New Strategy for Unmet Need in Relapsed/Refractory DLBCL - Episode 5

Using Novel Therapy in Relapsed-Refractory DLBCL

Matthew J. Matasar, MD:Polatuzumab vedotin-[piiq] is an antibody-drug conjugate targeting the protein CD79B, which is ubiquitously expressed across the surface of B-cell malignancies, including DLBCL [diffuse large B-cell lymphoma].

As an antibody-drug conjugate, the antibody targeting CD79B serves as a delivery mechanism for delivering the potent toxic substance to the cell. With polatuzumab vedotin, it is MMAE [monomethyl auristatin E], which is the same one that is delivered in brentuximab vedotin, the anti-CD30 antibody-drug conjugate that’s FDA approved in the treatment of classical Hodgkin lymphoma as well as certain forms of T-cell lymphoma.

The rationale for using BR [bendamustine, rituximab] as the backbone for the addition of polatuzumab vedotin was more of consideration of non—cross-resistant toxicities, rather than any anticipation of synergy, per se. Since MMAE is the payload being delivered by polatuzumab vedotin, we know that this agent has certain toxicities, including the risk of neuropathy and myelosuppression. Combining this with a program that was not in and of itself overly myelosuppressive and didn’t offer the risk of stacked neurotoxicity made sense to us as clinical investigators. BR [bendamustine, rituximab] is such a regimen, and knowing that it is already frequently used in the treatment of relapsed diffuse large B-cell lymphoma made a very rational partner for trying to answer this question.

The practical implications for the findings of an improved overall survival with polatuzumab combined with BR [bendamustine, rituximab] versus BR [bendamustine, rituximab] alone is that we have a new standard-of-care chemoimmunotherapy option for third-line plus patients with relapsed-refractory diffuse large B-cell lymphoma.

We understand that there are now 2 therapeutic approaches that are FDA approved. We have polatuzumab—BR [bendamustine, rituximab], and we have CAR [chimeric antigen receptor] T-cell therapy. These can be seen as complementary or even potentially cooperative treatments. Certainly, we know that not all patients are eligible for CAR T-cell therapy, given that approach has a unique toxicity profile. We know that not all patients have access to centers that have the ability to administer CAR T-cell therapy.

For those who do have access to CAR T-cell therapy, many patients with relapsed-refractory large-cell lymphoma in such a setting have aggressive and progressing disease. Those patients require bridging therapy, a treatment that can stabilize or control, potentially reduce their burden of disease while awaiting cellular manufacturing.

Here, polatuzumab—BR [bendamustine, rituximab] can be used as destination therapy for patients ineligible for or without access to CAR T-cell therapy. Or it can be considered as bridging therapy for patients in need of and who may benefit from CAR T-cell therapy but require a bridge.

Important reminders on how polatuzumab—BR [bendamustine, rituximab] is given for diffuse large B-cell lymphoma: In the study, polatuzumab–BR [bendamustine, rituximab] was intended to be given as an every-3-week regimen. This defers from how most oncologists are accustomed to giving bendamustine-based treatment, typically given on a 4-week schedule. It was done because we worry about the kinetics of the disease. We try to get in treatment in a little more dosage-dense fashion by giving it every 3 weeks. Some patients, but certainly not all, were able to tolerate a 3-week schedule. For patients who were having delayed-count recovery or toxicity, we certainly were comfortable and would be comfortable backing off to a Q4 [every-4-week] schedule.

Sometimes count recovery can be poor, despite giving every 4 weeks. One can consider dose modification of the bendamustine, which was given at 90 mg/m2. That can be dropped to 70 mg/m2or even 60 mg/m2. Whereas, if you feel that the polatuzumab is the offending agent, you’re having unexpected moderate to severe neuropathy, polatuzumab can be dose-reduced from the 1.8 mg/kg dose to 1.2 mg/kg without, I believe, significantly sacrificing activity.

My approach now is to take third-line patients and treat them almost in a similar intellectual exercise as we’ve always historically done with second-line patients. Whereas with second line, the question is, is this patient transplant eligible or transplant ineligible? With third line, the question is, CAR T-cell therapy: yes or no? For no—either ineligible for or no access to—polatuzumab—BR [bendamustine, rituximab] is a very reasonable standard of care.

For yes, then the next question becomes, do they require a bridge or not? If they do require bridging therapy, polatuzumab—BR [bendamustine, rituximab] is an evidence-based approach to offering such a bridge. For patients who don’t need bridging therapy, proceeding directly to CAR T-cell therapy is appropriate. There, one could reserve polatuzumab–BR [bendamustine, rituximab] for CAR T-cell therapy failure.

Transcript edited for clarity.