CAR T-Cell Therapies Fulfill Unmet Need in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Jason Westin, MD

Jason Westin, MD

Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, has beenapproved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma(DLBCL) in May 2018 based on findings from the JULIET trial. In updated findings of the phase II clinical trial, the CAR T-cell product led to promising response rates and sustained responses in this patient population.

In the JULIET study, patients had an overall response rate (ORR) of 54% (95% CI, 43%-64%) and a complete response (CR) rate of 40%. In addition, the median overall survival was 10.3 months after a median follow-up of 26 months. However, the median duration of response had not yet been reached.

CAR T-cell therapy has been associated with the occurrence of cytokine release syndrome (CRS) and neurotoxicity. In the study, 57.4% of patients experienced any grade CRS, while 22.6% had grade 3/4 CRS. Twenty percent of patients had any grade neurological adverse events (AEs), and 11.3% were grade 3/4. Investigators noted that out of the 66 patients with any grade CRS, 19 patients went on to develop neurotoxicity.

“The key takeaway is that CAR T cells are very active and efficacious in patients with relapsed/refractory DLBCL. The duration of response is very impressive,” said Jason Westin, MD. “The toxicities are largely manageable in specialized centers of excellence that do CAR T cells. I think the main message is to refer your patients for CAR T cells because this is potentially a home run therapy.”

In an interview withTargeted Oncology,Westin, leader of the DLBCL research team at the University of Texas MD Anderson Cancer Center, discussed findings from a correlative analysis of the CRS and neurotoxicity associated with the CAR T-cell therapy in the JULIET trial. He highlighted other important takeaways on the data on CAR T cells in DLBCL.

TARGETED ONCOLOGY: What was the rationale for this study?

Westin:The abstract we presented at the SOHO meeting in 2019 was looking at patients treated on the JULIET clinical trial. The JULIET trial was looking at patients with relapsed/refractory DLBCL and treated them with tisagenlecleucel. That population has historically had very poor outcomes. We know from the SCHOLAR-1 data that the patients tend to not respond well to chemotherapy in the third-line and beyond setting. Responses are not as good as we would like, while survival is quite short.

In the JULIET trial, we found an ORR of 54%, a CR rate of 40%, and the abstract I presented shows that the responses are durable. We are at a median of 26 months, and patients who have achieved a CR have had a duration of response in the study that was not yet reached. However, it appears to be plateauing beyond 3 to 6 months, so it is durable.

TARGETED ONCOLOGY:How are these data impacting the DLBCL treatment landscape?

Westin:CAR T-cell is having a dramatic impact on the landscape for patients with relapsed/refractory DLBCL. It has been a seat change for how we view this disease because previous patients who did not have a durable response after an autologous transplant reviewed as palliative or viewed as patients who may benefit from clinical trials, but there was not an established standard of care. The recent approval from the FDA of 2 products, and perhaps soon a third product, has changed practice in a major way.

In the abstracts that we presented at SOHO, we looked at what we can learn from the patients on these studies in terms of who might have toxicity, such as CRS or neurotoxicity, which are 2 of the most dreaded complications. What we found is that the patients who have very high cytokine levels tend to have very significant toxicity. It’s difficult to predict prior to treatment which patients will have those toxicities, but during therapy, the cytokine levels do have a strong correlation with the severity of toxicity.

TARGETED ONCOLOGY:What toxicities are associated with the CAR T cells?

Westin:The AEs of the CAR T-cell products are unique and quite different from chemotherapy or other targeted therapies. The most concerning and most commonly talked about side effects of CAR T-cell therapy is CRS. The second, which is often partnered with [CRS], is neurotoxicity, which is now referred to as immune-effector cell-mediated neurotoxicity. In our presentation, we tried to figure out which patients are going to get those toxicities. That’s been the biggest challenge for people treating patients with CAR T cells, managing toxicities and ideally preventing these toxicities. We don’t do a good job at that currently, but we found that patients with an elevated baseline LDH are a commonly attested assay corresponded in univariant as well as multivariant analysis with CRS. It did not correlate with neurotoxicity, so we still struggle to decipher which patients will struggle with neurotoxicity from CAR T cells.

TARGETED ONCOLOGY:What is the key takeaway for physicians?

Westin:The key takeaway is that CAR T cells are very active and efficacious in patients with relapsed/refractory DLBCL. The duration of response is very impressive, and we think that patients who have a durable response from 1 treatment of CAR T cells longer than 3 or 6 months are likely cured, if we can be bold and say “cured,” from what would have been a fatal disease. The toxicities are largely manageable in specialized centers of excellence that do CAR T cells. I think the main message is to refer your patients for CAR T cells because this is potentially a home run therapy.

TARGETED ONCOLOGY:How do you determine who is eligible to receive CAR T-cell therapy?

Westin:Determining which patients are an ideal patient for CAR T cells is still a bit of a challenge. It’s still early, and we don’t have great data as to which patients should not get CAR T cells. We do know that patients with relapsed/refractory DLBCL tend to have very poor outcomes and need new advances. The excitement around the 2 approved CAR T-cell products is based on the high response rates and durable responses. When we looked at what patients are getting treated with off clinical trials, the so-called real-world data, we are seeing clinical trial criteria don’t need to be adhered to strictly for good responses and toxicity.

The idea of who is eligible for CAR T-cell therapy is not the same population we thought of before, which was transplant-eligible patients. It’s probably a larger proportion of patients who are CAR T-cell-eligible because the toxicities, while they do appear more severe, are manageable than chemotherapy and transplant. I would say a referring physician should not prespecify a patient as a candidate. We treated patients up to age 89 years old with CAR T cells. Granted, these are fit 89-year old’s, but the idea that someone is too old or frail, I don’t believe that is true for CAR T cells. I believe they should be evaluated as a potential candidate.

TARGETED ONCOLOGY: Does the cost of CAR T-cell therapy create a barrier to accessibility?

Westin:One of the main barriers for CAR T cells is access to receiving them. These are quite expensive therapies. CAR T-cell is a 1-shot therapy, not something you receive sequentially overtime. It is a 1-time treatment, so the pricing is generally comparable to what a transplant costs. However, it is prohibitive for some patients. We are still struggling with the idea of what government payers and private payers are willing to pay for CAR T cells. For most patients who receive CAR T cells, this has not been a rate-limiting step for them to get it. However, as CAR T-cell indications begin to change and as more and more patients become eligible for patients, the cost will certainly become more of an issue to negotiate moving forward.

Reference:

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 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.