Key data from the CRB-401 phase I trial of bb2121 was presented by Noopur Raje, from the Massachusetts General Hospital Cancer Center, Boston, US, at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Bb2121 is a BCMA-targeted second-generation CAR which incorporates the 4-1BB co-stimulatory domain, and appears to drive less acute toxicity and more durable CAR T-cell persistence, compared to the CD28 domain.
Initial data from the CRB-401 trial was presented at ASCO 2017 – read here, and data from the dose-escalation phase in which 21 patients were included was presented at ASH in December 2017 – read here. On the basis of this data, bb2121 was granted breakthrough therapy designation in December 2017. The dose expansion phase included another 22 patients, and injections began with 50 million cells, increasing up to 800 million. Patients with low BCMA expression were also included in this cohort as activity of bb2121 has been observed in cells with a low receptor density of 222 receptors/cell, therefore pre-screening for BCMA receptor does not appear to be important.
- Number of patients (pts) = 43
- Median age (min, max): escalation cohort = 58 (37, 74), expansion cohort = 65 (44, 75) years
- Median time since diagnosis: 4-6 years
- High-risk disease: escalation cohort = 38%, expansion cohort = 41%
- Mean number of prior therapies: escalation cohort = 7, expansion cohort = 8; all had received most of the available therapies for MM
- Pts in the expansion phase had all received prior daratumumab and were refractory to their last line of therapy; no BCMA expression was required
- Lymphodepletion was carried out with Flu (30 mg/m2)/Cy (300 mg/m2) administered daily for 3 days, then pts received one infusion of bb2121
Data from the expansion cohort:
- Cytokine release syndrome (CRS) = 63% overall, ≥grade 3 = 2%; no fatal toxicities
- Overall neurotoxicity = 33%; one patient had severe neurotoxicity but has recovered and done well
- Myelotoxicity was reported but the majority of cases were resolved within a month
- Neutropenia and thrombocytopenia usually resolved by day 30 and day 32
- CRS = 60% but mostly grade 1 and 2; few pts required tocilizumab
- Higher CRS as associated with infusions above 150 million cells but it was manageable
- Doses higher than 150 million cells were required for effective and robust expansion of the bb2121 cells and persisted for 6 months or more; a dose of 50 million cells was ineffective
- Persistence and high vector copy numbers correlated with response
- Overall response rate in pts receiving > 150 million cells = 95.5%
- MRD negative = 16 pts
- PFS = 11.8 months (for those receiving >150 million cells); MRD negative pts = 17.7 months
A minimum dose of 150 million cells is required for activity of bb2121, with a median PFS in these patients of 11.8 months. Testing of bb2121 will now be expanded in the phase II KarMMa trial, which is currently enrolling and aims to recruit a total of 94 participants. This data provides strong proof of concept and is extremely positive even in a group of heavily pre-treated patients. It will, therefore, be interesting to see the outcomes if this product moves earlier into the treatment pathway. Alongside these clinical trials, there are ongoing studies to look for biomarkers to predict toxicity, as well as studies to elucidate the mechanisms of progression in non-responders.