Data presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition on the longer-term follow-up analysis of results from the ZUMA-1 trial investigating the effectiveness of axicabtagene ciloleucel (Yescarta) in patients with refractory non-Hodgkin lymphoma (NHL) showed impressive outcomes. According to the analysis, more than 1 year after an infusion of axicabtagene ciloleucel, a chimeric antigen receptor (CAR) T-cell therapy that targets the CD19 antigen on B cells, 42% of the 108 patients enrolled in the trial had maintained remission, and 40% of the patients exhibited no evidence of lymphoma. In addition, at the time of the follow-up analysis, which combined phase I and II trial data, more than half of the patients were alive at the median follow-up of 15.4 months—more than double the median survival of 6.6 months for patients treated with conventional therapy.1,2
Axicabtagene ciloleucel is the second gene-altering therapy approved by the U.S. Food and Drug Administration (FDA) in the treatment of cancer in 2017 and the first specifically for adults and for those with certain types of NHL, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. (On August 30, 2017, the FDA approved tisagenlecleucel [Kymriah] for pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia.)
Despite the notable responses to axicabtagene ciloleucel in some patients in the ZUMA-1 trial, more than half of the study participants did not experience a durable response to the therapy, highlighting the need for additional research. Also tempering excitement of the CAR T-cell therapy is its hefty price tag: $373,000 for axicabtagene ciloleucel—and $475,000 for tisagenlecleucel—to extract a patient’s T cells, reengineer them to produce CARs on the surface of the cells, and infuse the cells back into the patient. The cost does not include fees for hospital stays, supportive care, or physician visits.
Frederick L. Locke, MD
In a wide-ranging interview with The ASCO Post, Frederick L. Locke, MD, Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida, and co-lead investigator of the ZUMA-1 trial, discussed the significance of the trial results for patients with aggressive NHL, the possible reasons for variation in response to therapy, and how to evaluate the cost of CAR T-cell treatment vs its value.
Potential for Durable Remissions and Possible Cures
Please talk about the importance of the ZUMA-1 trial results and the impact of FDA approval of axicabtagene ciloleucel on the treatment of aggressive B-cell lymphomas.
Axicabtagene ciloleucel is the first CAR T-cell therapy approved for adults with cancer, and it is likely to lead to long-lasting responses for many patients with aggressive B-cell NHL. With a median of 15.4 months of follow-up in the ZUMA-1 study, 42% of patients are in ongoing remission. This is pretty remarkable when you consider these patients had not responded to their last line of chemotherapy, had disease progression after an autologous stem cell transplant, and had less than a 10% chance of obtaining a complete response if they had instead received standard chemotherapy. It is important to note that data from an earlier study at the National Cancer Institute show a handful of patients with DLBCL are in remission 4 years after receiving this therapy,3 suggesting the remissions seen in ZUMA-1 are likely to remain durable. We are truly excited to offer this treatment as a standard-of-care therapy for our patients with refractory aggressive B-cell NHL.
Variation in Patient Response to Gene Therapy
Not all patients benefit from CAR T-cell therapy. Do you know why there is a variation in response to gene therapy?
No, not yet. In the ZUMA-1 trial, over 80% of patients responded to the therapy; however, responses are durable beyond a year in just 42% of patients. Something is likely driving resistance to the therapy, including either disease- or patient-specific features, factors within the CAR T-cell product, immune evasion within the tumor, or evolution and growth of lymphoma without the CD19 target. Understanding the reasons will help us to design new clinical trials, and in the future we will be better able to tailor the therapy for each patient.
We’ve looked at many pretreatment patient and disease features, International Prognostic Index risk score, bulky disease, extranodal disease, activated B-cell vs germinal center B-cell subtypes, and advanced-stage disease, among others, and we don’t see any obvious patient risk factor that would flag a nonresponder.
We know that CAR T-cell products that have a more naive or central memory phenotype are likely to have higher in vivo expansion, which is tied to response. A small set of patients had paired biopsies before and shortly after receiving CAR T-cell therapy, and we see upregulation of genes associated with negative regulation of the immune response. Early investigation of biopsies from those patients who relapse suggest the loss of the CD19 epitope is likely one mechanism of resistance. Continued analysis of data sets from the ZUMA-1 trial is ongoing.
“Patients with a high inflammatory state at the time of CAR T-cell infusion are most likely to have severe life-threatening toxicities.”— Frederick L. Locke, MD
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Who Should Receive Cellular Immunotherapy?
Who are the best candidates for CAR T-cell immunotherapy?
I am a transplant physician and in many ways approach CAR T-cell therapy for patients the way I approach hematopoietic stem cell transplantation: Patients have to be in a certain state of health and an appropriate state of disease to benefit from the treatment. The first step is to assess whether the patient is eligible for the treatment based on the number of prior lines of chemotherapy and diagnosis, among other disease features. Second, we evaluate the patient’s physical fitness to withstand potential toxicities from the therapy.
To do this, we perform a series of tests, including an echocardiogram and an electrocardiogram and in some cases I recommend a lumbar puncture and magnetic resonance imaging (MRI) of the brain to evaluate whether a patient has secondary central nervous system lymphoma, because the neurologic toxicities associated with CAR T-cell therapy might be potentiated if disease is present. If a patient is very ill, and in a wheelchair, either from disease progression or comorbidity, he or she may not be able to handle the treatment toxicities, so we have to evaluate every aspect of the patient’s health very carefully before proceeding with such treatment.
