CAR T Cells Continue to Be Leveraged in Lymphoma

Frederick L. Locke, MD

Chimeric antigen receptor (CAR) T-cell therapy has shown durable responses in patients with subtypes of non-Hodgkin lymphoma; however, the key to optimizing responses is early referral, said Frederick L. Locke, MD.

“It's important that community oncologists realize that early referral for CAR T likely drives outcomes,” said Locke, a medical oncologist at Moffitt Cancer Center. “We need to get these patients to us earlier because of the time that is needed to set up the therapy. The more widespread that understanding is, the more lives will be saved by this therapy.”

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 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. 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 (ALL) 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.

OncLive: You have been involved in the trials with axi-cel. What is it like to see its FDA approval?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Locke, one of the lead authors of ZUMA-1, discussed the expansion of CAR T-cell therapy in patients with lymphomas following the 2017 approval of axi-cel and remaining research questions with the therapy.Locke: We now have 2 FDA-approved CAR T-cell products for the treatment of adult [patients with] aggressive B-cell lymphomas. It's been fantastic. We knew from single-center trials that tested CD19-directed CAR T-cell therapy that it could work for patients with B-cell malignancies. As we were running the phase I and then phase II ZUMA-I trial, we saw the greater than 80% response rate in patients who had very little chance for response or complete response. Those responses are durable. Over 40% of patients remain in remission 1 year out with almost a 1.5-year median follow-up. The results have been remarkable.

What else have clinical trials revealed about the therapy?

Transitioning it to real-world care has also been very rewarding. We're able to treat any patient who needs the therapy. One of the main things I wanted to get across to my colleagues is that it's key that these patients are referred early for consideration of CAR T-cell therapy. If I was a practicing oncologist treating many different diseases, and had a patient with aggressive lymphoma who progressed through frontline R-CHOP chemotherapy, I would already be thinking about referring that patient for CAR T-cell therapy. It takes time. It takes up to 4 weeks from the initial consult until the insurance approvals [come through] and [the cells are shipped and returned]. We want the patients to go to the centers that administer CAR T-cell therapy as soon as possible.One of the key things we've learned is that it's OK to give bridging chemotherapy. In the ZUMA-I trial, we collected cells for [the] manufacturer of axi-cel and then waited for them to return. On average, it took 17 days. In both the JULIET trial and now the ongoing TRANSCEND trial with other CAR T-cell products for lymphoma, bridging chemotherapy was allowed.

When will we hear updates of the axi-cel and atezolizumab (Tecentriq) trial in DLBCL?

Are there any forthcoming updates on other ongoing trials?

What are the biggest challenges that remain with CAR T-cell therapy?

Now that we have FDA approval for axi-cel and tisagenlecleucel, we are able to give bridging chemotherapy once the cells are collected. We believe that can make a difference for these patients. The use of bridging chemotherapy may reduce disease burden and might even be responsible for some of the differences in toxicities that are seen across the pivotal trials for these competing products.The last update was presented at the 2017 ASH Annual Meeting. We hope to present the final data set from the phase I portion of that study at the 2018 ASH Annual Meeting. That's an important prospective study combining axi-cel with a PD-L1 antibody for patients with DLBCL—–the same population as in the ZUMA-I trial. The early data suggest that the combination may increase the expansion of CAR T cells within the patient’s body. In the early phase I data set, it appears to be safe with similar efficacy as axi-cel alone. It's still early for that data, but we're excited about that trial.We are preparing and will present long-term follow-up data with the opportunity of a median follow-up of 2 years in all patients [on ZUMA-I]. I expect that results will look good. We're still waiting for the final data cut to analyze. We have also prepared a large consortium of 17 centers to pool data on the commercial axi-cel patients. We're hopeful to present that data in the near future that will show the efficacy and toxicity of axi-cel when used as a standard-of-care therapy.There are a number of challenges. One is durability of response. We're seeing about 40% durable responses. What about the other 60% of patients? We need to better understand why it does or doesn’t work. We're starting to see signs that there is CD19 loss in some patients who progress, though it doesn't appear to be in all patients. We're starting to understand the mechanisms that drive resistance to the therapy and progression. In the ZUMA-I trial, we collected biospecimens from our patients. We are testing those and hope to better understand the therapy. Those data will come out in the near future.

How has CAR T-cell therapy expanded across lymphomas?

Why should community oncologists refer their patients early for CAR T-cell therapy?

Then, can we move the therapy earlier? We know we can use it in the relapsed/refractory setting in patients whose lymphomas progressed despite 2 or more lines of therapy. Can we give it as a second-line therapy? Randomized trials are testing that question. We're actively enrolling patients. Should salvage chemotherapy followed by autologous stem cell transplant (ASCT) versus CAR T-cell therapy be considered the gold second-line standard? Ongoing trials should answer that question in the coming years. This is another reason to refer patients early. We could potentially offer them CAR T-cell therapy earlier in the course of their disease on one of these trials if they're eligible.Tisagenlecleucel was the first FDA-approved CAR T-cell product for pediatric and adolescent young adults with B-cell ALL. Then, axi-cel was approved for adults with DLBCL and its variants. Any B-cell malignancy can be targeted with a CD19-directed CAR T-cell therapy. It's only a matter of time before the trials are appropriately designed and the evidence is there to safely administer these therapies, whether it be for mantle cell lymphoma, chronic lymphocytic leukemia, or adult ALL. All of these trials are coming along. I expect we will eventually see approvals in all these different indications.A community oncologist who sees some lymphoma [cases] occasionally and gives R-CHOP chemotherapy may cure 60% of those patients or more. That's great, but if that upfront therapy isn't working and the patient's lymphoma is progressing, they will need some second-line treatment. There's no best second therapy, so they'll go ahead and give whatever they're familiar with.

Typically, they'll refer that patient for ASCT if they're fit. That usually happens a 1 or 2 months down the road. Patients in remission will get ASCT. If they don’t respond to the second-line therapy, they might not be referred for ASCT, or they might show up with progressing disease. At that point, it might be too late. When these patients don’t respond to chemotherapy, the growth of the disease gets faster after each line of therapy.

We need those windows in order to collect the cells and get the patient with a good performance status through the therapy. The oncology community must understand these therapies can work and lead to durable responses, especially in patients who have a good performance status and who don't have rapidly progressive disease or high disease burden.

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.