Chimeric antigen receptor T-cell therapies have quickly moved from early phase clinical trials to FDA approval for diffuse large B-cell lymphoma, with research now exploring ways to shift these agents earlier in the treatment paradigm.
Anas Younes, MD
Chimeric antigen receptor (CAR) T-cell therapies have quickly moved from early phase clinical trials to FDA approval for diffuse large B-cell lymphoma (DLBCL), with research now exploring ways to shift these agents earlier in the treatment paradigm, according to a discussion at the 2nd Annual Live Medical Crossfire on Hematologic Malignancies.
The quick arrival of CAR T-cell therapies for DLBCL was preceded by several setbacks in clinical trials, which were attempting to improve on standard R-CHOP therapy. These failed strategies explored dose intensity, R-CHOP plus a maintenance therapy, R-CHOP with another agent added plus several other strategies, said program chair Anas Younes, MD.
The unmet need in relapsed/refractory DLBCL was further enhanced by an announcement on July 11, 2018, that the phase III PHOENIX trial combining ibrutinib (Imbruvica) with R-CHOP failed to meet its primary endpoint of improvement in event-free survival. This disappointment came despite very promising phase II findings. Data from the PHOENIX trial will be presented at the 2018 ASH Annual Meeting, said Younes.
Adding to these unsuccessful strategies, findings from the CORAL study and the SCHOLAR-1 trial helped to further illuminate the high unmet need for patients with refractory DLBCL.1,2 In each of these studies, the long-term overall survival (OS) rate was just 15% to 20% for patients relapsing within ≤12 months of stem cell transplant or with refractory disease.
CAR T-cell Therapies Emerge
In October 2017, axi-cel (axicabtagene ciloleucel; Yescarta) became the first CAR T-cell therapy approved for patients with relapsed or refractory non-Hodgkin lymphoma, based on findings from the phase II ZUMA-1 study. 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 durable CR rate was 40%.3
Tisagenlecleucel (Kymriah) joined axi-cel in May 2018, with an approval for large B-cell lymphoma that was based on the phase II JULIET study. In an update from this study,4 the best ORR was 52% and the best CR rate was 40%. Based on the EHA presentation, Younes postulated that the durable ORR was likely 34% and the durable CR rate was 29%.
Another CAR T-cell therapy in development, liso-cel (Lisocabtagene maraleucel; JCAR017), has also shown promise in a phase II study, which will likely lead to FDA approval, Younes noted. In the phase II TRANSCEND study at the dose level being explored for FDA submission,5 the best ORR was 80% and the best CR rate was 59%. At 6 months, the durable ORR was 47% and the durable CR rate was 41%.
"This has been a paradigm shift. These therapies are definitely going to be moving forward to earlier lines of therapy," said discussant Sattva S. Neelapu, MD, The University of Texas MD Anderson Cancer Center. "Besides DLBCL, I think these therapies are also going to be approved for other B-cell malignancies, like mantle cell lymphoma."
The median progression-free survival (PFS) with axi-cel was 5.8 months and the 12-month OS rate was 59%. The JULIET study showed a median PFS of 2.9 months for tisagenlecleucel and a 12-month OS rate of 49%. These data points were not yet available for liso-cel.
"When you look at the data you cannot compare them head-to-head because there are differences in the eligibility criteria in terms of refractory and relapsed and so forth, but it is good to know the data," said Younes. "The median PFS with these agent is not high, up to about 5 months, but there's a tail on the curve. Even though median PFS is not very long, there is a handful of patients who are doing very well and are probably curable."
The most concerning adverse events with the CAR T-cell therapies were cytokine release syndrome (CRS) and neurotoxicity (NT). For axi-cel, grade ≥3 CRS occurred in 13% of patients and grade ≥3 NT was seen in 31% of patients, with steroids and anti-IL6 therapies needed for 29% and 45% of patients, respectively.
For those treated with tisagenlecleucel, the rates of grade ≥3 CRS and NT were 22% and 12%, with 11% and 15% requiring tocilizumab or steroids. For liso-cel, grade ≥3 CRS was experienced by just 1% of patients and 13% had grade ≥3 NT. Steroids were required for 21% of patients and 15% received tocilizumab.
Different adverse event grading systems were used across the studies. The Lee criteria was used for CRS grading in ZUMA-1 and TRANSCEND whereas a University of Pennsylvania scaling model was utilized in the JULIET study. All trials used CTCAE criteria for NT grading.
