Flinn Examines Improved Response Rates with KTE-X19 in Mantle Cell Lymphoma

Ian W. Flinn, MD, PhD

Ian W. Flinn, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy KTE-X19 induced a 67% complete response (CR) rate in patients with relapsed/refractory mantle cell lymphoma (MCL), as well as an objective response rate (ORR) of 93%, according to data from the phase II ZUMA-2 trial presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

After a median follow-up of 12.3 months, 47% of patients had been followed for at least 24 months. Findings showed that 40% of patients who initially had a partial response or stable disease transitioned to a CR with a median time to CR of 3 months.

At the time of analysis, the median duration of response had not yet been reached, but of those who achieved a CR, 78% of patients remained in remission at the time of analysis. For the first 28 patients who were treated with the CAR T-cell therapy, the median follow-up was 27 months, whereas 43% of the responders remained in remission. The 12-month progression-free survival (PFS) rate was 61%, and the 12-month overall survival (OS) rate was 83%.

“This is a significant improvement for patients with MCL, and it is hard to really articulate that in words,” said Ian W. Flinn, MD, PhD. “Compared to what you would expect for this patient population, this therapy is an exciting advancement.”

Overall, 63% of patients experienced any grade neurotoxicity, including 31% who had a grade 3 or greater neurotoxicity event. Cytokine release syndrome (CRS) was also a concern for the CAR T-cell therapy and occurred in 91% of patients, of which 15% were at least grade 3 in severity. There were no grade 5 cases of neurotoxicity or CRS with the treatment of KTE-X19.

Based on these findings,developers of the CAR T-cell product plan to submit a biologics license application to the FDAfor KTE-X19 in patients with relapsed/refractory MCL. Additionally, a marketing authorization application will also be submitted during the first quarter of 2020 to the European Medicines Agency.

In an interview withTargeted Oncology, Flinn, director of Lymphoma Research at Sarah Cannon Research Institute, discussed the results from the ZUMA-2 trial which evaluated the efficacy and safety of KTE-X19, a CAR T-cell therapy, in patients with relapsed/refractory MCL. He highlighted how unique this product is compared to other CAR T-cell therapies and where he believes it will fit into the treatment landscape for patients with MCL.

TARGETED ONCOLOGY: Could you provide some background the ZUMA-2 trial?

Flinn:ZUMA-2 is a phase II pivotal trial in patients with relapsed/refractory MCL. This is an important study because it is in a patient population that has exhausted standard therapies and in whom outcomes are generally poor. The eligibility criteria included prior treatment with a BTK inhibitor. The expected outcome in this patient population is a response rate in the neighborhood of 25% to 40% with survival around 6 to 9 months. It’s truly a patient population in need of new therapies.

CAR T-cells are an exciting therapy because they have shown efficacy in patients with DLBCL for which they are now FDA-approved. There is hope that using CAR T-cells in patients with MCL may lead to similar results in this very challenging patient population.

TARGETED ONCOLOGY: How is KTE-X19 unique compared to other CAR T-cell therapies?

Flinn:KTE-X19 is a CD19-targeted CAR T-cell therapy that contains the CD28-signaling domain. The real difference between this and the commercially-available product axicabtagene ciloleucel (axi-cel; Yescarta) is it has a manufacturing process to remove circulating tumor cells. That is an important difference in this patient population where there are often circulating lymphoma cells compared to other malignancies, such as large cell lymphoma, where you wouldn’t expect that to be a problem. Basically, there is a selection process in the development of these CAR T-cells, which is not present in the commercially available product.

TARGETED ONCOLOGY: How was the ZUMA-2 trial designed?

Flinn:This trial is for patients with 1 to 5 prior lines of therapy, including anthracycline- and/or bendamustine-containing regimens. Patients had to have received either ibrutinib (Imbruvica) or acalabrutinib (Calquence). Otherwise, there were standard criteria in terms of performance status and organ function. However, patients had to have progressed after their last regimen. I think that this points out how difficult of a patient population this is. Unfortunately, when patients who had a prior ibrutinib or acalabrutinib treatment progress, they tend to progress very quickly and become quite ill. It is often challenging to get these patients onto a clinical trial, which is 1 of the hurdles with this study.

Patients who went on to this trial, as is necessary with all CAR T-cell products, underwent leukopheresis, and the product was sent for manufacturing. Patients could have optional bridging after the leukapheresis prior to starting the CAR T-cell therapy. The goal of bridging was therapy to try to keep the lymphoma under control while the CAR T-cells were being manufactured. The bridging therapy was very modest in intensity- steroid treatment and/or 1 of the 2 BTK inhibitors. After the optional bridging therapy, patients went on to receive the conditioning regimen of fludarabine and cyclophosphamide, which is very standard across different CAR T-cell therapies. They received their product after this lymphodepleting therapy.

