Treatment with the CAR-T cell therapy ciltacabtagene autoleucel (cilta-cel) led to a 97.9% response rate at two years in patients with relapsed/refractory myeloma in a recent clinical trial.
Nearly all patients with relapsed/refractory multiple myeloma achieved a treatment response after receiving ciltacabtagene autoleucel (cilta-cel) at the two-year follow-up mark of a phase 1b/2 clinical trial.
Results of the CARTITUDE-1 trial were presented at the 2021 ASH Annual Meeting. They showed that 97.9% of patients had their disease shrink as a result of treatment with the CAR-T cell therapy, and 82.5% experienced stringent complete response, which is seen as an even deeper response than complete response.
Additionally, the two-year progression-free (the time when a patient lives with cancer without worsening) and overall survival (the time when a patient with cancer is still alive) rates were 60.5% and 74.0% in all patients, respectively. Minimal residual disease negativity — which indicates that there is no detectable disease after treatment — was achieved in 92% of the 61 patients who were evaluable for the presence of MRD. The two-year progression-free survival (PFS) rates were improved in those who had MRD negativity sustained for at least six and 12 months, at 91% and 100%, respectively, as well as the two-year overall rates at which was 100% for both groups.
“These data are encouraging, and they suggest that cilta-cel will be an important treatment option for patients with multiple myeloma,” lead study author Dr. Thomas Martin, clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program, and associate director of the Myeloma Program at the University of California, San Francisco, said in a presentation on the data.
Cilta-cel is a CAR-T cell therapy that is targeted at the BCMA protein, whose overexpression is associated with the formation of cancer cells. After promising findings in clinical trials like CARTITUDE-1, the Food and Drug Administration is expediting its review and potential approval of the drug to treat relapsed/refractory myeloma. The agency is set to make a decision by Feb. 28, 2022.
At the prior readout of CARTITUDE-1 data, which had a median follow-up of 12.4 months, the overall response rate with the CAR-T cell therapy was also 98% and the stringent complete response rate was 67%. The one-year PFS and overall survival (OS) rates were 77% and 89%, respectively. Additionally, neither the average PFS nor the duration of response had been reached.
In the open-label, multicenter, phase 1b/2 CARTITUDE-1 trial, investigators enrolled patients with progressive multiple myeloma as per International Myeloma Working Group criteria, an ECOG performance status of less than 1 (meaning that their disease did not majorly impact their daily life), who had measurable disease, had received at least three prior therapies or were double refractory, and prior exposure to a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Following screening and removing blood then separating it into plasma and cells and then reintroducing it to the patient’s body (a process called apheresis), patients underwent bridging therapy, if needed, before they received lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2, both administered daily for three days. Five to seven days following lymphodepletion, patients were administered a single infusion of the CAR-T cell therapy at a targeted dose of 0.75 x 106 CAR-positive viable T cells/kg (range, 0.5 x 106-1.0 x 106).
Following the infusion, patients were evaluated for efficacy and safety.
The main goal of the phase 1b portion of the trial was to characterize the safety of cilta-cel and confirm the recommended phase 2 dose; in the phase 2 portion, evaluating the study drug’s efficacy was the main goal.
Regarding baseline characteristics for the 97 patients, the median age was 61.0 years (range, 43 to 78), 58.8% of patients were male, and 17.5% of patients were Black. Moreover, 19.6% of patients had plasmacytomas that were either extramedullary (13.4%) or bone-based (6.2%). High-risk cytogenetic profiles were reported in 23.7% of patients, which included del(17p) in 19.6%, t(14;16) in 2.1%, and t(4;14) in 3.1% of patients. Most patients (91.9%) had tumor BCMA expression on at least 50% of cells.
On average, patients received about six prior lines of therapy, with a range of three to 18. Most patients received at least five prior therapies (66.0%). Additionally, 87.6% of patients were triple-class refractory and 42.3% were penta-drug refractory. Patients were refractory to Kyprolis (carfilzomib; 64.9%), Pomalyst (pomalidomide; 83.5%), and/or an anti-CD38 antibody (99.0%). Nearly all patients (99.0%) were refractory to their last line of therapy, and the median years since diagnosis was 5.9 years (range, 1.6 to 18.2).
In the longer follow-up, the data demonstrated that the overall response rate (the percentage of patients who experience a decrease in measurable disease) was 97.9%. Of those responses, very good partial response rate or better was 94.9% and the partial response rate was 12.4%. Of the two patients whose disease did not respond to the therapy, one did not have measurable disease at baseline and consequently could not be evaluated for response but is currently in remission; the second patient had evidence of increased lytic disease (when there is a hollowing out of the bone) and did not experience an objective response before that time.
The average time to first response was one month (range, 0.9 to 10.7), the median time to best response was 2.6 months (range, 0.9 to 17.8), and the median time to complete response or better was 2.9 months (range, 0.9 to 17.8). The median duration of response was still not estimable.
The median PFS was not reached in those who achieved a stringent complete response. In patients who achieved a stringent complete response, the two-year PFS rate was 71.0%. The median overall survival has also not been reached.
Cilta-cel was also found to have a manageable safety profile, with no new safety signals, including new events of neurotoxicity and neurocognitive treatment-emergent side effects, observed with the longer follow-up.
“After implementation of mitigation strategies throughout the CARTITUDE program with more than 200 patients treated, the incidence of movement in neurocognitive (side effects) has decreased to 0.5%,” Martin, who is also co-leader of the Cancer Immunology & Immunotherapy Program at the UCSF Helen Diller Family Comprehensive Cancer Center, said. “There were no additional treatment-related deaths at two years of follow-up.”
Fifteen secondary primary malignancies were previously reported in 11 patients overall, all of which were found to be unrelated to cilta-cel via researcher assessment; six of these new secondary primary malignancies (acute myeloid leukemia, myelodysplastic syndrome, and four cutaneous) were reported since the median estimated one year of follow-up.
“I’ll remind everyone that this was a heavily pretreated population, with all patients having previously being exposed to IMiDs and alkylators, and the majority of patients receiving stem cell transplantation,” Martin added. “These patients are also experiencing unprecedented survival, and thus, I think these rates of secondary malignancy appear consistent with the population that was involved in this study.
Cilta-cel is currently being tested in earlier-line settings for patients with multiple myeloma, as seen in the CARTITUDE-2, CARTITUDE-4 and CARTITUDE-5 studies.
“Outpatient administration of cilta-cel is also being explored in these studies,” Martin concluded.
This article originally appeared on OncLive as “Cilta-Cel Continues to Impress With Durable and Deep Responses in Relapsed/Refractory Multiple Myeloma.”
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