SAN DIEGO – Gilead Sciences and Arcellx's autologous B-cell maturation antigen (BCMA)-directed CAR T-cell therapy anitocabtagene autoleucel (anito-cel) could be an effective treatment option for advanced multiple myeloma patients, according to new Phase II data presented at the American Society of Hematology's annual conference on Monday.
Ciara Freeman, an oncologist at the Moffitt Cancer Center, presented preliminary results from the Phase II, registration-directed iMMagine-1 clinical trial designed to assess the safety and preliminary efficacy of anito-cel in patients with heavily pretreated multiple myeloma.
Gilead subsidiary Kite has been a pioneer in the autologous CAR T-cell therapy space. The drugmaker markets Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel) for patients with certain lymphomas and leukemias. But when it comes to advancing CAR T-cell therapies for multiple myeloma, the firm has lagged behind its competitors Bristol Myers Squibb and Johnson & Johnson, both of which market BCMA-directed CAR T-cell therapies for advanced multiple myeloma. BMS markets Abecma (idecabtagene vicleucel) and J&J markets Carvykti (ciltacabtagene autoleucel), both for advanced multiple myeloma patients.
Now, through a collaboration with Arcellx inked in 2022, Gilead is advancing its own BCMA-directed CAR T-cell therapy that it believes could offer advantages over existing treatments in the class, partly thanks to its differentiated construct.
Anito-cel is similar to the other autologous multiple myeloma CAR T-cell therapies in that it is designed to bind to BCMA on the surface of cancer cells. Like other treatments, anito-cel also involves harvesting patients' immune cells, modifying them to express a chimeric antigen receptor targeting BCMA, then reinfusing them as a one-time bespoke treatment. However, anito-cel is also, according to Freeman, "unique from other products in its binding domain."
Freeman explained that the product's binding domain, which was developed by Arcellx and is called a D-Domain, is a small, synthetic protein with "simple architecture and minimal folds." Due to this construct, she said that protein expression levels may be higher with anito-cel, "therefore allowing for improved transduction efficiency, lower number of CAR-negative cells, and a lower total T-cell dose." This unique binding domain could potentially make the therapy more effective and tolerable, and patients less likely to relapse following their infusions.
"The combination of higher density of expression with a faster off-rate may confer benefit with improved cytotoxicity and reduced inflammation," she said.
The Phase II iMMagine-1 trial was a single-arm study, and there's been no head-to-head comparison of anito-cel with Carvykti or Abecma, so there's no direct evidence that anito-cel is superior to these other treatments. That said, the response rates were encouraging to oncologists.
"It's a little too early to make declarations," said Peter Forsberg, a hematologist-oncologist at the Sarah Cannon Research Institute at Colorado Blood Cancer Institute, who was not involved in the study. "But I do think that if the final analysis of the IMMagine-1 trial bears out the promise of this preliminary data, it's going to be an appealing option to offer patients in the myeloma clinic."
IMMagine-1 efficacy, safety
In the Phase II iMMagine-1 trial, patients were eligible if they'd received three or more prior therapies. Of 117 patients who received anito-cel infusions, 86 were included in the efficacy analysis and 98 were in the safety analysis.
As of the trial's most recent data cutoff of Oct. 31, overall response rate on anito-cel was 97 percent and the complete response rate was 62 percent. In patients who were evaluable for minimal residual disease (MRD) testing, 93 percent achieved MRD negativity within a median of one month.
Freeman also presented preliminary survival data estimates. After six months following anito-cel, 93.3 percent of patients were alive without disease progression, and after one year, the same was true for 78.5 percent of patients. "This is likely to evolve with more follow-up," she said. The median overall survival has not yet been reached, though Freeman and colleagues pointed out that 96.5 percent of patients were alive after one year.
Notably, Freeman pointed out that several patients — eight in the safety-evaluable arm and five in the efficacy-evaluable arm — received their anito-cel infusions in the outpatient setting. "This will increase as more of us become more comfortable toward the end of this study to treat patients on an outpatient basis," she said. This marks a departure from other available CAR T-cell therapies that, due to their toxicity risks, require patients to be admitted to specialized centers in the inpatient setting.
Part of the reason that anito-cel could be administered in the outpatient setting is its potentially improved safety profile. Of patients treated on iMMagine-1, 83 percent experienced cytokine release syndrome of any grade, but none of these were grade 3 or grade 4, and only one patient had a grade 5 event.
"For context, this was a 76-year-old patient who unfortunately had rapid disease progression occurring between leukapheresis and lymphodepletion in the absence of bridging therapy," Freeman said, framing this as an unfortunate outlier in a trial where anito-cel's safety profile seemed otherwise encouraging.
Just nine patients on the trial developed immune-effector cell-associated neurotoxicity syndrome (ICANS), and "all events resolved primary to discharge with a median time to resolution of four days," she said. None of these instances of ICANS were grade 4 or grade 5, and just one was grade 3.
"Notably, there have been no reports of any non-ICANS delayed neurotoxicities," she said, pointing out that this remains true for patients who had received anito-cel in an earlier, Phase I study, as well.
"The safety profile described to date [is] really promising," Sarah Cannon's Forsberg said. "The data is particularly exciting as it combines a high-level efficacy profile with a reduced rate of some toxicities … that have been a challenge with myeloma CAR-Ts."
In a recent analysis, also presented at ASH, 12 out of 236 patients treated with Carvykti experienced grade 3 or higher cytokine release syndrome, and 24 experienced delayed neurotoxicity. With Abecma, six patients out of 350 experienced grade 3 or higher cytokine release syndrome and two patients experienced delayed neurotoxicity.
In the wake of the encouraging safety and efficacy results from iMMagine-1, Freeman noted that Gilead and Arcellx are now conducting the Phase III iMMagine-3 study, comparing anito-cel to standard of care therapy in advanced multiple myeloma patients who've received between one and three prior lines of therapy.
Freeman estimated that the turnaround time for manufacturing anito-cel would probably fall within two to three weeks.
Although Forsberg acknowledged that the data are still too preliminary to draw firm conclusions, especially in the absence of any sort of direct comparison to existing multiple myeloma cell therapies, he said that "it does appear that the very high overall and deep response rates and the durability of disease control … compare favorably to currently approved multiple myeloma CAR T-cell therapies."