are that only 20% of lymphoma patients who actually need autologous CAR-T cell therapy are actually receiving it. So, 80% of the patients are not receiving it. And that I think it's partly because of the accessibility.

 | So currently, autologous CAR T is being administered at approximately 80 centers across the US, which averages out to only one or two centers per state, which is clearly not enough. And to receive autologous CAR T-cell therapy, the patient and the caregiver, need to travel to a CAR T center, need to stay locally for at least a 5 to 6-week period, which is not practical for most patients. On the other hand, if you were to have an off-the-shelf CAR T approach, it could potentially improve the accessibility because it simplifies the logistics and infrastructure that is required to administer CAR T-cell therapy. For example, a center is not required for allogenic CAR T-cell administration only. All the centers would need is a liquid nitrogen freezer to be able to freeze the product and keep it in storage until administration to the patient besides the standard infrastructure required for patient monitoring and management of any adverse events.

Sattva S. Neelapu, MD, discusses the challenges surrounding chimeric antigen receptor T-cell therapy for the treatment of follicular lymphoma and other lymphomas.

Challenges Surrounding CAR T-Cell Therapy in Follicular Lymphoma 

What are your thoughts about the future? What is on the horizon in terms of research across these diseases, follicular lymphoma, marginal zone lymphoma, and CLL [chronic lymphocytic leukemia]? What are you investigating that you think is exciting that is, ultimately, going to get to the market? We have seen a lot of different agents being tested: bispecifics, CAR [chimeric antigen receptor] T cells, a lot of other immunotherapies. What is exciting to you?

I think my goal would be to get chemotherapy-free regimens; it would be wonderful. I really like that trial you are looking at, the one where you are using the 2 agents up front. I think that is exciting. As you mentioned, we just had the CAR T approval for treating relapsed follicular lymphoma; I do not know how much CAR T in its present form I am excited about for treating patients with low-grade lymphomas. I think there is a subset of younger patients with aggressive disease that it makes sense for. I hope to get more therapies that are less toxic as these patients live many years. I hope the bispecifics that you can even get off the shelf will be something you can use in the future.

They are looking at those, and we have some trials we have been working with in myeloma. Some of them are even subcutaneous with a whole lot less cytokine release syndrome and neurologic toxicity, so hopefully those will also help in the treatment follicular lymphoma, be good treatment option, and a lot easier to use, I think, than the CAR T therapy. The newer BTK [Bruton tyrosine kinase] inhibitor—the LOXO-305 [Pirtobrutinib] agent—I know that it is used in the treatment of CLL and mantle cell lymphoma, but that is so good, and so hopefully that will also spill over into some of the treatments for other lymphomas. That looks, to me, like it has minimal [adverse] effects and excellent response rates in people who were unable to take other agents. That is another agent that looks pretty exciting overall that is an oral agent. Are you seeing things other than that, or in that same realm, that you think are exciting?

 Yes, I think it is very similar to your experience. We are investigating several different bispecific antibodies. The most mature is thymosin, which has been presented several times at ASH [the American Society of Hematology annual meeting] and other forums. It is highly active; the adverse event profile is much easier for patients to process than say, CAR T cells, and so it is getting away from all the cytokine release syndrome and the neurotoxicity. It is much easier. They can be given subcutaneously, and that is so much easier to give than CAR T cells. It can be given in the community offices; it does not take a specialized center to do that, and so hopefully, we’ll see that make its way through the regulatory pathway soon. Hopefully, that will come out.

I think CAR T cells are important, and the next-generation CAR T cells that we are investigating have a much more benign safety profile as well. Those look like they might be easier for patients, but as you mentioned, there are not that many patients with follicular lymphoma who would benefit from CAR T cells. Based on some of these studies, such as those utilizing data from the National LymphoCare database, 80% of patients with follicular lymphoma have nearly a normal rate of survival. It is only that 20% of patients, the early progressors, the patients with so-called POD24 [progression of disease within 24 months] who really benefit from these aggressive therapies. It is going to be a rare patient who I’d really want to give CAR T cells to—at least, as you mentioned, in their current configuration, with their current adverse event profile.

I do look at the EZH2 [enhancer of zeste homolog 2] inhibitors a bit, too, and hopefully, with their effectiveness, we can put them in there. Again, combination therapy is going to be the answer there, whether we add it with another CD20 agent or get to triplets with R squared [rituximab and lenalidomide] plus another oral agent, or something like that. I do not know how aggressive we need to be with these cases of follicular lymphoma, but maybe one day we can start saying we are curing those patients with follicular lymphoma with some pills up front. That would be wonderful.

Absolutely, I think that would be a great day. To bring up large cell lymphoma, within some of the new classification schemas there is a recognition of PI3K inhibitors being important in the treatment of some patients. It is a subset of patients with large cell lymphoma, so it is conceivable that PI3 kinase inhibitors—probably not as a single agent, but in combination with other therapies—might be important in treating a subset of patients with large cell lymphoma. We have seen, in all the early phase 1 trials with all the different inhibitors, that there was a response rate. Unfortunately, the duration of remissions was short in that, but it shows the activity of the drug in some patients with large cell lymphoma, and so you can imagine trying to incorporate these drugs in that setting in the future.

I know that even in the UNITY trial, there was an arm studying B-cell lymphoma that was initially in there. I think we used it with bendamustine, if I recall correctly—bendamustine Rituxan [rituximab] plus—but I have not seen any of the data for that, which makes me concerned there was not great effectiveness, but I don’t know. It would be nice if we could find some oral agents that would do a great job for patients with diffuse large B-cell lymphoma.

This transcript has been edited for clarity.

Expert hematologist/oncologists provide thoughts on the potential role of PI3K inhibitors in managing R/R FL and MZL, as well as other diseases.

Follicular Lymphoma

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