NEW YORK – In recent years, autologous CD19-directed CAR T-cell therapy has cemented its position as third-line treatment for relapsed or refractory lymphoma patients with few other treatment options. Now, new data presented at the American Society of Hematology's annual meeting show that the one-time therapy could benefit patients when administered earlier as second-line treatment.
Gilead subsidiary Kite and Bristol Myers Squibb both presented data this weekend showing that lymphoma patients receiving their respective CAR T-cell therapies, axicabtagene ciloleucel (Yescarta; axi-cel) and lisocabtagene maraleucel (Breyanzi; liso-cel), had longer event-free survival than those on standard second-line therapies, such as chemotherapy and stem cell transplant.
The randomized Phase III trials, Gilead's ZUMA-7 and BMS' TRANSFORM, don't lend themselves to direct apples-to-apples comparison, in part because their patient populations differed somewhat. While ZUMA-7 involved only diffuse large B-cell lymphoma patients, TRANSFORM included patients with various non-Hodgkin lymphoma types including DLBCL, grade 3B follicular lymphoma, and transformed non-follicular lymphoma, among others.
Data from the two studies are also at different stages of maturity. While the ZUMA-7 results on axi-cel come from a primary analysis with two years of follow-up — the longest in any randomized CAR T-cell therapy study to date — the TRANSFORM data on liso-cel are from a preplanned interim analysis with a median follow-up of 6.2 months. That said, the studies are worth considering together given their shared goals of evaluating autologous CD19-directed CAR T-cell therapy for second-line LBCL.
Both autologous CAR T-cell therapies have US Food and Drug Administration approval for LBCL patients in the third- or later-line treatment settings where, due to the lack of existing treatment options, regulators accepted overall response data from single-arm clinical trials as sufficient evidence of treatment benefit. Gilead's axi-cel first entered the market in 2017, while BMS' liso-cel approval came in early 2021.
But now that drugmakers have proven these therapies can lead to durable responses in the later-line settings, the field is wondering whether lymphoma patients might benefit even more when their cancers aren't so progressed and heavily treated. Treatments in earlier disease settings have a higher evidence burden since they must be compared to standard therapies in use, which in second-line LBCL includes platinum-containing salvage chemotherapy, followed by high-dose chemotherapy, and then autologous stem cell transplant for those who respond to the chemo portion.
Accordingly, ZUMA-7 and TRANSFORM both compared their CAR T-cell therapies head-to-head against the chemo-stem cell regimen, randomizing patients to receive one or the other.
During a press conference on Saturday, Frederick Locke, co-leader of the cellular immunotherapy program at the Moffitt Cancer Center, presented data from ZUMA-7, which included around 360 relapsed or refractory LBCL patients who were randomized to receive either a single infusion of axi-cel or the standard regimen. The study's primary endpoint was event-free survival.
After more than two years of follow-up, the median event-free survival time — defined as the time between randomization and disease progression, beginning a new lymphoma treatment, or death by any cause — was 8.3 months for patients on axi-cel and 2 months for those on standard treatment. Two-year event-free survival rates were 40.5 percent and 16.3 percent, respectively, for axi-cel and standard-of-care arms.
Tumors shrank in 83 percent and 50 percent of patients on axi-cel and the standard regimen, respectively. And although the overall survival data are immature, so far they appear to favor axi-cel, Locke reported, with patients on standard therapy living for a median of 35.1 months while the median has not yet been reached in the axi-cel arm.
"Results from the ZUMA-7 trial herald a paradigm shift," Locke said in the press briefing, concluding that "axicabtagene ciloleucel should be a new standard for second-line relapsed or refractory large B-cell lymphoma."
Meanwhile, in the TRANSFORM study, researchers randomized 184 LBCL patients to either liso-cel or standard of care. Here, too, the outcomes favored the CAR T-cell therapy over chemo and stem cell transplant.
At the press conference, Manali Kamdar, clinical director of lymphoma services at the University of Colorado Cancer Center, reported that the median event-free survival was 10.1 months among liso-cel-treated patients versus 2.3 months in the comparator arm, and event-free survival rates at one year were 44.5 percent and 23.7 percent, respectively.
