Ciltacabtagene autoleucel has a manageable safety profile at its recommended phase 2 dose, and yielded early, deep, and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma.
Ciltacabtagene autoleucel (cilta-cel) has a manageable safety profile at its recommended phase 2 dose, and yielded early, deep, and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data presented from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) during the Virtual 47th Annual Meeting of the EBMT.1
A low dose of cilta-cel at 0.75 x 106/kg demonstrated an overall response rate (ORR) of 96.9% with a stringent complete response rate (sCR) of 67.0%, a very good partial response (VGPR) rate of 25.8%, and a partial response rate of 4.1%. The VGPR or better rate with the product was 92.8%. Notably, 72.2% of patients maintained their responses at the time of data cutoff.
At a median follow-up of 12.4 months, the median PFS had not yet been reached with cilta-cel, and the 12-month PFS rate was 76.6% (95% CI, 66.0%-84.3%). In patients who achieved sCR, the 12-month PFS rate was 84.5% (95% CI, 72.0%-91.8%), while in patients who achieved a VGPR, this rate was 68% (95% CI, 46.1%-82.5%). The median PFS had also not yet been reached in either of these patient groups. Moreover, the 12-month overall survival rate was 88.5% (95% CI, 80.2%-93.5%) with the CAR T-cell product.
“We saw how heavily pretreated these patients were, so to see a one-time treatment give these kinds of responses is quite exceptional,” Deepu Madduri, MD, lead study author and an assistant professor of medicine in the division of Hematology and Medical Oncology at Mount Sinai, said in a presentation on the data. “What’s even more impressive is that 72% of these patients maintained their responses at the time of data cutoff.”
Cilta-cel, formerly JNJ-68284528, is a second-generation CAR T-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer avidity. In the phase 1b portion of the trial, the product induced durable responses with an acceptable safety profile in patients with relapsed/refractory multiple myeloma. The same CAR gene construct was evaluated in the phase 1/2 LEGEND-2 trial (NCT03090659), according to Madduri.
The primary objective of the phase 1b portion of CARTITUDE-1 was to examine the safety profile of cilta-cel and to determine the recommended phase 2 dose. For the phase 2 portion of the trial, investigators set out to evaluate the efficacy of the agent by looking at ORR.
To be eligible for enrollment, patients had to have progressive disease per International Myeloma Working Group criteria, an ECOG performance status of 0 or 1, measurable disease, and have received at least 3 prior therapies or be double refractory. Patients also needed to have previous exposure to either a proteasome inhibitor, immunomodulatory drug, or an anti-CD38 therapy.
Once screening and enrollment was completed, patients underwent apheresis, followed by bridging chemotherapy, as needed. All patients then received lymphodepleting chemotherapy with fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2. On day 1, patients were infused with cilta-cel at a targeted dose of 0.75 x 106/kg (0.5-1.0 x 106) CAR+ viable T cells/kg. The median administered dose of cilta-cel was 0.71 x 106 (0.51-0.95 x 106) CAR+ viable T cells/kg.
In total, 97 patients were treated with cilta-cel on this study, with 29 patients enrolled to the phase 1b portion and 68 patients enrolled to the phase 2 portion. Seventy-three patients received bridging therapy. Moreover, the median turnaround time for cilta-cel was 29 days, and no patients discontinued from the trial due to a manufacturing failure. At the time of data cutoff, 83 patients remained on the study, Madduri noted.
The median age of study participants was 61 years and the majority were male (58.8%). Approximately 13% of patients had extramedullary diseae. The population was heavily pretreated, noted Madduri, with a median of 6 prior lines of therapy received (range, 3-18).
All patients enrolled to the study (100%) were triple-class exposed, 83.5% (n = 81) were penta-exposed, while 87.6% of patients (n = 85) were triple refractory and 42.3% (n = 41) were penta-refractory. Although patients enrolled to the study were not required to be refractory to their last line of therapy, according to Madduri, 99% (n = 96) were.
