Flinn Highlights CAR T-Cell Developments in Lymphoma

Ian W. Flinn, MD, PhD

With several approvals this past year, chimeric antigen receptor (CAR) T-cell therapy is becoming a significant part of treatment for select patients with hematologic malignancies.

Tisagenlecleucel (Kymriah) was approved by the FDA in May 2018 for adult patients with relapsed/refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma, after 2 or more lines of systemic therapy. The approval was based on findings from the phase II JULIET study, updated data of which showed an overall response rate (ORR) of 52%, with a complete response (CR) rate of 40%.¹

Previously, the FDA approved the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in October 2017 as a treatment for adults with relapsed/refractory non-Hodgkin lymphoma (NHL). The decision was based on findings from the single-arm ZUMA-1 study, in which axi-cel demonstrated an ORR of 82% and a CR rate of 54%. After 8.7 months of follow-up, 39% of patients remained in CR.²

Longer follow-up presented at the 2018 ASCO Annual Meeting showed that, at a median follow-up of 15.4 months, the ORR was 82% and the CR rate increased to 58%.³

According to Ian W. Flinn, MD, PhD, this new avenue of treatment has brought hope to doctors and patients alike, but there is still a long way to go before it becomes part of frontline therapy.

OncLive: Can you provide some background to your presentation on lymphoma?

What are some key updates from these recent data?

In an interview during the 2018 OncLive^® State of the Science Summit™, A Summer of Progress: Updates from ASCO 2018, Flinn, director of lymphoma research, principal investigator, Sarah Cannon Research Institute, discussed the latest developments with CAR T-cell therapies and other recent advances in the field of lymphoma.Flinn: I spoke about a number of different presentations that have occurred over the last 6 months, at the 2018 ASCO Annual Meeting and other meetings, looking at advances in both Hodgkin lymphoma and NHL, including small molecule inhibitors, chemotherapy, and CAR T-cell therapy. In follicular lymphoma, one of the key updates is the RELEVANCE study that compared rituximab (Rituxan) and chemotherapy with rituximab and lenalidomide (Revlimid; R²). This study was a large, international trial. It was based on some phase II data that suggested the R² regimen, rituximab plus lenalidomide, had very high remission rates and very tolerable toxicity. Therefore, that was an exciting phase II study that led to this randomized trial.

In this randomized trial—while technically it did not meet its primary endpoint, which was superiority of the R² regimen to chemotherapy—the response rates and progression-free survival between the 2 treatments was nearly identical. This is interesting because it offers a nonchemotherapy approach to frontline treatment of [patients with] follicular lymphoma. I suspect that some patients and their doctors will want to use this approach to avoid the toxicity that we normally see with rituximab and chemotherapy.

Other updates included CAR T cells from the JULIET and ZUMA-1 trials. The ZUMA-1 trial is a study of CD19-targeted CAR T-cells. This was previously published in the New England Journal of Medicine and now we see response rates in this update. The interesting thing that we saw here was the durability of the remission.

It turns out that if people achieve a full or partial response, and if they keep that remission for 3 months, they are very likely to maintain that for a long time. This was a great update for us as we continue to learn more about CAR T cells.

The JULIET trial involves the competing product [axicabtagene ciloleucel] that was just FDA approved for relapsed/refractory large cell lymphoma. Again, it's a CD19-targeted CAR T-cell product. As difficult as it as to compare the trials, a lot of people want to compare them. However, they are both very exciting. It involved 2 very different patient populations.

How do physicians manage atrial fibrillation?

Going back to CAR T-cell therapy, it has been less than 1 year since the first one was approved. What do you think are some of the key challenges or questions that oncologists might still have with this treatment?

One last publication to think about is the data we've seen involving Waldenström macroglobulinemia where rituximab was compared with the combination of ibrutinib (Imbruvica) and rituximab. This was a mixed population of patients who were previously untreated as well as those who had received prior therapy. What we saw was a substantial improvement in responses in the patients who had the combination versus rituximab alone. Atrial fibrillation is easily managed for the most part. It does require the patients being placed on antiarrhythmics. It is a bit of a complication, and sometimes because of the medicines being used to control it, you also have to change the dose of ibrutinib because of the drug-to-drug interactions that occur. It is definitely a hassle, and no one wants to get atrial fibrillation. However, it is manageable, for sure. The challenges are some of the toxicities. We know that CAR T cells are involved with a couple major toxicities. One is cytokine release syndrome (CRS) and the other is neurotoxicity. They vary from trial to trial, and perhaps from product to product, based on the second signal that is used in creating the CAR T-cell therapy.

Neurotoxicity, to me, is one of the most disturbing parts because patients often get this sort of vacant, “wide-awake, but no one is home” type of feeling. This is obviously disturbing to family members. Thankfully, for all these patients, it is a self-limited problem that gets better over time.

The one that also gets people scared is CRS. This can be very significant; people can get hypertensive and have to go to the intensive care unit. It is a big deal if it happens to your patient. With that being said, the whole community of investigators using CAR T-cell therapies are getting better at controlling these side effects and decreasing the severity of them. It is getting safer. The next generation of CAR T-cell therapies will be a lot more manageable.

Are there any other potentially practice-changing trials with other types of lymphoma where CAR T-cell therapies are being explored?

We would also like to move them, in the future, to being earlier in therapy and not just as sort of a last-ditch treatment. It is all very interesting and the whole oncology world is hoping that the “CAR T-cell side” wins because it would be a major improvement in survival for our patients, but only time will tell. CAR T-cell therapy is being explored widely not just across lymphoma, but across all hematological malignancies. It is also making its way into solid tumors. We see trials now focusing on follicular lymphoma, mantle cell lymphoma, and other malignancies, like acute lymphoblastic leukemia. The issue for some of these other diseases might be, “Is it worth the risk of a CAR T-cell therapy versus another therapy?” It is just not clear yet when the right time is to intervene for patients.

References

1. Borchmann P, Tam CS, Jager U, et al. An updated analysis of JULIET, a global pivotal Phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL). Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.
2. 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.
3. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. J Clin Oncol. 2018;36 (suppl; abstr 3003).