Subgroup Analyses of Phase 2 Study: Evaluating the Efficacy of Fully Human BCMA-Targeting CAR T Cells (Zevorcabtagene Autoleucel) in Patients with Relapsed/Refractory Multiple Myeloma

Background

Clinical efficacy of B-cell maturation antigen (BCMA) targeting CAR T-cell products in the treatment of relapsed/refractory multiple myeloma (RRMM) can be influenced by patient characteristics such as Age, International Staging System (ISS) stage, and high-risk cytogenetics. Zevorcabtagene autoleucel (zevor‑cel) is a fully human, BCMA-targeting autologous CAR T-cell therapy. In the ongoing Phase I/II study LUMMICAR STUDY 1 (NCT03975907), zevor-cel has shown compelling efficacy with an acceptable safety profile in heavily pre‑treated patients with RRMM. Here, we conducted subgroup analyses to evaluate the impact of baseline characteristics on the efficacy of zevor‑cel in patients treated in the Phase II stage of LUMMICAR STUDY 1.

Aims

To assess the potential impact of patient characteristics on the clinical efficacy of zevor‑cel in RRMM through subgroup analyses.

Methods

Patients with RRMM who had received at least 3 prior lines of therapy including an immunomodulatory drug and a proteasome inhibitor were enrolled in the study. A single dose of 150 × 10⁶ zevor‑cel (target dose of 150 × 10⁶ or 180 × 10⁶ CAR-positive T cells based on body weight of ≤80 kg or >80 kg, respectively) was administered 1 to 2 days after the completion of lymphodepletion. Response was assessed per the international myeloma working group (IMWG) 2016 criteria by an independent review committee (IRC). Subgroups with sample size greater than 20% of the total study population including, Age (<65 years [yrs] versus ≥65 yrs), International Staging System (ISS; I/II versus III), and the presence or absence of high-risk cytogenetics were selected for subgroup analyses.

Results

Between December 1^st, 2020, and March 2^nd, 2022, a total of 102 patients were enrolled. Overall, the median age was 59.5 years (range: 38 to 75) with 31 (30.4%) patients aged 65 years or older, 39 (38.2%) patients had ISS Stage III and 61 (59.8%) patients had high-risk cytogenetics.

The objective response rate (ORR) was 92.2% (95% CI: 85.13, 96.55) for the whole study population; 73 (71.6%) patients achieved stringent complete response (sCR, n=69) or complete response (CR, n=4), 20 (19.6%) achieved very good partial response (VGPR), 1 (1.0%) achieved partial response (PR). The ORR or the CR/sCR rate was not affected by any of the baseline characteristics tested: In age-based subgroups, ORR and CR/sCR rate for ＜65yrs versus ≥ 65yrs were 93.0% (66/71) versus 90.3% (28/31) and 71.8% (51/71) versus 71.0% (22/31), respectively. In ISS-based subgroups, ORR and CR/sCR rate for ISS I/II versus ISS III were 89.7% (35/39) versus 93.7% (59/63) and 61.5% (24/39) versus 77.8% (49/63), respectively. Subgroup without high-risk cytogenetics had ORR and CR/sCR rates of 90.2% (37/41) and 73.2% (30/41), respectively, compared to ORR and CR/sCR rate of 93.4% (57/61) and 70.5% (43/61), respectively in patients with high-risk cytogenetics.

With a median follow-up of 20.3 (range: 0.4 to 27) months, the median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) data were not mature and therefore, 18-month (18m) and estimated 30-month (30m) event free rates were used as efficacy outcomes for subgroup analyses. The DOR, PFS and OS were not impacted by age or ISS. In the age-based subgroups ＜65yrs versus ≥ 65yrs, 18m DOR rate was 62% versus 60%, 18m PFS rate was 63% versus 58% and the estimated 30m OS rate was 81% versus 77%. In ISS-based subgroups I/II versus III, 18m DOR rate was 57% versus 64%, 18m PFS rate was 58% versus 63% the estimated 30-month OS rate was 76% versus 81%. There was a trend towards favorable outcomes which was seen in patients without high-risk cytogenetics compared to those with high-risk cytogenetics: 18m DOR rate of 66% versus 58%, 18m PFS rate of 69% versus 56% and an estimated 30m OS rate of 85% versus 76%, however, none of these differences were statistically significant.

Conclusion

The subgroup analyses of the pivotal Phase II stage of LUMMICAR STUDY 1 indicated that the clinical efficacy of zevor‑cel is not significantly impacted by baseline characteristics suggesting that even patients with RRMM with poor prognostic factors may benefit from zevor-cel.