Four-Year Follow-Up Data Confirm Durable Responses With CAR T-Cell Therapy in B-Cell Lymphomas

Elise Chong, MD

Elise Chong, MD

Although chimeric antigen receptor (CAR) T-cell therapies tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta) have been approved by the FDA, the longest reported follow-up for these products is 19 months and 24 months, respectively. Researchers at the University of Pennsylvania sought to investigate these CAR T-cell products with long-term follow-up in patients with B-cell lymphomas.

Twenty-four patients with diffuse large B-cell lymphoma (DLBCL) and 15 with follicular lymphoma (FL) were enrolled in a single-institution trial of tisagenlecleucel,¹which wasapproved in May 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma, including DLBCL and transformed FL, after ≥2 prior lines of systemic therapy. Patients in this trial had no curative options, prognosis of less than 2-years survival, and less than a complete response (CR) to their last therapy.

The median follow-up was 49 months. In the DLBCL cohort, 46% of patients had a CR while 71% of patients in the FL cohort had a CR. The median progression-free survival (PFS) was 5.8 months in patients with DLBCL, with a median overall survival (OS) of 22.2 months. Patients with FL had a median PFS of 32.4 months, and the median OS was not reached. Median duration of response was not reached in either arms.

“Compared to historical controls of similar populations of patients—specifically thinking of the SCHOLAR-1 data—this is quite impressive and shows that these remissions appear quite durable, at least through 4 years in DLBCL,” said Elise Chong, MD.

These data demonstrate that CAR T-cell therapy can provide durable remissions over a median follow-up of 4 years in patients with relapsed/refractory DLBCL and FL. This is also the longest follow-up for tisagenlecleucel reported to date.

In an interview withTargeted Oncology, Chong, a fellow at the University of Pennsylvania, discussed the 4-year follow-up data for CAR T cells in patients with DLBCL and FL. She also addressed the challenges that need to be overcome in order to give more patients access to this type of therapy.

TARGETED ONCOLOGY: What was the rationale to investigating this therapy in patients with B-cell lymphomas?

Chong:We were initially interested in looking at long-term follow-up with CAR T cells. There are good 2-year data for both multicenter trials for the FDA-approved products, the ZUMA-1 trial with axi-cel and the JULIET trial with tisagenlecleucel. However, that follow-up is limited to around 2 years, so there are many questions. Two important questions are how durable are these responses and is there any long-term toxicity from CAR T cells?

What we did was a long-term analysis of a single-center, investigator-initiated study conducted at the University of Pennsylvania that we had actually started in 2014. This enrolled both patients with DLBCL and FL. We initially reported these data in theNew England Journal of Medicinein 2017,²so this is our long-term follow-up analysis. The data were [analyzed] as of February 2019.

TARGETED ONCOLOGY: What were the findings from this trial?

Chong:We infused a total of 24 patients with DLBCL and 14 with FL. These were all very heavily pretreated patients with advanced-stage disease. Looking at our responses for DLBCL, we saw that 35% of patients continued to be progression-free at a median follow-up of 49 months, which is quite long follow-up. For patients who had a response to therapy, 60% of those patients remained responding at that follow-up of 49 months. Additionally, the OS for the DLBCL cohort was 22 months. Compared to historical controls in similar populations of patients—specifically thinking of the SCHOLAR-1 data—this is quite impressive and shows that these remissions appear quite durable, at least through 4 years in DLBCL.

TARGETED ONCOLOGY: What challenges need to be overcome to incorporate CAR T-cell therapy into this space?

Chong:There are a few things. First of all, I think currently because of this is a very specialized therapy, there are only a certain number of centers that have expertise in this type of therapy. Finding a center where this therapy is offered is the first challenge.

Physically manufacturing the cells is something else, in terms of the time of manufacturing, that people are really interested in. The issue is that some of these patients are very sick, especially with DLBCL, so having a sufficient window to manufacture those cells and wait, even if we administer different therapies, it can be problematic in these patients. Not everyone’s cells that we collect we are able to infuse because the disease needs to be controlled for this therapy to be successful.

Finally, not all patients are responding, so figuring out why these patients aren’t responding is important. Our FL data, in terms of response rates, looked even better. We saw 78% overall response rate, and those remissions were also very durable, with 60% of patients being relapse-free at 4 years. The OS was also not reached at 4 years, so that also looked very encouraging.

TARGETED ONCOLOGY: What other studies have you seen outside of this with CAR T-cell therapies that have been encouraging?

Chong:I think what’s interesting and where the field is moving is [toward looking at] how can we either overcome resistance or make this therapy more available. There are EBV-specific T cells where people are engineering CAR, which is very interesting, but there is no real data for that yet; however, it looks good. I think there are off-the-shelf or allogenic CARs, which are also interesting. These are CAR cells that would already be available for manufacturing.

The closest thing we need to look for in terms of data is pushing this therapy earlier from third-line therapy to second-line therapy and looking for the results of both the ZUMA trial comparing autologous stem cell transplant (SCT) to CAR T-cell therapy, as well as the BELINDA trial, which is doing the same thing with tisagenlecleucel and autologous SCT versus standard-of-care therapy. I think seeing what those randomized trials show is going to be crucial.

There’s also some new trials looking at combinations with CAR. Checkpoint blockade with CAR is a big, hot area where there are multiple, different CAR products being combined with checkpoint, and those response rates look really great. It’ll be interesting to see what the long-term follow-up data is for that. There are other combinations as well, such as ibrutinib (Imbruvica) plus CAR T-cell therapy, that may have some increased efficacy as well.

TARGETED ONCOLOGY: What do you want oncologists to take away from this in terms of enrolling patients into CAR T-cell therapy studies?

Chong:Either patients who are primary refractory to first-line therapy, specific to patients with DLBCL, or patients who are not responding quickly to salvage therapy, do need to be referred early to a CAR center because their prognosis and their likelihood of responding to SCT is much lower. Unfortunately, when these patients get too sick, it’s difficult for us to have the time to manufacture a CAR product as well as even just get through arranging for that to happen. It’s not an immediate process; it takes several weeks for that to happen, so sooner referral is better.

TARGETED ONCOLOGY: Are there any other advances outside of CAR T-cell therapy that you find particularly hopeful?

Chong:A lot of the bispecific antibodies are interesting. The early data, in terms of response and the types of patients who are responding, is very exciting, especially for the B-cell lymphomas. I think that some of the immunoconjugates, such as polatuzumab vedotin (Polivy), which is very exciting, and I think that FDA approval was quite exciting for DLBCL as well. I think just understanding mechanisms of resistance better and the biology of these tumors is going to help guide therapy better in the future.

References

1. Chong EA, Svoboda J, Nasta SD, et al. CD19‐directed car t cell therapy (CTL019) for relapsed/refractory diffuse large B‐cell and follicular lymphomas: four year outcomes.Hematol Oncol. 2019;37(suppl S2):137-138. doi: 10.1002/hon.96_2629.
2. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor t cells in refractory B-cell lymphomas.N Engl J Med. 2017;377:2545-2554. doi: 10.1056/NEJMoa1708566.