Cirmtuzumab Added to Ibrutinib Induces Responses in R/R MCL and CLL

Compelling objective responses and safety results were demonstrated with the combination of cirmtuzumab and ibrutinib in cohorts of patients with mantle cell lymphoma and chronic lymphocytic leukemia, who were treated in the phase 1b/2 clinical trial.

Compelling objective responses and safety results were demonstrated with the combination of cirmtuzumab (UC-961) and ibrutinib (Imbruvica) in cohorts of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), who were treated in the phase 1b/2 clinical trial (NCT03088878).1

A group of investigators led by Hun Ju Lee, MD, hypothesized that cirmtuzumab/ibrutinib would increase activity, deepen responses, and extend the durability of responses compared to ibrutinib alone based on the mechanism of action of cirmtuzumab, a monoclonal antibody that addresses re-expressed ROR1 in hematologic malignancies and solid tumors. As a single agent, cirmtuzumab led to antitumor activity in an earlier study and it was suggested that the drug could be additive to the effects of Bruton’s tyrosine kinase (BTK) inhibitors. It was also hypothesized that the addition of cirmtuzumab to ibrutinib would not interfere with the tolerable safety profile of either agent.

The study enrolled patients with relapsed/refractory (r/r) MCL or r/r CLL and small lymphocytic leukemia (SLL) who had measurable disease and little or no prior exposure to BTK inhibitor therapy. Overall, the study included 46 patients, 12 of whom were evaluable to be enrolled in the MCL cohort and 34 evaluable for the CLL/SLL cohort. At baseline, the MCL cohort showed a median of 2.5 prior treatment regimens (range, 1.0-5.0). The prior regimens consisted of chemotherapy, biologics, PI3K/BCL-2 inhibitors, stem cell transplant, and chimeric antigen receptor (CAR) T-cell therapy. In the CLL/SLL cohort, the median number of prior regimens was 2.0 (range, 1.0-9.0), which consisted of chemotherapy, biologics, and PI3K/BCL-2 inhibitors.

Ten out of 12 evaluable patients in the MCL cohort had an objective response as their best response (83.3%). Of the patients with MCL who had an objective response, 58.3% had a complete response (CR), 25% had a partial response (PR), and 16.7% had stable disease (SD). These responses led to a clinical benefit rate of 100% in the MCL cohort. Thirty of the 34 evaluable patients with CLL or SLL achieved an objective response, which included a CR in 3% of the cohort, a PR or PR with lymphocytosis in 85%, and SD in 12%. The clinical benefit rate for the CLL/SLL cohort was also 100%. Neither cohort had any cases of progressive disease.

Lee et al noted in a swimmer plot that the majority of patients in the MCL cohort who achieved CRs did so in less than 5 months. A large majority of the complete responders in the MCL cohort also had prior ibrutinib. In a presentation of the poster, Lee stated that this signaled synergy between cirmtuzumab and ibrutinib. The CLL/SLL cohort did not show any notable signals for response.

The waterfall plots showed significant tumor regression in both cohorts.

At a median follow-up of 8.3 months, the MCL cohort showed a 17.5-month median progression-free survival (PFS), which showed favorable comparability to historical data from a pooled analysis of 3 clinical trials published in a 2019 issue of Haematologica2 that showed a PFS of 12.5 months with ibrutinib monotherapy in patients with r/r MCL and 10.3 months in patients with more than 1 prior line of therapy.

Median follow-up in the CLL cohort was 12.8 months, but the median PFS had not yet been reached.

The safety analysis showed that the combination of cirmtuzumab and ibrutinib was well tolerated in patients with MCL and CLL, with most adverse events (AEs) being grades 1 or 2 in severity. There were no dose-limiting toxicities or grade 3 events observed in the study that were found to be related to cirmtuzumab. Fatigue, diarrhea, and contusion were frequent AEs that were potentially related to cirmtuzumab alone or in combination with ibrutinib. Six subjects (8.6%) experienced any-grade neutropenia, which is known to occur in 50% to 60% of patients who received ibrutinib, according to the prescribing information.

Serious treatment-related AEs occurred in 1 patient with MCL and 9 patients with CLL, which were likely related to ibrutinib or ibrutinib plus cirmtuzumab. The serious AEs of grade 3 or higher included atrial fibrillation in 5 patients; pneumonia in 3; and pericardial hemorrhage, pleural effusion, pyrexia, hyperkalemia, gastrointestinal hemorrhage, and staph infection, which occurred in 1 patient each.

A larger proportion of patients in the MCL cohort (86.7%) experienced treatment-emergent AEs (TEAEs) of any grade than in the CLL cohort (83.6%). The same was true for grade 3 or higher TEAEs. The combination regimen was overall well tolerated.

Three patients with CLL in the study discontinued treatment due to AEs. There was also 1 patient who opted for alternative therapy and another patient who required therapy for pre-existing prostate cancer. Three patients with MCL discontinued treatment due to PD. Also, one patient with CLL was diagnosed with coronavirus disease 2019 but has a good prognosis overall.

At the time of data cutoff, the majority of the study population had completed 1 year of treatment with cirmtuzumab/ibrutinib. Sixteen individuals from the CLL cohort has also enrolled in the extended therapy while continuing treatment with cirmtuzumab plus ibrutinib.

Overall the study of cirmtuzumab in combination with ibrutinib was encouraging.

All patients in the study were 18 years of age or older with an ECOG performance status of 3 or lower, radiographically measurable disease, and in need of treatment of their disease. The study was conducted in 3 parts: dose escalation, dose expansion, and phase 2 randomization to cirmtuzumab/ibrutinib versus ibrutinib alone. Part 1 has completed enrollment, whereas parts 2 and 3 continue to accrue patients.


1. Lee HJ, Choi MY, Siddiqi T, et al. Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: Interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). J Clin Oncol. 2020;38(suppl)8036. doi:10.1200/JCO.2020.38.15_suppl.8036

2. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the Treatment of Relapsed/Refractory Mantle Cell Lymphoma: Extended 3.5-year Follow Up From a Pooled Analysis. Haematologica. 2019;104(5):e211-e214. doi:10.3324/haematol.2018.205229