Antibody-Drug Conjugates in Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Episode 1

Treatment Advances in Relapsed/Refractory DLBCL

A historical overview of treatment advances for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and the rationale for treating appropriate patients with an approved antibody-drug conjugate therapy.

Tycel Jovelle Phillips, MD: The current landscape for diffuse large B-cell lymphoma [DLBCL] has been evolving. For frontline therapy, the long-standing win has been R-CHOP [rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone]. We’ve had several studies looking to improve upon R-CHOP, which, at least in phase 3 studies, have all come back as negative studies. We’re currently awaiting the final report from the POLARIX study, which is R-CHOP versus R-CHP [rituximab-cyclophosphamide, doxorubicin, and prednisone]-pola [polatuzumab vedotin], polatuzumab being a CD79B [human gene B29 protein] antibody-drug conjugate.

The relapsed/refractory setting has been a bit more challenging, especially for what we consider to be primary refractory patients. Those have been one of our higher-risk patient populations, given the poor outcomes as indicated in the study by Dr Crump, which showed that most of these patients do not do well and will ultimately succumb to their disease with standard chemoimmunotherapy. This is a patient population we’ve tried our best to improve upon. That includes what we would consider double-hit patients, which are also a difficult patient population to treat.

If you’re dealing with a primary refractory patient, at this point, the data does not suggest that they will respond to high-dose chemotherapy or go on to an autologous stem cell transplantation. In this population, CAR T [chimeric antigen receptor T-cell therapy] has been one of the biggest improvements we’ve made with the cure rates expected around 40% to 50% of those patients. Now, what we do to bridge patients to CAR T has come into question, given that CAR T does need a manufacturing process, so it’s not an off-the-shelf treatment. There are a couple of different agents that have been used in this situation, from lenalidomide to radiation to polatuzumab, or polatuzumab plus bendamustine. The key point being to not cause any issues with the apheresis product, but to also keep the disease under control and not beat up the patient too much before they go to CAR T.

For patients with relapsed disease, which means that they have an initial longer-term response to frontline therapy and subsequently have the disease come back, those patients are easier to treat. They tend to have some sort of response to chemoimmunotherapy, and we can hopefully get those patients to an autologous stem cell transplantation with consolidation. Again, clinical studies that have come out with some of the new FDA-approved agents would be ideal for these patients if they are deemed to be transplant ineligible, given some of the response rates. Lenalidomide-tafasitamab has data indicating good outcomes and responses in patients in a second-line setting, and you would anticipate that at least some of the newer therapies would do better in an earlier line of treatment, where most of them are now approved in the third-line setting.

For the post-CAR T patient—not that CAR T does anything to their disease, but these are just patients with high refractory disease—we still don’t have a good method of treating these patients. Further research is needed to see what outcomes we can get with these newer studies, especially with the bispecific antibodies and some of these combination drugs. It is an exciting time with the newer approvals, but still a fair amount of work that we need to do for a number of our patients.

We talked about some of these antibody-drug conjugates, which are antibodies directed to the B-cells connected to a drug payload. We have 2 that have mainly been approved and utilized in our patients. We have polatuzumab, which is a CD79B antibody-drug conjugate, so it’s conjugated to a drug called monomethyl auristatin E, or MMAE. This treatment is approved in combination with bendamustine and rituximab and is given on an every-3-week basis for a total of 6 cycles, or until intolerance. The newer kid on the block is loncastuximab tesirine, which is a CD19 antibody-drug conjugate. This has a very different payload to it, as in it’s different from MMAE. It has a different side effect profile than what we see with polatuzumab, and different medications that need to be given with it, but overall, if you compared it to studies that are fairly equivalent in how they enroll patients, outcomes between the two are equivalent. The issue will come up being—with loncastuximab targeting CD19—how we incorporate that into the utilization with CAR T. Is that something we can use pre-CAR T as a bridging therapy or is it something that should be reserved for those patients who fail CAR T or are ineligible for CAR T with the failures of making sure we document that they still have CD19 expression?