Cirmtuzumab when given in combination with ibrutinib is a well-tolerated and active regimen for patients with b-cell lymphoid malignancies, according to study findings presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Cirmtuzumab is a humanized monoclonal antibody that inhibits the tumor protecting activity of ROR1 and has demonstrated additive and synergistic activity with many anti-cancer agents, including ibrutinib, according to the study’s investigators.

Thus, Hun Ju Lee, MD, and colleagues, developed a Phase 1/2 study to determine the safety and effectiveness of cirmtuzumab in patients with relapsed/refractory mantle lymphoma (MCL), as well as patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL).

In Part 1, 12 patients with MCL received either 300 mg or 600 mg of cirmtuzumab intravenously every 2 weeks for 5 cycles, and then every 4 weeks of 2-16 mg/kg. The safety of cirmtuzumab was examined during the first 28 days, and then ibrutinib was added for each indication. The recommended dosing regimen for Part 2 and Part 3 was 600 mg of cirmtuzumab intravenously every 2 weeks for 3 cycles, and then every 4 weeks with ibrutinib starting on day 0.

For CLL, 34 patients (12 treatment-naïve, 22 relapsed/refractory) enrolled in Part 1 (18) or Part 2 (16), with at least 74% being high-risk as determined by unmutated IGHV, del17p, and/or del11q.

In Part 3, 22 patients received cirmtuzumab and ibrutinib, (15) or ibrutinib alone (7).

The most common adverse events of all grades included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%), and arthralgia (23%). The most common adverse events of grade 3 or higher were neutropenia (13%) and thrombocytopenia (1%).  

In MCL, the best responses of 17 patients in Parts 1 and 2 included the objective response rate (ORR) of 82%, 41% complete remission/metabolic response (CR/CMR), 41% partial response (PR), 12% stable disease (SD), and 6% progressive disease (PD). CR/CMR remained durable for 8-28+ months. Most responses occurred rapidly after 3 months of the combination therapy. Notably, responses were achieved in all patients who received prior stem cell transplant with or without CAR-T therapy (4CR, 1PR), or prior ibrutinib (2CR, 2PR).

At median follow-up of 14.6 months, the median progression-free survival (PFS) was not reached (95% CI, 17.5-NA). In CLL, the best responses from 34 patients in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR, 9% SD, and 0% PD. In Part 3, both arms achieved 100% ORR. At a median follow-up of 20.2 months, the median PFS was not reached (95% CI, NA) and the PFS estimate at 25 months was 95% for relapsed/refractory and 87% for treatment-naïve.

Overall, cirmtuzumab did not appear to negatively impact the safety of ibrutinib.

“Cirmtuzumab/ibrutinib is a well-tolerated, active regimen in both MCL and CLL,” reported Dr Lee and colleagues. “For CLL, the high ORR and PFS are encouraging, particularly for relapsed/refractory CLL. The study is ongoing, with MCL enrollment expanded to study cirmtuzumab plus ibrutinib in patients who have had a suboptimal response to an ibrutinib regimen, or who have failed other approved BTKi agents.”—Emily Bader

Lee HJ, Choi MY, Siddiqi T, et al. Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). Presented at: the 2021 ASCO Annual Meeting; June 4-8, 2021; virtual. Abstract 7556.