"These are really exciting times. Anyone who has seen a CAR T cell patient respond with their tumor melting away in less than 4 weeks can see that this is truly astounding," said discussant David Maloney, MD PhD, Fred Hutchinson Cancer Research Center, University of Washington, Seattle. "We're learning a lot, in terms of CRS and neurotoxicity, we know that some patients are going to have substantial toxicity."
With the knowledge gained in the refractory setting, Maloney, Neelapu, and Stephen J. Schuster, MD, who also discussed the findings, all agreed that CAR T-cell therapy would likely move toward the frontline setting.
"Any new therapy is going to start in refractory patients. While we can get responses in completely refractory patients, it will likely be better if you can do this at an earlier time," said Maloney. "We're going to see these start moving to a place where we think about them before people have failed several lines of salvage."
Which CAR Is Best?
Although a significant advance, there are still many questions facing the use of these agents. Moreover, in the absence of head-to-head trials, treatment selection is a challenge. Each of the studies exploring the agents had variations in patient populations and the construct of each agent is unique, making cross-study comparisons a challenge. Despite these obstacles, some characteristics have emerged to help guide therapy, the experts noted.
The typical criteria for deciding between effective treatment options is to first look at the efficacy, Neelapu noted, from there, if efficacy is equal, there is an analysis of the toxicity and logistics. At this point, the researchers noted that the longest follow-up was available for axi-cel providing the highest certainty for its clinical efficacy; however, in their experience, axi-cel also seemed to elicit the highest rate of adverse events.
The patient characteristics in each trial could also help determine which agent to use in a case-by-case scenario, Maloney said. In the JULIET study, some patients had received prior allogeneic stem cell transplant prior to tisagenlecleucel, suggesting this agent works in this setting. Additionally, JULIET also included children and those with CNS involvement, suggesting it may be ideal in this population.
"Having these data could help with reimbursement," said Maloney. "If you have prior allo [transplant] and CNS involvement, my selection goes toward tisagenlecleucel, right now."
In some cases where a distinct advantage is not apparent, it may boil down to familiarity and comfort with the available data. "My own experience with tisagenlecleucel is really quite long," said Schuster, University of Pennsylvania, Abramson Cancer Center. "Familiarity leads to comfort. You ask what I might choose, I would say what I am comfortable with."
Costs and Patient Selection
In an informal poll of the audience, which consisted of approximately 75 healthcare providers, only 1 to 2 individuals said they had used or referred a patient to receive CAR T-cell therapy. Questions from the audience tended to center around predictors of response, given the high costs associated with each therapy.
Although early predictors of response have been identified, there is not one clear winner, said Neelapu. Responses have been noted across most patient subgroups. Maloney noted that in some early studies with JCAR014 that pre-lymphodepletion serum LDH was associated with better response and outcomes. He also added that tumor burden can be used to predict responses.
In long-term findings for 19-28z CAR T cells,6 patients with low disease burden (<5% bone marrow blasts) had superior OS and event-free survival compared with patients with high disease burden. The median OS was 20.1 months in the low disease burden group compared with 12.4 months for those with high burden (P = .02). Additionally, there were more adverse events in patients with high disease burden compared with the low group.
Another obstacle remains the price tag associated with the CAR T-cell therapies, which is beyond $373,000. At this point, CMS has decided to reimburse a set rate for CAR T-cell infusion, which does not cover the total costs involved in the procedure. CAR T cell infusions require hospitalization and other associated costs, which often bring the grand total for these therapies close to $1 million.
Along these lines, Maloney noted that he has treated all patients in the outpatient setting when using liso-cel, given its comparatively mild adverse event profile. This approach avoids the added costs associated with a 2-week hospital stay. Adding to this, Schuster said that he has also started using tisagenlecleucel in the outpatient setting, without major issues.
Both tisagenlecleucel and liso-cel utilize a 4-1BB costimulatory domain whereas axi-cel has a CD28 domain. This differentiator could be key in the ability to treat in the outpatient setting, the panelists suggested. Moreover, liso-cel potentially holds further safety advantages via a fixed 1:1 ratio of CD4 to CD8 cells. Maloney felt this added feature helped to make the safety profile more predictable.
Although not yet in regulatory review, cohorts from the TRANSCEND study will be submitted to the FDA once mature. Several factors, especially the specific FDA label and outpatient treatment potential, will dictate how this agent is utilized. Additionally, the list price for the T-cell therapy along with CMS reimbursement will also play a major role.
"The past several years of research had not taken us anywhere, and then the CAR T cells showed up, and now we have 2 FDA-approved products with a third one on the way," said Younes, chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center. "These are not identical products but there are similarities between them."