CARTIFAN-1: Initial results of the phase II clinical trial

Ciltacabtagene autoleucel (cilta-cel) is licensed in Europe and the United States for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received three or more prior therapies, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti‑CD38 antibody, and have demonstrated disease progression on the last therapy.¹ The approvals of cilta-cel approvals were based on long-term data from the CARTITUDE-1 trial (NCT03548207).¹

CARTIFAN-1 (NCT03758417) is a phase II clinical trial of cilta-cel for the treatment of patients with RRMM.² In November 2022, Mi et al.² published the initial safety and efficacy results from this trial, which we are pleased to summarize here.

Study design

CARTIFAN-1 is a phase II, open-label clinical trial, with a sample size of ≥45 patients to give the study >90% power. All patients had received ≥3 prior lines of treatment, including a PI and IMiD; however, prior anti-CD38 antibody exposure was not required as no relevant drug was licensed in China at the start of recruitment. Patients were excluded if they had received previous chimeric antigen receptor T-cell or B-cell maturation antigen-targeted therapy or had hepatitis B virus positivity. Eligible patients received a single cilta-cel infusion 4–6 weeks after lymphodepletion with cyclophosphamide and fludarabine.

Results

As shown in Figure 1, a total of 64 patients were recruited, among which 16 discontinued treatment prior to cilta-cel infusion. Overall, 47 patients received the full dose of cilta-cel, with one patient receiving a reduced dose.

*Adapted from Mi et al.^2
†47 received the target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶) chimeric antigen receptor-positive viable T cell/kg.

Patient characteristics of the all-treated population can be seen in Table 1.

Table 1. Characteristics of patients who received ciltacabtagene autoleucel*

BCMA, B-cell maturation antigen; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor. *Adapted from Mi, et al.2 †Maximum value from bone marrow biopsy and bone marrow aspirate selected. ‡n = 37. §One or more PI, one or more IMiD, and one anti-CD38 antibody.
Characteristic, % (unless otherwise stated)	All treated patients (n = 48)
Median age (range), years	61.0 (30–72)
Male	66.7
Median time since diagnosis (range), years	3.7 (1.4–10.2)
Presence of extramedullary plasmacytomas	10.4
Bone marrow plasma cells ≥60%†	16.7
Tumor BCMA expression ≥50%‡	64.9
ECOG performance status score
0	45.8
1	54.2
ISS stage
I	43.8
II	37.5
III	18.8
High-risk cytogenetics	43.8
t(14;4)	22.9
De17p	20.8
t(14;16)	0
Median number of prior therapies, range	4 (3–9)
Prior therapy
Exposed to carfilzomib	6.3
Refractory to carfilzomib	4.2
Exposed to bortezomib	100
Refractory to bortezomib	75.0
Exposed to ixazomib	39.6
Refractory to ixazomib	37.5
Exposed to lenalidomide	87.5
Refractory to lenalidomide	83.3
Exposed to pomalidomide	6.3
Refractory to pomalidomide	6.3
Exposed to thalidomide	77.1
Refractory to thalidomide	64.6
Exposed to daratumumab	31.3
Refractory to daratumumab	27.1
Triple-class exposed§	31.3
Triple-class refractory§	18.8
Refractory to PI	85.4
Refractory to IMiD	91.7
Refractory to last line of therapy	97.9

Efficacy

• With a median follow-up of 18 months, the overall response rate (ORR) was 89.6% (95% confidence interval [CI], 77.3–96.5).
  • Median time to first response was ~1 month.
• Overall, 77.1% of patients (95% CI, 62.7-88.0) achieved at least a complete response.
  • Of the 37 patients who achieved at least a complete response, 94.6% also achieved minimal residual disease negativity.
• Median duration of response, progression-free survival, and overall survival were not reached.
• The 18-month progression-free survival and overall survival rates were 66.8% (95% CI, 49.4–79.4) and 78.7% (95% CI, 4.0–88.0), respectively.

Safety

• Hematologic adverse events were the most frequent, including anemia (100%), neutropenia (97.9%), lymphopenia (95.8%), and thrombocytopenia (87.5%).
• Cytokine release syndrome occurred in 97.9% of patients (35.4% were Grade 3 or 4), with a median time to onset of 7 days and median duration of 5 days.
• Infections occurred in 85.4% of patients (37.5% were Grade 3 or 4).
• Ten deaths occurred following cilta-cel infusion; two within 30 days of infusion and eight within 60 days. Eight deaths were considered treatment-related by the investigator, due to:
  • Hemorrhage following Grade 4 thrombocytopenia (no platelet transfusion available)
  • Sudden cardiac death with hemoglobin <50 g/L (no blood transfusion available)
  • Intracranial hemorrhage following Grade 4 thrombocytopenia (limited platelet transfusion availability
  • Septic shock
  • Hepatic failure
  • Pneumonia
  • Multiple organ failure
  • Pulmonary fungal infection

As of the data cut-off of July 2012, two patients had been retreated with cilta-cel.

Discussion

Considering an ORR of 89.6%, the results of CARTIFAN-1 were similar to CARTITUDE-1 (ORR, 97.9%), but with a higher rate of deaths (16.7% vs 6.2%) and Grade 3/4 cytokine release syndrome (35% vs 4%). With high CR rates and minimal residual disease negativity, the initial results demonstrate cilta-cel can achieve deep treatment responses in patients with RRMM. However, the study also highlights the significant treatment-related morbidity associated with cilta-cel, and the need for supportive measures such as blood and platelet transfusions. Patients treated with cilta-cel must be regarded as heavily pre-treated, with healthcare infrastructure and services that can support treatment to ensure patients can safely derive maximum benefit.