One thing we know based upon our prior experience is that patients with a high inflammatory state at the time of CAR T-cell infusion are most likely to have severe life-threatening toxicities.4 In patients who have a fever, we evaluate and treat them for infection before proceeding with the therapy.
Evaluating Treatment Success
What do you consider a success with this treatment: cure or remission for several years?
The ZUMA-1 trial primary endpoint was based on an objective response rate: How many patients had at least a partial or complete response to a single infusion of CAR T cells? We now know the objective response rate is 82%. But what matters to a patient is whether we eradicated the lymphoma and it stays away. Now, we can never predict the future or promise cure, but a patient who can achieve prolonged disease-free survival with this therapy is a success.
How long might the remission last? Hopefully, responses continue indefinitely. I think the real value of CAR T-cell therapy is that with a single infusion, we can put a significant proportion of highly refractory patients into a remission that is ongoing beyond a year.
It is worth noting that this therapy does not directly compete with autologous stem cell transplantation, because the patient populations are different. We now have randomized clinical trials for second-line therapy in patients with relapsed DLBCL comparing salvage chemotherapy followed by autologous stem cell transplant vs CAR T-cell therapy. It is possible that CAR T-cell therapy could be the first therapy we want to utilize in a patient who has relapsed. These trials will answer this crucial question and could further change the landscape for patients with relapsed lymphoma.
Potential Last Line of Therapy
Is CAR T-cell therapy a one-time therapy?
In the ZUMA-1 trial, there were patients who were re-treated if their disease progressed after 90 days and their tumor still expressed CD19. Some of those patients have had a complete response. This is a very small number of patients, so we can’t draw many conclusions from these data.
We can say that perhaps for patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who have had late relapse, a second infusion may be beneficial. Carefully designed clinical trials should address the question of whether a second treatment with CAR T cells, either again directed at CD19 or an alternate target, might be beneficial. However, we know a single infusion of this CAR T-cell therapy could put patients into remission for at least 1 year and perhaps for many years.
Cellular Immunotherapy as First-Line Therapy
So far, CAR T-cell therapy has been limited to patients with advanced-stage disease. Do you envision this treatment being used in earlier-stage cancers, when patients might tolerate it better and cure might be more likely?
It is a logical question to ask; can we use this therapy upfront in patients with aggressive B-cell NHL? I think we must first determine whether CAR T-cell therapy can be used as the preferred therapy at fist relapse. These randomized trials should be our primary focus for new indications; however, if we could carefully define a patient population at extremely high risk for early relapse after frontline therapy, the treatment could be tested as a stand-alone or adjunct to upfront treatment.
“Simply looking at the price tag of cellular immunotherapies in isolation is deceptive, because it does not include the cost of administration, hospitalization, physician visits, or associated supportive care.”— Frederick L. Locke, MD
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Evaluating Cost vs Value
The cost of CAR T-cell therapy is extremely high: $373,000 for axicabtagene ciloleucel and $475,000 for tisagenlecleucel. Can patients afford this therapy?
At our institution, we have a financial counselor to help patients determine their out-of-pocket costs involved with this therapy and obtain insurance authorization before going forward with the procedure. We don’t want patients to be surprised by the cost or to have to send them a bill for the cost of the treatment.
I am not able to answer the question as to what is an acceptable price for the addition of many high quality-of-life years for a patient with a life-threatening lymphoma. I can speak about the value of the therapy. The question is, what is the real value of a single infusion of CAR T-cell therapy if it can put 40% of patients with advanced-stage lymphoma into a long-term remission of a year or longer? What does having that time mean to the patient? What would the alternative be?
This therapy has the potential to provide an extension and quality of life, which is invaluable. We have to remember that the only option for patients prior to enrollment in the ZUMA-1 trial was to receive more chemotherapy. We know that the last round of chemotherapy in these patients did not work; therefore, the chance that more chemotherapy would be successful in stopping disease progression was even less. And for patients who do end up receiving multiple cycles of chemotherapy, their quality of life is usually diminished due to multiple hospital stays to treat infections and other treatment side effects, and the cost of that care is extremely high.
Until we fully understand these factors and how long remissions will last, it will be difficult to accurately quantify the value of this therapy. It is also important to note that simply looking at the price tag of cellular immunotherapies in isolation is deceptive, because it does not include the cost of administration, hospitalization, physician visits, or associated supportive care.
Until we better understand these costs, it will be difficult to determine whether the costs and value are matched. Some organizations, such as the Institute for Clinical and Economic Review, are attempting to answer this question, but we do not have a definitive answer yet.5 ■
DISCLOSURE: Dr. Locke has served as a scientific advisor to Kite Pharma and is a consultant for Cellular BioMedicine Group Inc.
REFERENCES
1. Neelapu SS, Locke FL, Bartlett NL, et al: Long-term follow-up ZUMA-1: A pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma. 2017 ASH Annual Meeting. Abstract 578. Presented December 11, 2017.
2. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR-T cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.
3. Kochenderfer JN, Somerville RPT, Lu T, et al: Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther 25:2245-2253, 2017.
4. Locke FL, Neelapu SS, Bartlett NL, et al: Phase I results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther 25:285-295, 2017.
5. Institute for Clinical and Economic Review: Chimeric Antigen Receptor T-Cell Therapy for B-Cell Cancers: Effectiveness and Value. December 19, 2017. Available at https:// icer-review.org/wp-content/uploads/2017/07/ICER_CAR_T_ Draft_Evidence_Report_121917.pdf. Accessed March 15, 2018.