Overall survival data were also immature in the TRANSFORM study, but trended toward favoring liso-cel, Kamdar said, with patients on the standard-of-care regimen living for a median of 16.4 months while the median was not yet reached in the liso-cel arm.
Toxicity is a concern for patients whether they're receiving the chemo-stem cell transplant regimen or autologous CAR T-cell therapies. These are intensive therapies requiring risky immune cell depletion, and with CAR T-cell therapy, there is also the possibility of cytokine release syndrome. In their presentations, Locke and Kamdar said these CAR T-cell therapies didn't cause any new adverse events. Still, in both trials, nearly all patients in the investigational and standard-of-care arms experienced some toxicity.
In ZUMA-7, 42 percent and 40 percent of patients on axi-cel and standard treatment, respectively, experienced a serious toxicity that was grade 3 or above. With axi-cel, 88 percent of patients experienced cytokine release syndrome. One patient died from axi-cel-related toxicities and two patients died from adverse events from the standard treatment.
Frank Neumann, SVP and global head of clinical development at Gilead's Kite, said the company is continuously trying to improve the safety of its CAR T-cell therapy. "This [treatment] has side effects that are definitely not to be ignored," Neumann said. "We're really, really working on that and applying modifications to the protocols that will ultimately make these products safer and will hopefully bring these treatments to more patients."
Meanwhile, the number of treatment-related deaths in the TRANSFORM study was the same: One patient on liso-cel and two patients on standard treatment died. With liso-cel, 49 percent of patients experienced cytokine release syndrome, none of which were grade 4 or 5. Only one patient had grade 3 cytokine release syndrome, which Kamdar pointed out as "strikingly different" from what was shown in other studies. In the ZUMA-7 trial, for example, 6 percent of axi-cel-treated patients had grade 3 or higher cytokine release syndrome. The toxicity profile in this study is something that "makes liso-cel appealing, not just from a standpoint of efficacy but also extremely tolerable safety," said Kamdar.
Financial toxicity, of course, is another concern with CAR T-cell therapy, which involves an expensive process of harvesting patients' immune cells, modifying them to express CD19-directed CARs, and reinfusing them after a lymphodepleting chemo regimen. A single infusion of axi-cel can cost upwards of $373,000.
When asked during the press briefing to compare the cost of CAR T-cell therapy to the cost of standard therapy involving chemo and stem cell transplants, both Locke and Kamdar struggled to offer a definitive answer, in part because it is challenging to measure the cost of the multi-step standard regimen.
"Obviously when you're doing an autologous hematopoietic stem cell transplant, you're not purchasing the cells; it's the patient's own hematopoietic mobilized stem cells," Locke offered, adding that the full transplant process itself does involve many of the same ancillary costs as CAR T-cell therapy, including admission to a hospital and a lot of intensive care.
But in earlier lines of treatment, where patients have other options, CAR T-cell therapy will have to not only compete with standard regimens in terms of efficacy and safety, but also on price.
Locke and Kamdar highlighted the fact that CAR T-cell therapies are a one-time treatment, which they proposed as somewhat of a defense of the high price tags. Although no formal economic analysis has been done, receiving a "one-and-done" therapy, they argued, should mean that patients don't have to receive additional treatment later on, which can add cost. "We're very confident that CAR T-cell therapy provides value to patients," Locke said. "And if you can get the best therapy to patients early, ultimately that's probably going to save lives and dollars."
Although it's impossible to directly compare the benefit of axi-cel to that of liso-cel given the different trial designs and patient populations, Kamdar and Locke highlighted what they saw as potential advantages of the CAR T-cell treatments in their respective trials. For Kamdar, the key difference was the lower rates of high-grade toxicities seen with liso-cel, and for Locke, the key difference with axi-cel was that patients in ZUMA-7 were not permitted to receive bridging chemotherapy before the cell therapy. TRANSFORM did allow bridging chemotherapy for patients on liso-cel, which 58 patients had received by the interim analysis. Had this been allowed on ZUMA-7, Locke said it could have made it difficult to discern axi-cel's efficacy from that of chemo.
"We just have to recognize the differences in those study designs as we extrapolate" treatment benefit, he said, adding that in a real-world setting, the choice between two similar therapies often comes down to considerations that no clinical trial can account for, such as patient comorbidities and the resources available.