TARGETED ONCOLOGY: What did the patient population look like that was enrolled on this trial?

Flinn:There were 74 patients who were enrolled on the trial, and 69 patients underwent the conditioning chemotherapy, and ultimately 68 of the patients received the CAR T-cell therapy. There were a few people who progressed and couldn’t receive the conditioning therapy, and there were people for which they had a manufacturing failure. However, this translated into a very high manufacturing success and administration. Of the 71 patients for whom the cells were successfully manufactured, 68 patients received the CAR T-cells, so 92% of the 74 patients on the study received the CAR T-cells.

These patients were representative of patients with refractory mantle cell in general. The median age was 65 years and were predominantly men and predominantly stage IV disease. I think 1 of the important things in MCL is there are various forms of MCL with different outcomes. The blastoid variant is a particularly aggressive form of MCL. In this study, 25% of the 68 patients who were treated had the blastoid variant, and another 6 patients had the pleomorphic variant, another aggressive sub-type. Many patients, 69%, had a very high Ki67, which is a proliferation marker. By anyone’s estimate, this is a very high-risk patient population. They had a median of 3 prior therapies in this study, and 100% of patients received a prior BTK inhibitor, either acalabrutinib or ibrutinib. Some of the patients had both agents. Around 43% of patients had relapsed after autologous stem cell transplant, and as you can see, this is a very challenging patient population.

TARGETED ONCOLOGY: What were the findings?

Flinn:The results were that the ORR was 93% and two-thirds, 67%, of patients achieved a CR. Compared to what you would expect from this patient population where responses are typically in the low 30s with not very durable remission, this is quite promising.

The median follow-up at the time of this presentation was just over a year at 12.3 months, but there was a group of patients, the first 28 patients who entered on to the trial that had a median follow-up greater than 24 months. We do have some data to suggest some of these responses were durable.

Another important thing is the median time to response was just 1 month and 3 months for a CR. Some other key findings from the study were that the ORR was consistent across different subtypes. If you looked at morphology, and whether it was blastoid or classical MCL, younger or older, high Mantle Cell Lymphoma International Prognostic Index (MIPI) or low MIPI, all the subgroups seemed to benefit equally from the therapy.

The other really important finding is that the duration of response had not been reached after more than 12 months. 57% of all patients and 78% of all patients who were in a CR remained in remission with that median follow up of 12 months. Again, in those first 28 patients who were treated early on in this study, 43% of them remained in CR without any additional therapy.

In my mind, this is a significant difference than anything else you would expect for this patient population. If we looked at survival, the 12-month PFS rate was 61%, and the 12-month OS rate was 83%. This again clearly showed it was different than what you would see with other available therapies.

TARGETED ONCOLOGY: How did the toxicity profile compare to that of other CAR T-cell therapies?

Flinn:There are 2 AEs that come to mind when you think about CAR T-cells. There are neurological events that occur and CRS that occurs. This study was not immune from those, whereas 15% of patients had grade 3 or higher CRS. This was generally managed with tocilizumab (Actemra) or corticosteroids. Twenty-one patients or 31% had grade 3 or higher neurological toxicities.

No one died from any of the neurological events, which is important. The vast majority of these patients had a reversal of their neurological events. However, there was 1 patient who had grade 3/4 cerebral edema who required very aggressive therapy in the intensive care unit. Thankfully this patient recovered and remains in CR.

TARGETED ONCOLOGY: What are the next steps for KTE-X19 in MCL?

Flinn:The investigators are hopeful that this will lead to an FDA approval and ultimately commercial availability. We will have to wait to see if that comes to fruition. Ultimately, treating patients in this very refractory state is a setup for having the worst result in terms of AEs and response rates. Despite these challenges, these response rates and durations of response are really remarkable. However if we are going to advance this therapy, we need to move it earlier in the natural history of this disease. Many of the investigators would like to move this earlier, perhaps as a second-line therapy rather than a third-line therapy and perhaps earlier than that.

TARGETED ONCOLOGY: What role do you think KTE-X19 has in this patient population in the future?

Flinn:MCL is a relatively uncommon lymphoma, so there are not that many patients with MCL every year who would be eligible. However, we are getting durable remissions from this therapy. It is going to have an important role in patient management. Hopefully, subsequent trials will take it into an earlier setting in the natural history of the disease.