Q&A with Mark Roschewski, MD: Treating Follicular Lymphoma

Mark Roschewski, MD

Multiple PI3K inhibitors are approved for the treatment of patients with follicular lymphoma in the relapsed or refractory setting, but these targeted treatments are usually given indefinitely, leading to toxicity and increased cost for patients.

An ongoing phase 2 study presented at the 62nd American Society of Hematology Annual Meeting and Exposition aimed to determine if patients with follicular lymphoma could achieve a deep and durable remission after a fixed duration of copanlisib (Aliqopa)-based therapy in an earlier treatment setting. Patients with untreated grade 1-2, 3A follicular lymphoma were treated with 60 mg of copanlisib on days 1, 8, and 15 of a 28-day window. Following the window, participants received 6 cycles of the drug on days 1, 8, 15, and 28 along with 375 mg of rituximab (Rituxan) weekly.

The study also seeks to determine if a response-adapted approach to treatment could help with reducing the need for further treatment. Patients who achieve a complete response will stop therapy while those who achieve a partial response will receive another 6 cycles of the combination therapy. Non-responding patients will receive standard chemotherapy.

Preliminary results from the study have shown that all 10 patients enrolled in the study who have completed the copanlisib monotherapy window had a reduction in their tumor size with a median reduction of 40% (range, 16%-62%). Four patients have also completed 6 cycles of combination therapy and have all responded, with 2 achieving complete responses.

The regimen has been well tolerated with no patients discontinuing treatment due to toxicity. The most common events of rash, diarrhea, and mucositis have all been of grade 1 or 2 in severity with only 1 case of grade 3 neutropenia reported. 

Study author Mark Roschewski, MD, a senior clinician and clinical director of the Lymphoid Malignancies Branch at the National Cancer Institute Center for Cancer Research, discusses the early results of this study in an interview with Targeted Oncology.

TARGETED ONCOLOGY: What is the current treatment landscape for patients with newly diagnosed follicular lymphoma?

Roschewski: 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 disease is threatening an organ system. And then when you need treatment, the most common thing to do would be to give combination chemotherapy, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or bendamustine/rituximab. Or another good option is lenalidomide (Revlimid) with rituximab. And a sort of fourth option would be to give rituximab or obinutuzumab (Gazyva) by itself. So, there's sort of a lot of different options. You know, and one of the things we were trying to do here was to come up with another option that's a little more targeted, but doesn't go indefinitely.

TARGETED ONCOLOGY: What are the current unmet needs in this space right now?

Roschewski: I think the most important unmet need is to develop regimens that treat these patients that have high-risk biology. Today, we know there's a group of patients, about 20%, [where] standard therapies don't really get durable remissions. The majority of patients actually do, so the majority of patients that are diagnosed with follicular lymphoma will have life expectancies that are almost near normal age-match controls, but there's this subset of patients that have particularly resistant disease. And we don't fully have an understanding of who those patients are. But that's really where we want to improve our treatments.

TARGETED ONCOLOGY: What was the rationale for using this combination in this phase 2 study?

Roschewski: The rationale was to focus on the PI3-kinase pathway, which we know is critical for germinal center lymphomas, and therefore, follicular lymphoma. We were impressed with the activity of this drug in the relapsed setting, and we wanted to move it up front, with that being copanlisib. So, the way we designed the study is we wanted to be able to give them an anti-CD20 antibody with the targeted agent. But we wanted to have a better understanding of how copanlisib was acting. So, we first give a cycle of copanlisib by itself, so we can sort of delineate people that have a better and worse response in that window. But we also recognize that a lot of times these targeted therapies when they [are given] to patients, they're given indefinitely. And for upfront treatment, recognizing some of these people may have very good prognosis, we didn't want to do that, we wanted to stop at a defined period of time and use time-limited treatment. That's how we designed it.

TARGETED ONCOLOGY: What did the patient population look like in this study?

Roschewski: So far, it's a broad patient population, it's not targeted for low tumor burden. And it's not targeted for high tumor burden. It's simply patients that meet the criteria. So, you'll see there's all ages, there's all different stages. And, for the most part, that turned out to be relatively high risk, because it's not a study designed to treat patients earlier than you would have otherwise. A lot of these patients we've been following for a while before we thought they needed treatment. So, they all sort of have a little more bulky tumor and advanced-stage disease than you would in a cross section of all follicular [lymphomas that are] newly diagnosed.

TARGETED ONCOLOGY: What were the findings from this study?

Roschewski: Well, so far, the most interesting finding, I think, is that everybody in the window at least had a tumor reduction. So, we knew that the number of patients that would have a response to copanlisib would be high. So far it has been everyone, which is always exciting. The median [tumor reduction] is about 40%. So, we also see in that window, that the responses are quite rapid. So, you know, if one cycle of treatment you're reducing your tumor burden by almost 50%, that's usually a very good thing. And then the patients that have finished therapy so far, the majority of them have been in complete response after just 6 cycles. So, I think that's the main takeaway of the abstract. The other things for toxicity that I would point out [is] that a lot of patients do get a rash. But if you keep going with treatment, that rash kind of abates, it doesn't persist. So, it's not something that causes us to stop treatment. In fact, none of our patients have had to stop treatment because of toxicity.

TARGETED ONCOLOGY: What are the implications of these data?

Roschewski: Well, it's a little early. That's why it's a preliminary response. I mean, it's just showing that it's active in this situation. It's an ongoing trial. So we anticipate accruing another 45 patients to get a full understanding of who has the best responses, but I do you think we're going to be able to learn quite a bit about patients who have the best response to PI3-kinase inhibitors, so kind of a precision medicine approach, where if we can identify something that helps select those patients, they can be prioritized for this type of drug in further studies, or in combination. That's kind of one of the things we'll get, we don't have that yet. But that's something we aim to get.

TARGETED ONCOLOGY: What’s the key take-home message from this trial and its findings?

Roschewski: Well, I think the key take-home message is this drug in this class of drugs is highly active in the untreated setting, and that it is a good patient population to study with first-line treatments that even when you use novel agents here, you're going to get a lot of responses. And so, I think what it means for patients is there's going to be more options in the future as all of these drugs are coming along. And they have their own risk/benefit tradeoffs.

_Reference

_{Lakhotia R, Melani C, Muppidi JR, et al. Preliminary Results from a Phase II Study of Response-Adapted Therapy with Copanlisib and Rituximab for Untreated Follicular Lymphoma. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 1137.}