DLBCL Landscape Shifts Dramatically With Axicabtagene Ciloleucel FDA Approval

Reem Karmali, MD, discusses ongoing key trials of CAR T-cell therapy, the chronic safety concerns with the treatment, and what combinations have the most potential.

Reem Karmali, MD

The non—Hodgkin lymphoma landscape recently underwent a major transformation, as researchers in the field saw the FDA approval of axicabtagene ciloleucel (axi-cel; Yescarta), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for transplant-ineligible patients with relapsed or refractory disease.

The approval was specifically for patients with large B-cell lymphoma following 2 prior therapies, including those with diffuse large B-cell lymphoma (DLBCL). Additionally, the CAR T-cell therapy is indicated for primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.

The FDA based its decision on data from the phase II ZUMA-1 study, in which axicabtagene ciloleucel was associated with an objective response rate of 82% and a complete response rate of 54%. Thirty-nine percent of patients continued to have a CR after 8.7 months of follow-up.

“The last 5 years have been focused on novel targeted agents, and we are entering an era of cellular immunotherapeutics—and CAR T-cell therapy is something that has a great deal of potential,” said Reem Karmali, MD.

OncLive: There have been several developments in CAR T-cell therapy over the last few months. What did you share in your presentation?

In an interview during the 2017 OncLive® State of the Science SummitTM on Hematologic Malignancies, Karmali, assistant professor of medicine (hematology and oncology), Feinberg School of Medicine, Northwestern University, discussed ongoing key trials of CAR T-cell therapy, the chronic safety concerns with the treatment, and what combinations have the most potential.Karmali: We went through a little bit of an overview of immunotherapy as a segue to CAR T-cell therapy, and then, with respect to CAR T cells, we talked about the construct itself, its mechanism of action, and then we spoke about some of the key clinical trials for CAR T-cell therapy—specifically focusing on some of the encouraging results we are seeing in DLBCL.

We spoke about 3 of the main multi-institutional pivotal trials that are currently ongoing, including the JULIET study, which is for relapsed/refractory patients with DLBCL who received 2 or more prior lines of therapy. We talked about the ZUMA-1 study which looks at a different CAR T-cell product. Then, we talked about the TRANSCEND study, which looks at a third CAR T-cell product. Essentially, we went through and discussed results for the DLBCL population, the refractory/relapsed DLBCL population, and showed some of the encouraging results that we've managed to get out of these products.

We have seen safety challenges thus far with CAR T-cell therapy. What do we know so far?

We ended with addressing some of the challenges that we’re facing with respect to CAR T-cell therapy, from a patient selection and toxicity management standpoint. We also went through how we think CAR T-cell therapy may fit into existing modalities of treatment and how it may change treatment paradigms for DLBCL. There are really 2 main toxicities that we are most concerned with. One is cytokine release syndrome (CRS), which is a state of inflammation driven by various cytokines—IL-6 being one of the major cytokines that drive that process.

The other main toxicity that we're concerned with is neurotoxicity. In fact, with some of the earlier products, cerebral edema has been an issue that has led to deaths. More recently, we haven’t seen as many of those specific events occur, but certainly CRS and neurotoxicity are the big issues.

It's not clear what the mechanism is for neurotoxicity. When we think about patient selection, there really needs to be an understanding of the fact that we need to pick patients for CAR T cells that have relatively preserved organ function, so that they can withstand those toxicities with minimal neurological comorbidities. There are some other issues with respect to limitations for CAR T-cell therapy, and that includes the need for adequate hematopoietic reserve so that we can collect adequate CAR T-cell product.

We also saw the approval of tisagenlecleucel (Kymriah) in acute lymphoblastic leukemia. What has it been like to observe a wave of CAR T-cell therapy research unfolding this year?

Will we get to a point where there will be combinations with CAR T-cell therapy?

With respect to their disease, it needs to be relatively stable moving into CAR T-cell therapy because of the logistics of the manufacturing. It can take anywhere from 3 to 6 weeks for CAR T-cell products to be manufactured, so we must ensure patients can be bridged in a way where they can receive their CAR T-cell product. It has been unremarkable. It is just great to be able to see patients who are so refractory to their chemotherapy have this as an option. One of the studies that is looking at the outcomes of patients with refractory DLBCL is the SCHOLAR-1 study. [In this population], median overall survival is just a little bit over 6 months; it’s not very good. To be able to see these CAR T-cell products come to fruition as an agent that is available to such patients is just great.That is being looked at. There have already been clinical trials underway with CAR T-cell therapy and checkpoint inhibitors, with the hope that checkpoint inhibitors may actually rev up CAR T-cell function. That is underway.

What else should community physicians know about the state of CAR T-cell therapy?

At Northwestern University, we hope to [launch a study] of CAR T-cell therapy in combination with novel agents, and the first arm on that study will include CAR T-cell therapy with the anti—PD-L1 agent durvalumab (Imfinzi). The hope is that it serves to investigate various combination strategies. Essentially, the right partner will be something that revs up CAR T-cell functionality and optimizes the ability for these CAR T cells to exert their antitumor effects. However, we have to keep in mind not to exaggerate the toxicities that can be associated with CAR T-cell therapy. It is important to understand that this is a very encouraging modality of therapy. We are entering an era of cellular immunotherapy, if you will. There are going to be challenges, and some of the biggest ones are going to be toxicity management and how we can incorporate CAR T-cell therapy with existing modalities. However, overall, the consensus is that results thus far have been encouraging and we expect that it is going to dramatically change the therapeutic landscape for DLBCL.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.