Results of a phase 1b and 2 study of cirmtuzumab and ibrutinib in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Cirmtuzumab is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive and synergistic activity with many anticancer agents, including ibrutinib,” explained Hun Ju Lee, MD Anderson Cancer Center, Houston, Texas, and co-investigators.

During dose escalation, patients received cirmtuzumab intravenously every 2 weeks for 5 cycles, then every 4 weeks with 2-16 mg/kg, and 300 mg or 600 mg were examined.

Researchers determined the recommended dosing regimen for the expansion phase, and for CLL patients was cirmtuzumab 600 mg intravenously every 2 weeks for 3 cycles, then every 4 weeks in combination with ibrutinib.

In all, 28, 34, and 28 patients were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (cirmtuzumab plus ibrutinib [n=18] or ibrutinib alone [n=10]).

“In MCL Parts 1 & 2, the median number of prior systemic regimens was 1.5, including patients relapsing after ibrutinib (n=4), autologous stem cell transplant (auto-SCT, n=6), auto-SCT and allogenic-SCT (n=1), or auto-SCT and chimeric antigen receptor therapy (CAR-T) (n=1),” continued Dr Lee and co-authors.

Further, the median number of prior systemic regimens for CLL Parts 1 & 2, and CLL Part 3 (R/R), was 2 (1-15), including auto-SCT (n=1).

The most frequent treatment emergent adverse events (TEAEs, ≥30%) for both MCL and CLL patients treated with cirmtuzumab plus ibrutinib (n=80) included contusion and fatigue (40%) and diarrhea (37.5%). Grade 3≥ TEAEs included hypertension (10%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%).

Notably, most TEAEs in MCL or CLL patients were related to ibrutinib alone in 64 percent or 84 percent, respectively, versus cirmtuzumab alone in 14.3 percent or 16 percent, respectively.

In the MCL group, 20 evaluable patients in Parts 1 & 2 had a complete response (CR) rate of 35 percent and a partial response (PR) rate of 45 percent. At a median follow-up of 14.9 months the objective response rate (ORR), clinical benefit rate (CBR), and median duration of response (DOR) for overall, >30% Ki-67 disease, and <1 prior systemic regimen subgroups were 80 percent, 90 percent, and not reached (95% CI, 11.9-NR); 81.8 percent, 81.8 percent, and 13.8 percent (95% CI, 8.7-NR); and 90 percent, 100 percent, and NR (95% CI, 8.7-NR), respectively.

In the CLL group, 34 evaluable patients in Parts 1 & 2 included a 94.1 percent ORR, 11.8 percent CR, 82.3 percent PR, and a 100 percent CBR rate. At a median follow-up time of 24.8 months, the DOR for overall and >1 prior systemic regimen subgroups were NR, (8.3-35.9) and NR (12.0-29.6).

The median progression free survival (PFS) for overall, patients achieving CR, and >1 prior systemic regimen subgroups were NR (9.1-35.8), NR (95% CI, 22.5-NR), and NR (9.1-35.2). The median PFS rate was not met during Part 3 for patients with CLL.

“Cirmtuzumab plus ibrutinib is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of patients with MCL or CLL regardless of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR, CR of 35 percent, and a DOR that was NR within the study period,” concluded Dr Lee and co-researchers.

The researchers also noted that the study is ongoing, with MCL enrollment expanded to include cirmtuzumab plus ibrutinib in patients who have had an inadequate response to an ibrutinib regimen or are refractory to approved Bruton’s tyrosine kinase inhibitor agents.—Alexa Stoia

Lee HJ, Choi M, Siddiqi T, et al. Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL). Presented at: the 2021 ASH Annual Meeting. Dec 11-14, 2021. Abstract 3534.