THE EMERGENCE of chimeric antigen receptor (CAR) T-cell therapy has sparked a wave of optimism in hematologic malignancies, but as experience in using CAR T-cell therapy has grown, new challenges have surfaced. A pioneer in the field, David G. Maloney, MD, PhD, enlightened attendees on these issues at the 2018 Pan Pacific Lymphoma Conference in Maui.1 Dr. Maloney is Medical Director of the Bezos Family Immunotherapy Clinic at the Seattle Care Alliance and the Norma and Leonard Klorfine Endowed Chair for Clinical Research at Fred Hutchinson Cancer Research Center, Seattle.
David G. Maloney, MD, PhD
Dr. Maloney’s presentation was the first Oliver Press Memorial Lecture. Dr. Press held the David and Patricia Giuliani/Oliver Press Endowed Chair in Cancer Research at Fred Hutchinson and the Dr. Penny E. Petersen Memorial Chair for Lymphoma Research there.
Dr. Maloney described data from pivotal studies of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) receiving one of the three CD19-directed CAR T-cell products available or in late-stage development: axicabtagene ciloleucel (Yescarta; KTE-C19), tisagenlecleucel (Kymriah; CTL019), and lisocabtagene maraleucel (JCAR017). Although outcomes with these agents can be remarkable in some patients, unresolved issues with reimbursement and logistics are creating problems in the clinic, as outlined by Dr. Maloney.
Three CD19-Directed CAR T-Cell Products
AXICABTAGENE CILOLEUCEL was approved based on the ZUMA-1 trial.2 “The results are quite spectacular,” Dr. Maloney commented. The response rate was 82% for patients with diffuse large B-cell lymphoma (DLBCL) and 83% for patients with transformed follicular lymphoma/primary mediastinal B-cell lymphoma, with complete responses achieved by 49% and 71%, respectively. Overall, 42% were progression-free at 15 months.
Tisagenlecleucel was approved based on the JULIET trial, the results of which have been presented but not yet published.3 The “very satisfying” overall response rate with this product was 53%, with a 40% complete response rate and, in this group, a “promising” duration of response. “Progression rates are low, with 74% of complete responders relapse-free at 6 months. “It looks like, so far, patients with complete responses have a good chance of being cured,” he commented.
Adverse events were less common with tisagenlecleucel than with axicabtagene ciloleucel. Of note, grade ≥ 3 cytokine-release syndrome occurred in 23% and grade ≥ 3 neurotoxicity, in 12%. He cautioned, however, that the criteria for grading cytokine-release syndrome and neurotoxicity differed for this product making direct comparisons difficult.
Also, he added, in contrast to axicabtagene cioleucel, tisagenlecleucel was administered in both inpatient and outpatient settings, “which is an important difference.”
“The response rates [to lisocabtagene maraleucel] in this highly refractory population are very encouraging, and the duration of response is quite favorable. This has translated into an overall survival that’s excellent….”— David G. Maloney, MD, PhD
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Lisocabtagene maraleucel is not yet approved but is in late-stage development. This product is different from the other two in that cells are preselected for CD4 and CD8, and two populations of CAR T cells are manufactured and administered. The cells are tagged by a transduction marker, which allows them to be easily detected by flow cytometry and potentially eliminated by an anti–epidermal growth factor receptor antibody if necessary. The drug has been able to be manufactured in 99% of apheresed patients in the DLBCL cohort and being evaluated for outpatient administration at specialized centers.
In the core patient population of the phase I/II TRANSCEND trial, the response rate was 80%, and the complete response rate was 59%.4 At 6 months (the longest follow-up available), most complete responders remained in remission. Patients achieving a complete response with the pivotal dose had a 12-month overall survival rate of 89%, with a median survival that has not yet been reached.
“The response rates in this highly refractory population are very encouraging, and the duration of response is quite favorable,” Dr. Maloney commented. “This has translated into an overall survival that’s excellent, especially for patients with complete remissions.”
The chief differentiating factor between this T-cell product and the two approved agents appears to be the rate of adverse events. Cytokine-release syndrome of any grade occurred in 37%, but only one patient experienced a grade 3 event. “That seems to be less than what we have been seeing with the other agents,” Dr. Maloney observed.
Study Observations
DR. MALONEY offered a few observations from these and other studies:
- Achievement of complete response is important for durability.
- Several factors appear to be associated with complete and durable responses: lower pretreatment lactate dehydrogenase levels, robust T-cell proliferation, higher levels of interleukin 7 (IL-7) after CAR T-cell infusion and lower serum IL-18 thereafter.5 This information, however, is not ready for clinical use.
