Samhouri Discusses Practice Changing Data in the DLBCL Space

Partners | <b>Allegheny Health Network</b>

In an interview with Targeted Oncology, Yazan Samhouri, MD, discussed new agents, clinical trials, and developments creating change in diffuse large B-cell lymphoma, as well as the key takeaways from ASH 2022.

Over the past year, there have been numerous advances for the treatment of diffuse large B-cell lymphoma (DLBCL). Though rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the current standard of care for treating patients with DLBCL, experts are always looking for new ways to improve upon the combination or discover better options.

“There have been a lot of exciting changes in the last few years in diffuse large B-cell lymphoma. Usually in first-line setting, we still use chemoimmunotherapy as a standard of care, but we are always trying to improve that. R-CHOP is also usually a standard of care, but we're [also] trying to improve that by adding novel therapies to it like bispecific T-cell engagers or monoclonal antibodies,” said Yazan Samhouri, MD, in an interview with Targeted OncologyTM.

Recently, the additon of polatuzumab vedotin (Polivy) to the regimen significantly prolonged progression-free survival (PFS) vs R-CHOP alone in patients with previously untreated DLBCL. Orelabrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi) added to the regimen also showed promising efficacy in non-germinal center B cell-like diffuse large B-cell lymphoma (DLBCL) with extranodal disease.

There is also glofitamab, a CD20/CD3 T-cell-engaging bispecific monoclonal antibody being evaluated as a potential treatment option for patients with DLBCL. During the American Society of Hematology (ASH) 2022 Annual Meeting, data from the expansion cohorts of a phase 1/2 study (NCT03075696) evaluating glofitamab demonstrated a manageable safety profile in this patient population. Treatment with glofitamab also induced frequent and durable complete responses.

According to Samhouri, MD, a hematologist/oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network, these are just a few of the most impactful updates that have been seen for patients with DLBCL this year.

In the interview, Samhouri discussed more of the new agents, clinical trials, and developments creating change in DLBCL, as well as the key takeaways from ASH 2022.

Can you discuss some of the research your team at AHN is working on and presenting at ASH this year?

At Allegheny Health Network, we have a mission of being a center for cellular therapy. We produce our own CAR T-cell product. We have an in-house product that that we have an investigation initiated in clinical trials in diffuse large B-cell lymphoma currently, and we are expanding that into other sites. We're working on starting a new clinical trial for primary CNS lymphoma using our in-house product, and we are excited about it. Also, 2 parts of the cellular therapy is our tumor infiltrating lymphocyte program [TILs program] and we have a few clinical trials that are already accruing. That's for different disease sites and we are expanding on that soon as well.

What are some of the changes being seen in the treatment landscape for DLBCL?

There have been a lot of exciting changes in the last few years in diffuse large B-cell lymphoma. Usually in first-line setting, we still use chemoimmunotherapy as a standard of care, but we are always trying to improve that. R-CHOP is also usually a standard of care, but we’re [also] trying to improve that by adding novel therapies to it like bispecific T-cell engagers or monoclonal antibodies.

There’s a clinical trial ongoing at AHN of lenalidomide in addition to R-CHOP compared with R-CHOP in the first-line. This treatment usually cures around 60% of the patients, but still there are 40% of patients that relapse or need further treatment. In the second-line setting, it depends when the patient relapse. If it’s late relapse, we usually go for salvage chemotherapy followed by an autologous stem cell transplantation. If it’s an earlier relapse, we think of CAR T-cell therapy based on the ZUMA-7 [NCT03391466] trial from last year.

What new agents seem promising in the space?

Bispecific T-cell engagers are promising, and we were all excited in the field about them coming into ASH to hear about all the data for glofitamab and other bispecific T-cell engagers like epcoritamab [DuoBody®-CD3xCD20]. Those are exciting drugs because the mechanism of action. They bind to CD3 on the T cells and bind to another target which is usually a CD20 on the lymphoma cells, and then they bring the T cells to the lymphoma cells to kill it and activate the immune system. They are a useful tool because they can be given in the community in contrast to CAR T-cell therapy which needs to be in a transplant or a CAR T Center. This can expand access of a very useful treatment for our patients in this field. The toxicity of these agents also seems similar to CAR T-cell therapy in terms of the cytokine release syndrome and neurotoxicity, but the rate of that these toxicities are lower, and the grades are also lower.