In 57 evaluable patients, 93.0% (n = 53) achieved MRD 10-5 negativity, with 57.9% of patients (n = 33) achieving MRD negativity and sCR and 86.0% of patients achiving MRD negativity and a VGPR or better. The median time to MRD 10-5 negativity was 1 month (range, 0.8-7.7). Moreover, among patients who had 6 months of individual follow-up, the majority had cilta-cel CAR+ T cells below the level of quantification in their peripheral blood.
The most common adverse effects (AEs) were hematological, according to Madduri. Notably, grade 3 or higher neutropenia occurred in 94.8% of patients (n = 92), and grade 3 or higher thrombocytopenia was reported in 59.8% of patients (n = 58). The median time to recovery for these AEs was 2 weeks for neutropenia (95% CI, 1.4-2.0), and 4 weeks for thrombocytopenia (95% CI, 3.7-6.1). Late recovery, defined as more than 1 month, of grade 3/4 neutropenia and thrombocytopenia from first onset occurred in 10.3% and 25.8% of patients, respectively.
Any-grade infections were observed in 57.7% of patients; although the majority were grade 1/2, according to Madduri, 19.6% were grade 3 or higher. The most commonly experienced infections included pneumonia, which occurred in 8.2% of patients, and sepsis, which occurred in 4.1% of patients.
“In general, most patients resolved their hematologic toxicities fairly quickly and without the complication of too many infections,” Madduri noted.
Non-hematological AEs that were grade 3 or higher in severity were uncommon among patients enrolled in the study, noted Madduri, although the most frequently observed included neurotoxicity (9.3%), cytokine release syndrome (CRS; 4.1%), hypophosphatemia (7.2%), and fatigue (5.2%).
CRS was experienced by 94.8% of patients (n = 92), although most cases (94.6%) were grades 1 or 2. Of those cases, 98.9% (n = 91/92) were resolved within 14 days of onset, and most patients were treated with tocilizumab (Actemra; 69.1%) or corticosteroids (21.6%). Notably, the median time to onset of CRS in this study was 7 days (range, 1-12); 89% (n = 82) of patients experienced CRS onset at day 4 or later and 73.9% (n = 68) at day 6 or later. This indicated the possibility for outpatient administration and could be explained by the fact that the maximum peripheral expansion of cilta-cel occurred at a median of 13 days (range, 9-55), according to Madduri.
CAR T-cell neurotoxicities occurred in 20.6% of patients (n = 20), and grade 3 or higher effects were reported in 10.3% of patients (n = 10). The most common neurotoxicity was immune effector cell–associated neurotoxicity syndrome (ICANS), which occurred in 16.5% of patients (n = 16), 2.1% of which (n = 2) were grade 3 or higher in severity. The median time to onset of ICANS was 8 days (range, 3-12), while the median time to recovery was 4 days (range, 1-12). Incidents of ICANS were resolved in all patients.
Other neurotoxicities occurred in 12 patients (12.4%), 9 of whom experienced a grade 3 or higher effect (9.3%), and all occurred after resolution of CRS and/or ICANS. Among those 12 patients, 5 experienced AEs involving movement and/or neurocognitive changes, while 7 experienced effects like nerve palsy or peripheral motor neuropathy. The median time to onset for these neurotoxicities was 27 days (range, 11-108), and the median time to recovery was 75 days (range, 2-160). These AEs were resolved in 6 patients, and were not resolved in the remaining 6 patients. Of those patients where these effects were not resolved, 1 patient has ongoing neurotoxicity, 1 patient died due to complications from neurotoxicity, and 4 patients died from other causes.
Of the 97 patients enrolled, 14 died while on the study. Five of those deaths were due to progressive disease, 3 were caused by AEs unrelated to treatment, and 6 were due to AEs related to treatment, which included sepsis, CRS/hemophagocytic lymphohistiocytosis, lung abscess, respiratory failure, and neurotoxicity.
Cilta-cel is currently under further exploration in other populations of patients with multiple myeloma, specifically in earlier-line settings, and outpatient administration of the product is being examined in both the phase 2 CARTITUDE-2 trial (NCT04133636) and the phase 3 CARTITUDE-4 trial (NCT04181827).