- Cytokine-release syndrome and neurotoxicity correlate with CAR T-cell engraftment and expansion.
- Adverse events can be successfully managed by trained staff.
- The defined composition approach may facilitate a better definition of the therapeutic index of the product.
- Optimization of lymphodepletion with cyclophosphamide plus fludarabine dramatically improved CAR T-cell peak and persistence as well as options for retreatment.
Choosing Among Therapies
ASSUMING THREE anti-CD19 CAR T-cell products become available in the clinic, how will clinicians choose among them? “I think efficacy will be the driving factor, which means complete response rate, duration of response, and risk of relapse,” Dr. Maloney maintained. “Safety will be the number two factor, because the risk for cytokine-release syndrome and neurotoxicity is both troublesome and costly, and it requires a lot of resources.”
Cost differences based on efficacy and toxicity may ultimately surface and become important in product selection. Inpatient delivery will be more expensive, which could ultimately favor products that can be delivered to outpatients, he added.
Table 1 shows a snapshot of the current landscape for CAR T-cell therapy in NHL.
| CD19-Directed CAR T-Cell Therapy |
KTE-C19 (axi-cel) |
CTL019 (tisagenlecleucel) |
JCAR017 (liso-cel) |
|---|---|---|---|
| Study populations | DLBCL, TFL, PMBCL N = 101 |
DLBCL, TFL N = 99 |
DLBCL, TFL, FL3B, ECOG 0-1 N = 73 (Core) |
| CR (best) | 54% | 40% | 59% |
| CR (6-month) | 46% | 30% | 41% |
| ORR (best) | 82% | 53% | 80% |
| ORR (6-month) | 48% | 37% | 47% |
| CRS (all grades) | 93% | 58% | 37% |
| CRS (≥ grade 3) | 13% | 23% | 1% |
| NT (all grades) | 64% | NR | 25% |
| NT (≥ grade 3) | 28% | 12% | 15% |
| AEs (grade 5) | 4 total | 3 total | 2 total |
Dr. Maloney cautioned, however, that since head-to-head trials have not been done, the products cannot be directly compared for efficacy or toxicity. Although differences in manufacturing and composition do appear to lead to some differences in response and toxicity, Dr. Maloney maintained that generally “the outcomes for all of these therapies are quite encouraging.”
Financial and Logistic Challenges
“THERE ARE CHALLENGES in moving CAR T-cell therapy forward, and one of the major ones pertains to insurance,” Dr. Maloney continued. “At our center, it is quite difficult to obtain insurance clearance in some of these situations. Payers don’t have policies in place.” He continued: “An agreement that the procedure is medically necessary is not an agreement to pay for the delivery of the service. What is usually required is a one-off negotiated agreement for each patient.”
There is a possibility that CMS could bundle payments for inpatient therapy. In the current situation, he predicted, “you could essentially lose your shirt, if you have to add a $373,000 drug onto your $18,000 bill to care for a complicated patient.”
“There are challenges in moving CAR T-cell therapy forward, and one of the major ones pertains to insurance.”— David G. Maloney, MD, PhD
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Treatment facilities are already feeling the pain, as they are currently bearing the cost of treatment upfront. If the center is reimbursed for only a fraction of that actual cost, “it’s the center’s problem, not the manufacturer’s,” he pointed out. One of the challenges is finding a way for manufacturers to share the financial burden.
There are also numerous logistic challenges, among them the need for more reliable production, timelier turnaround, and wider distribution. New strategies such as universal CAR T cells may eventually help. “Lastly, the management of toxicity across these products is not consistent; each manufacturer has its own risk evaluation mitigation program. This could be confusing to clinicians using several different treatments, he said.
“I think we need to somehow get ourselves on the same page, across all of these different drugs,” Dr. Maloney concluded.
DISCLOSURE: Dr. Maloney is an advisor for Celgene/Juno, Roche/Genentech, Kite Pharma/Gilead, and Novartis and his institution has received research funding from Juno/Celgene and Kite Pharma/Gilead.
REFERENCES
1. Maloney D: Update on CAR T cell therapies for non-Hodgkin lymphoma. 2018 Pan Pacific Lymphoma Conference. Presented July 17, 2018.
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. Schuster SJ, Bishop MR, Tam CS, et al: Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. 2017 ASH Annual Meeting. Abstract 577.
4. Abramson JS, Gordon LI, Palomba ML, et al: Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. 2018 ASCO Annual Meeting. Abstract 7505. Presented June 3, 2018.
5. Gauthier J, Hirayama AV, Hay KA, et al: Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma. 2018 ASCO Annual Meeting. Abstract 7567. Presented June 4, 2018.