What clinical trials presented at ASH currently excite you most and seem the most promising for patients with hematologic malignancies?

The TRIANGLE clinical trial which was presented as a plenary session abstract and talks about adding BTKi and ibrutinib [Imbruvica] to chemotherapy as first-line in mantle cell lymphoma [seems exciting]. Mantle cell lymphoma is an interesting and challenging disease to treat because it's very heterogeneous. There are indolent forms of mantle cell lymphoma. There's an aggressive and there is a very aggressive form, which is a TP53 or blastoid form. We are always looking into improving the treatment landscape and improve outcomes for our patients with this disease. We cannot cure mantle cell lymphoma yet so, adding a BTKi like ibrutinib to first-line chemo immunotherapy seems to be doing well.

The presentation [at ASH focused on a] clinical trial where almost 900 patients were randomized into 3 arms. One arm got the standard of care chemotherapy followed by a transplant followed by maintenance reduction, which is our current approach. Another arm had standard chemotherapy plus ibrutinib, followed by transplant and maintenance rituximab and ibrutinib, and the third arm was without transplant. It seems that adding ibrutonib has benefit and more importantly, it didn't seem that it increased the toxicity a lot. This is something important that we are looking at, so we are excited to see more follow-up on these data, which is gonna be a practice changing in the field of mantle cell lymphoma.

What would you say is the most exciting practice changing data being presented at the meeting?

The TRIANGLE data is the practice changing data that I'm excited about, but I also can highlight some of the clinical trial in indolent lymphoma. For example, there was an exciting treatment in follicular lymphoma in the relapsed/refractory setting. It's called the EPCORE™ NHL-2 trial [NCT04663347]. We're starting to incorporate the bispecific T-cell engager earlier in the therapy of follicular lymphoma. Follicular lymphoma is indolent disease that we cannot cure. Usually, we treat with immune immunotherapy like rituximab, anti CD20 agents alone, or chemoimmunotherapy like bendamustine [Bendeka] and rituximab is the most common chemotherapy regimen used. If a patient relapsed, we go to a salvage treatment or second-line treatment like lenalidomide [Revlimid] and rituximab.

Now, this clinical trial is testing adding epcoritamab, which is a bispecific T-cell engager that binds to CD20 and CD3, to lenalidomide to try to improve outcomes. The data is promising. They presented safety data of about 62 patients that received this treatment. At this point, it doesn't seem it's it's going to be limiting to use this regimen. There are some cytokine release syndrome and neurotoxicity, but the rate is very acceptable, the grades were acceptable with manageable toxicity, and almost all the patients completed the therapy. This is an exciting treatment in the end and in the field of indolent lymphomas, specifically of follicular lymphoma.

With primary CNS lymphoma, we finally are starting to see the use of CAR T-cell therapy in this disease. For patients with either primary, or secondary CNS lymphoma, if they are refractory to chemotherapy, they have dismal prognosis and unfortunately, we don't have a good treatment option. That's part of the clinical trial that we're opening at Allegheny Health Network. Caron A. Jacobson, MD, MMSc, from Dana-Farber Cancer Institute presented nice data about using CAR T-cell therapy for these patients. She presented data on 9 patients, and what's important was we did not see more than neurotoxicity.

That's what was worrying us from giving CAR T-cell therapy for these patients. That's why those patients were excluded from the pivotal clinical trials because we were worried about increasing neurotoxicity. Now with increasing our comfort level with using CAR T-cell therapy, some patients in the real world received CAR T-cell therapy and had serious disease. There is a documented efficacy, but all anecdotal data, and now we are moving towards studying it in a systematic way in clinical trials. That's exciting for our patients as it will provide a useful and efficient treatment.

In your opinion, what has been the most impactful update in the DLBCL space this past year?

What I mentioned about follicular lymphoma and what Cyrus Khan, MD, mentioned in detail about glofitumamab that's in an article published in New England Journal of Medicine are impactful. Glofitumab is again bispecific T-cell engager. The efficacy and safety data are impressive, in relapsed/refractory diffuse large B-cell lymphoma. There are some patients who are not candidates for CAR T-cell therapy, there are patients who fail CAR T-cell therapy, and those are still difficult to treat patients. Bispecific T-cell engagers provide a tolerable treatment that can achieve durable responses, so we're excited about having similar drugs in the field.