Capitalizing on Promise of CAR T Cells in DLBCL

Babis Andreadis, MD

Chimeric antigen receptor (CAR) T-cell therapy has activity in patients with relapsed diffuse large B-cell lymphoma (DLBCL), but there are a number of considerations to keep in mind before choosing to proceed with this treatment, explained Charalambos (Babis) Andreadis, MD, MSCE.

“It's something that we're very excited about, especially for patients with relapsed disease. We also need to remember that it doesn't work for everyone, and it's not available to everyone,” said Andreadis. “It’s limited by significant financial considerations and coverage. Even in the patient who can get it, it works about one-third of the time. There's still room for improvement of CAR T-cell therapy with either new CAR designs or with the addition of adjunctive treatments.”

In October 2017, the FDA approved the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The approval was based on complete remission (CR) rates in the phase II ZUMA-I trial. Long-term follow-up data have since been shared showing an overall response rate of 82%, with 42% remaining in response at a median follow-up of 15.4 months.1 The median duration of response was 11.1 months (95% CI, 3.9-not estimable).

Axi-cel joined tisagenlecleucel (Kymriah), which, in August 2017, became the first FDA-approved CAR T-cell therapy. Tisagenlecleucel was initially approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. In May 2018, the FDA approved tisagenlecleucel for use in adult patients with relapsed/refractory large B-cell lymphoma—Including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.

Lisocabtagene maraleucel (liso-cel; JCAR017) has also demonstrated efficacy. Updated data from the phase I TRANSCEND trial presented at the 2018 ASCO Annual Meeting showed that the CAR T-cell therapy had a durable CR rate of 46% at 6 months for patients with high-risk DLBCL.

OncLive: How has CAR T-cell therapy impacted patients with DLBCL?

Could you elaborate on the 2 FDA-approved CAR T-cell products?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Andreadis, associate professor of clinical medicine, Department of Medicine, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed the use of CAR T-cell therapy in patients with DLBCL and the associated toxicities with each product, as well as other promising therapies in the paradigm.Andreadis: In the relapsed setting, DLBCL is still a disease in need of additional therapies. [Patients can do well with] transplant and may cure one-third of patients. There are a lot of patients who are ineligible for transplant or who don't respond well enough to chemotherapy to benefit from transplant. For those patients, we have CAR T-cell therapy, which can be active. My presentation focused on how we manage the toxicities of CAR T-cell therapies and how we triage patients for one or the other. Then, how we establish the production, efficacy, and toxicity of this treatment in the real-world setting.There are 2 approved products now. One is tisagenlecleucel, which is a 4-IBB product. The other is axicabtagene-ciloleucel, which is a CD28 product. They have very similar activity, in my mind. The clinical trials that have been done show response rates in the 50% range and long-term responses in the 30% to 40% category. Those are the responses we're interested in because those are potentially the patients who can be cured.

What is the eligibility criteria for CAR T-cell therapy?

They have a different toxicity profile in my experience and that of others. Toxicities with tisagenlecleucel are mostly low-grade cytokine release syndrome (CRS). There is a little bit of neurological toxicity that does not often require secondary agent support, such as tocilizumab (Actemra) or steroids. Axi-cel has more of a robust and early onset toxicity profile. We see higher rates of CRS, higher rates of neurotoxicity, and higher use of tocilizumab and steroids. That may make it harder to give in the outpatient setting.To be eligible for CAR T-cell therapy, patients must be in good physical health. Performance status is the main eligibility criteria. People do worse when they come in at a lower function, which is a higher ECOG performance score. In terms of other eligibility, neurological history or prior neurological disease makes patients more likely to experience neurological toxicity. That is something we pay attention to.

Does a delayed partial response mean that the therapy was not effective?

How do you choose which CAR T-cell therapy to administer?

Though you focused on CAR T-cell therapy in DLBCL, could ibrutinib (Imbruvica) still have a role in DLBCL following the negative readout of the PHOENIX trial?

Cardiac function is important because of the hemodynamic changes that can happen with CRS. Autoimmune diseases are also of concern because we're giving cells that can potentially release hormones that activate the immune response. It's a little less stringent than that for autologous stem cell transplant, but it is still pretty significant. The therapy is not for everyone.No. As we now know, from at least 2 of the 3 products that are being researched or marketed, patients can take a long time to respond. [We’ve seen patients take] up to 6 months with axi-cel and up to 12 months with tisagenlecleucel. That response is mostly an imaging epiphenomenon rather than a biological delay. PET scans can be positive for many reasons including inflammation and T-cell infiltration. It's important to have some signs of clinical progression or some evidence by biopsy that there is actual disease left before physicians abandon the therapy or change course.We have 1 that is commercially available at UCSF; we are in the process of opening up the other one. It's going to be hard to distinguish the activity profiles between them. I will tailor [treatment] toward the toxicity profile. For the outpatient setting, which is something we're highly interested in, tisagenlecleucel looks a little more promising in terms of keeping patients out of the hospital and out of serious toxicity. Each of them will be very different in the long run.Absolutely. Ibrutinib still has a role. It is hard to show a benefit in frontline treatment because so many patients do really well. The original data, showing that the activated B-cell (ABC) patients did a lot worse than the germinal center B-cell patients, have not panned out in subsequent studies. Since all patients start out doing better than expected, it's hard to show that a single agent can change that course, especially if the salvage options are as good as they are today.

Does the antibody-drug conjugate polatuzumab vedotin have potential in DLBCL?

I still think there is a role for ibrutinib in the second-line setting. Even as a single agent, ibrutinib has activity for relapsed ABC-subtype patients.It's an exciting treatment. I've seen phase II data showing that it's very promising. “The proof is in the pudding." We need to see whether it's going to make a difference compared with R-CHOP in the phase III setting. As we discussed, R-CHOP is hard to beat, but I'm cautiously optimistic.

References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up 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 ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 578.
2. Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36(suppl; abstr 7505).