OriCAR-017, a novel GPRC5D-targeting CAR-T, in patients with relapsed/refractory multiple myeloma: Long term follow-up results of phase 1 study (POLARIS).
Authors: Huang He , Hu Yongxian , Zhang Mingming , Wei Guoqing , Zhou Linghui , Fu Shan , Feng Jingjing , Hong Ruimin , Cui Jiazhen , Huang Simao , Zhou Jincai , Tang Yu , Ding Xiaomin , Zhuo Longquan , Zhang Yanni , Xu Rick , He Xiaowen 
Published: June 2024

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Background: OriCAR-017 is a novel GPRC5D-targeting CAR T-cells. Previously we had presented early study results (Lancet Haematol 2023: 10: e107–16) following OriCAR-017 treatment, the results of good durable response and long-term safety profile support OriCAR-017 is highly probable to be developed as a promising therapy for patients with relapsed or refractory multiple myeloma. All patients had completed at least 2-year follow-up per protocol. Methods: Ten median age of 64 years (range 41–71) pretreated RRMM pts with a median of 5.5 prior lines therapies (range 3-17) received OriCAR-017. Seven (70.0%) pts were cytogenetics high risk, 4 (40.0%) pts had EMD, 3 (30.0%) pts had ISS stage(III), 2 (20.0%) pts had received prior anti-CD38 and 2 (20.0%) pts were treated with auto-HSCT and 5 (50.0%) pts were treated with BCMA CAR-T. Patients were administrated in a single dose of intravenous OriCAR-017 at 1×10⁶CAR-T/kg (DL1,n=3), 3×10⁶CAR-T/kg(DL2,n=4), or 6×10⁶CAR-T/kg(DL3,n=3). Results: At data cut-off (Jan 16, 2024), all 10 enrolled pts had been evaluated for response with the last patient completed 24 months follow up. ORR was 100.0%, sCR was 80.0%, VGPR was 20.0%. All patients achieved MRD negativity at day 28. The mDOR was 10.43 months (95%CI, 5.00-17.00); mPFS was 11.37 months (95%CI, 5.93-18.00) while mOS has not reached (7 pts still undergo survival follow-up, 1 pt died from disease progress, 2 from COVID). The mDOR was 17.23 months (95%CI, 7.33-NR) and the mPFS was 19.10 months (95%CI, 8.30-NR) with 67% prior BCMA CAR-T pts at high dose level. Nine (90%) pts had grade 1 CRS, and 1 (10%) pt had grade 2 CRS. No ≥ G3 CRS was observed. Median time to CRS onset was 2 days (range 1–9) and median duration was 6 days (range 3–9). No ICANS, nor DLTs were observed. There were no SAE and no treatment-related deaths. No PK difference across dose levels with Cmax 7354.7 copies/μL and AUC0-28 68587 copies·day/μg. At high doses, CAR-T cells were detectable at 9 months and one responder at 21 months above the LLOQ. The patients with Tlast≧9 months had a longer PFS than those with Tlast <9 months. No correlation of antigen expression and efficacy was observed. All patients had the positive GPRC5D expression in bone marrow CD138+MMPC at baseline, compared with 50% of relapsed pts had a reduced expression measured by flow cytometry. Conclusions: The updated results showed OriCAR-017 continued to provide deep and durable responses, MRD negativity was achieved in all RRMM pts, including in pts refractory to anti-CD38, PIs and IMIDs and failure to BCMA-directed therapy with excellent safety profile. The results of long-term efficacy and safety follow up support that OriCAR-017 is highly probable to be developed as a promising therapy in RRMM. Further clinical development efforts are undertaking to confirm the clinical benefits of OriCAR-017. Clinical trial information: NCT05016778 .