Both trials also allowed patients progressing on standard treatments to receive other drugs, which, at least in the TRANSFORM trial, may impact the overall survival analysis. Patients in the ZUMA-7 comparator arm could receive standard third-line therapy off trial, while patients in the TRANSFORM study could cross over to the liso-cel arm.
For TRANSFORM, this could ultimately allow investigators to highlight the difference in responses among patients that got liso-cel first versus patients that got liso-cel after standard treatment. While the data aren't available yet, Kamdar said that patients who crossed over to the liso-cel arm after their stem cell transplant had inferior response rates and event-free survival rates, "which highlights the fact that giving liso-cel earlier was beneficial to this high-risk subset."
It remains to be seen how the two therapies might compare in a real-world setting, but given the maturity of the data in these studies, Gilead's therapy may reach the market for second-line LBCL faster than BMS' therapy. In fact, this October, Gilead announced that it had filed an application with the FDA seeking approval for axi-cel as a second-line therapy based on ZUMA-7 data. The firm is also evaluating axi-cel as a frontline LBCL treatment in the ongoing ZUMA-12 study and will present data on Monday at this meeting.
Of course, Gilead and BMS aren't the only drugmakers investigating CAR T-cell therapies in earlier treatment settings. Novartis has a Phase III trial called BELINDA comparing its CAR T-cell therapy tisagenlecleucel (Kymriah; tisa-cel) against standard therapy in the second-line setting. Although the firm won't release full data from BELINDA until later in the week, Novartis announced in August that in the study tisa-cel did not show an event-free survival benefit over standard chemotherapy followed by stem cell transplant.
Ensuring equitable access
Should any of these therapies become commercially available in these earlier treatment lines for LBCL, as many expect will be the case, the number of eligible patients will increase, and ensuring equitable access will become all the more important for drugmakers, payors, and cancer centers.
Concerns about equitable access featured prominently in a discussion following the ZUMA-7 plenary presentation on Sunday as meeting attendees pointed out that the trial included very few patients from racial and ethnic minority groups. The trial enrolled only 18 Black patients, 18 Hispanic or Latino patients, and 22 Asian patients, compared with 297 white patients.
"This study … was not representative of the patient population at large," Locke acknowledged, adding that he felt that this was "consistent with other trials."
Going forward, he said it would be important to conduct real-world studies "to figure out who's able to get CAR T-cell therapy and how we can get this therapy to patients who need it regardless of insurance status, racial or ethnic status, or socioeconomic status."
The current state of CAR T-cell therapy access isn't great, according to Sattva Neelapu, the deputy chair of the lymphoma/myeloma department at MD Anderson Cancer Center, who estimated that only about 25 percent of patients who could benefit from the treatment actually receive it. Neelapu, who conducted a separate axi-cel study, ZUMA-5, in follicular lymphoma and marginal zone lymphoma patients, estimated there are only about 120 centers in the US actively administering CAR T-cell therapy for lymphoma.
"That averages about two and a half centers per state, which is probably not nearly enough," he said, noting that patients often end up spending more money to travel to receive an already expensive therapy. "There is steady improvement [in access]," Neelapu noted. "Although it's not as fast as I'd like to see."
From the manufacturing perspective, meanwhile, Gilead has taken measures in recent years to ramp up capacity in anticipation of a potential increase in eligible patients. The company has a goal to bring axi-cel to 25,000 eligible patients by 2025.
"The uptake of CAR T-cell therapy has been exceeding expectations in a way that puts a bit of strain on the manufacturing," said Ibrahim El-Houssieny, Gilead's VP and global head of oncology and cell therapy medical affairs. "But the team has been able to catch up and continue to build that capacity in anticipation for that larger indication, [and] as we're ramping up, we're also trying to make sure that the quality and turnaround time is going to be at a very competitive level."
The promising ZUMA-7 and TRANSFORM data presented at ASH suggest these CAR T-cell therapies are likely headed to market for patients in earlier disease settings. It remains to be seen whether CAR T-cell therapy costs, toxicities, and access disparities will improve in step.
"The results from both of the studies are really quite remarkable," Laurie Sehn, a clinical assistant professor at the University of British Columbia, said in a discussion of the results during the press conference. "The results are so far in favor of the CAR T-cell therapy [that] I think it's inevitable that [for second-line LBCL], this will become the standard of care."