The high durable response rates seen with CAR T-cell therapies have helped fill a high unmet need for patients with relapsed/refractory diffuse large B-cell lymphoma, with questions remaining on the optimal way to use these agents following the FDA approval of 2 therapies in the past year.
Andre Goy, MD
The high durable response rates seen with CAR T-cell therapies have helped fill a high unmet need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with questions remaining on the optimal way to use these agents following the FDA approval of 2 therapies in the past year.
Now, with added experience in the clinic, researchers are looking to move these therapies to the outpatient treatment setting, as opposed to hospital administration. This move is meant to address reimbursement concerns, as hospitalization costs can surpass treatment costs in some scenarios.
“We have been trying to go in the outpatient setting, trying to use tisagenlecleucel [Kymriah] in this context, because there seems to be less [cytokine release syndrome] in the first 72 hours with this agent,” Andre Goy, MD, chairman and director of John Theurer Cancer Center (JTCC) at Hackensack University Medical Center in New Jersey, said during a panel discussion at the 36th Annual CFS®. “We’ve done half of patients in this setting, and this seems good for this transition phase.”
Axi-cel (axicabtagene ciloleucel; Yescarta) was the first CAR T-cell therapy, with an approval in October 2017. It was followed by tisagenlecleucel in May 2018, and one more candidate, liso-cel (lisocabtagene maraleucel; JCAR017), has also shown promise in early phase trials.
There are notable differences between each agent, for instance, both tisagenlecleucel and liso-cel utilize a 4-1BB domain, whereas axi-cel has a CD28 domain. A panel of experts at CFS® suggested that the CD28 domain was associated with a quicker onset of adverse events compared with the 4-1BB domain.
“The toxicity happens relatively early, with slight differences from product to product. The CD28-containing CAR T cells seem to work a little faster,” said panelist Jae Park, MD, from Memorial Sloan Kettering Cancer Center. Speaking for all the therapies, Park noted that “most of the toxicity happens within the first 2 weeks. It is rare to see delayed toxicity beyond 2 weeks.”
In each of the studies that led to approval,1-3 cytokine release syndrome (CRS) and neurotoxicity (NT) rates varied, although different grading systems were used in each trial. For axi-cel, grade >3 CRS occurred in 13% of patients and grade >3 NT was seen in 31% of patients. For those treated with tisagenlecleucel, the rates of grade >3 CRS and NT were 22% and 12%. For liso-cel, grade >3 CRS was experienced by just 1% of patients and 13% had grade >3 NT.
Outpatient administration is thought to be connected with the 4-1BB construct, the panel noted. To this end, this route of administration is being prospectively examined in the ongoing liso-cel trials. “It is very difficult to compare, because of the differences in patients,” said Goy. “If you look at toxicity profiles, there’s more earlier toxicity with axi-cel than the other CAR T cells. Early toxicity is also an issue for reimbursement, especially for Medicare.”
The axi-cel approval was based on findings from the phase II ZUMA-1 study,1 in which the best objective response rate (ORR) achieved with the therapy was 82% and the best complete remission (CR) rate was 54%. With a follow-up of 12 months, the durable ORR was 42% and the CR rate was 40%.
Tisagenlecleucel was approved for large B-cell lymphoma, based on the phase II JULIET study.2 The best ORR was 52% and the best CR rate was 40% with the therapy. Younes postulated that the durable ORR was likely 34% and the durable CR rate was 29%, although these findings had not yet been confirmed.
“The responses with these therapies have been very impressive. We’re talking about patients with very bulky disease who have failed multiple lines of therapies who are having major responses, and some of these responses are durable,” said Anas Younes, MD, chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center in New York.
Adding to the approved therapies, liso-cel has also shown promise in the phase II TRANSCEND study, which could lead to a future FDA approval. In the study,3 the best ORR was 80% and the best CR rate was 59% at a liso-cel dose level that is being explored for FDA submission. At 6 months, the ORR was 47% and the CR rate was 41%.
“There are differences between the dosing, the conditioning, and the manufacturing, so they are not all identical. What is interesting, is that the responses are all uniformly high,” said Younes. “We cannot compare apples-to-apples because the eligibility criteria were different.”
The next steps will focus on overcoming mechanisms of resistance, namely loss of CD19 expression and PD-1/PD-L1 expression. Moreover, researchers are looking to improve response.
“CAR T cells are making a big dent in this space but they’re not curing everyone, so we need to do more work to find additional treatment strategies for these patients,” concluded Younes.