Studies of chimeric antigen receptor (CAR) T-cell therapies presented at the ASCO Annual Meeting 2023 broke new ground and may change practice, according to researchers.
In the phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) outperformed standard care as second-line treatment for patients with relapsed or refractory large B-cell lymphoma (LBCL).1
In the phase 3 CARTITUDE-4 trial, ciltacabtagene autoleucel (cilta-cel) also bested standard care in patients with multiple myeloma (MM) who had received 1 to 3 prior lines of therapy and had lenalidomide-refractory disease.2
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In the phase 2 FELIX study, obecabtagene autoleucel (obe-cel) produced “unprecedented” responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), according to the study presenter.3
And results from the phase 1/2 TRANSCEND CLL 004 trial showed that lisocabtagene maraleucel (liso-cel) can produce durable responses in patients with heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).4
ZUMA-7: Axi-Cel as Second-Line Treatment for LBCL
Data from the ZUMA-7 trial showed a 27.4% reduction in the risk of death for patients who received axi-cel, even though 57% of patients in the standard care arm received subsequent cellular immunotherapy off protocol.1
The phase 3 trial (ClinicalTrials.gov Identifier: NCT03391466) included 359 patients with relapsed or refractory LBCL. They had received no more than 12 months of first-line therapy and were set to receive high-dose therapy and autologous stem cell transplant (HDT-ASCT).
The patients were randomly assigned to receive axi-cel (n=180) or standard care (n=179), which consisted of investigator-selected platinum-based chemoimmunotherapy, followed by HDT-ASCT in responders.
In the axi-cel arm, 172 patients underwent lymphodepletion, and 170 received an axi-cel infusion. In the standard care arm, 168 patients received chemoimmunotherapy, 80 responded to the treatment, and 64 underwent HDT-ASCT. More than half (57%) of patients in the standard care arm went on to receive third-line cellular immunotherapy off protocol.
At a median follow-up of 47.2 months, the median overall survival (OS) was not reached in the axi-cel arm and was 31 months in the standard care arm (hazard ratio [HR], 0.726; 95% CI, 0.540-0.977; P =.0168). The 4-year OS rate was 54.6% in the axi-cel arm and 46.0% in the standard care arm.
“This is the first randomized phase 3 trial in nearly 30 years to improve overall survival with second-line curative therapy for patients with aggressive lymphoma,” said study presenter Jason Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Progression-free survival (PFS) was improved with axi-cel as well. The median PFS was 14.7 months in the axi-cel arm and 3.7 months in the standard care arm (HR, 0.506; 95% CI, 0.383-0.669; P <.0001). The 4-year PFS rates were 41.8% and 24.4%, respectively.
No new safety signals were reported. Cytokine release syndrome (CRS) was seen in 92% of patients in the axi-cel arm, and the rate of grade 3 or higher CRS was 6%. The rate of neurologic events was 61% in the axi-cel arm and 20% in the standard care arm. The rate of grade 3 or higher neurologic events was 21% and 1%, respectively.
There was 1 treatment-related death — due to hepatitis B reactivation — in the axi-cel arm. The 2 treatment-related deaths in the standard care arm were due to cardiac arrest and acute respiratory distress syndrome.
“The quality of life for patients treated with axi-cel improved faster than those treated with chemotherapy, and our results support axi-cel as a second-line treatment for these patients,” Dr Westin said.
CARTITUDE-4: Cilta-Cel Could Be Used Earlier in MM
Results from the CARTITUDE-4 trial showed that cilta-cel significantly improved PFS, when compared to standard care, in patients with MM who had received 1 to 3 lines of prior treatment.2 The results suggest that cilta-cel could be used earlier in the course of MM treatment.
The phase 3 trial (ClinicalTrials.gov Identifier: NCT04181827) included 419 MM patients who had received prior treatment with a proteasome inhibitor and an immunomodulatory agent. They also had lenalidomide-refractory disease.
“CARTITUDE-4 study patients represent a patient population with a clear unmet need commonly seen in clinical practice,” said study presenter Binod Dhakal, MD, of the Medical College of Wisconsin in Milwaukee.
The patients were randomly assigned to receive cilta-cel (n=208) or standard care (n=211), which was investigator’s choice of pomalidomide plus bortezomib and dexamethasone or daratumumab plus pomalidomide and dexamethasone.
The overall response rate was 84.6% with cilta-cel and 67.3% with standard care (odds ratio, 3.0; 95% CI, 1.8-5.0; P <.0001). The median duration of response was not reached and 16.6 months, respectively.
The median PFS was not reached in the cilta-cel arm and was 11.8 months in the standard care arm (HR, 0.26; 95% CI, 0.18-0.38; P <.0001). The 12-month PFS rate was 76% and 49%, respectively.
“By using cilta-cel in earlier-line patients, we continue to see strong efficacy responses with a manageable safety profile,” Dr Dhakal said. “PFS benefit was seen across all subgroups, including patients with high-risk cytogenetics, plasmacytomas, and ISS stage III disease.”
OS data are still immature, but there were 39 deaths in the cilta-cel arm and 47 deaths in the standard care arm. There were 10 deaths due to treatment-emergent adverse events (AEs) in patients receiving cilta-cel (7 due to COVID-19) and 5 in patients receiving standard care (1 due to COVID-19).
Nearly all patients reported grade 3-4 AEs — 97% in the cilta-cel arm and 94% in the standard care arm. Common grade 3-4 AEs were hematologic AEs (94.2% and 86.1%, respectively) and infections (26.9% and 24.5%, respectively).
In the cilta-cel arm, 76.1% of patients experienced CRS, and 5% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Neurotoxicity was reported in 20.5% of patients, and grade 3-4 neurotoxicity was seen in 2.8%.
“Notably, for the CAR T-specific AEs, we observed lower incidence and severity of CRS, ICANS, and movement and neurocognitive treatment-emergent AEs compared to CARTITUDE-1, where patients were treated with 3 or more prior lines of therapy,” Dr Dhakal said.
Another key AE in CARTITUDE-4 was second primary malignancies, which occurred in 9 patients in the cilta-cel arm and 14 patients in the standard care arm. There were 3 cases of new hematologic malignancies reported in the cilta-cel arm.
“Development of treatment-related hematological malignancies is a concerning finding since those are difficult to treat and usually associated with poor outcomes,” said Samer Al Hadidi, MD, of the Myeloma Center at the University of Arkansas for Medical Sciences in Little Rock, who was not involved in this study. “This needs to be monitored with longer follow-up to assess if this early signal with the low number of patients affected will be higher with longer follow-up.”
Dr Al Hadidi also expressed concerns about the manufacturing time for cilta-cel. The median time from apheresis to cilta-cel infusion was 79 days (range, 45-246 days).
“The presentation stated that no patients discontinued the trial treatment because of drug manufacturing time, but I would consider the long time between apheresis and infusion to be a problem,” Dr Al Hadidi said. “Many patients with relapsed/refractory multiple myeloma, especially with aggressive disease, cannot wait that long for drug manufacturing.”
Nevertheless, the results of this trial have prompted the manufacturers of cilta-cel to submit a supplemental biologics license application for the therapy to treat patients with relapsed or refractory MM after at least 1 prior line of treatment.5
