Targeting ROR1 With Cirmtuzumab to Improve Efficacy and Safety of Ibrutinib in MCL

Hun Ju Lee, MD

Inhibition of ROR1 with the high-affinity humanized monoclonal antibody cirmtuzumab in combination with ibrutinib (Imbruvica) as treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) was investigated for safety and efficacy in a phase 1/2 study (NCT03088878), and demonstrated activity in these patients.

The MCL cohort included 12 patients. On treatment with cirmtuzumab, patients achieved an objective response rate (ORR) of 83%, which included complete responses (CRs) or complete molecular responses (CMRs) in 58%, partial responses in 25%, and stable disease in 17%. Achievement of either a CR or CMR was observed within a median of 3.8 months. Notably, this result was also achieved in heavily pretreated patients who had relapsed after treatment on ibrutinib (Imbruvica) monotherapy.

Safety data for patients with MCL and CLL showed that fatigue was the most common adverse event (AE), occurring in 6% of the study population. There were no dose-limiting toxicities or discontinuation related to treatment. Overall, the addition of cirmtuzumab to ibrutinib was well-tolerated in the MCL cohort.

In an interview with Targeted Oncology, Hun Ju Lee, MD, assistant professor of medicine in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, summarized the findings and future steps for the study of cirmtuzumab in patients with MCL.

TARGETED ONCOLOGY: Can you explain the importance of targeting ROR1 in patients with MCL?

Lee: ROR1 is becoming an important target. So far, we’re seeing some activity with VLS-101, but it is not as [active] as seen with cirmtuzumab. I think it [is because it is] an antibody-drug conjugate (ADC) that has a payload of chemotherapy and may be a little bit tougher to tolerate. When you try to add on a little bit of chemotherapy, you may get some efficacy benefit, if the patient is able to continue.

With brentuximab vedotin (Adcentris), the CD38 antibody conjugated to monomethyl auristatin E, we know that the naked antibody did not have any activity, but the ADC had high activity, but it came with a price of peripheral neuropathy.

It’s always challenging to know if you will get the efficacy when you add the risk of chemotherapy toxicity. We’re seeing this space play out with ROR1 antibodies and CAR T cells, and this is just the start. I feel fortunate to be a part of the research.

TARGETED ONCOLOGY: What was the overall goal of this study? What end points were explored to achieve the goal?

Lee: Cirmtuzumab is a new ROR1 antibody. In the part 1 dose-finding study, we were able to enroll both patients with CLL and MCL. I was the lead on the MCL portion of the study. We had rapid enrollment for this trial of patients who received ibrutinib plus cirmtuzumab. We had fairly exciting preliminary data coming out, which improved our enrollment numbers. We were able to get an overall response rate of 80% and a CR rate of 58% that was really the driver compared to the historical [data with] ibrutinib alone.

The combination was very well tolerated. Many of our patients with MCL get diagnosed in their 7th decade of life. Usually, these patients are aged 65 and up with a lot of comorbidities. This was very well tolerated. We did not see any additive toxicity with the combination.

TARGETED ONCOLOGY: To expand on the safety data you presented, how did the 2 drugs interact?

Lee: We did not see any signals that there was some kind of additive toxicity. It does have atrial fibrillation risks. We did try to note if there were any AEs of special interest, but we didn’t see an increase in atrial fibrillation. Other things like diarrhea and skin rashes were expected.

With the higher number of patients that we expect in part 2, I’m sure we’ll see the AEs of special interest.

TARGETED ONCOLOGY: You mentioned high responses observed during the study. Were these responses durable?

Lee: So far, what we reported is that the median PFS was not [yet] reached in the cirmtuzumab arm, so we are very pleased. With further follow-up [we will see] whether the meta-analysis of ibrutinib plus cirmtuzumab is comparable or superior to historical ibrutinib data.

We are pleased with the durability of responses and we now have the first patient on the trial for over 2 years, which was a post allogeneic transplant patient. These are all heavily pre-treated patients and we have some patients who are post CAR T and post-transplant with high Mantle Cell Lymphoma International Prognostic Index scores, and high Ki-67. We’re seeing a nice mix of patients that are coming through and we’re very excited. We are actively enrolling in part 2.

TARGETED ONCOLOGY: What unexpected findings did you see from this analysis?

Lee: In terms of MCL, the CR rates were much higher than compared with historical ibrutinib. We are very pleased with that. You don't know until you do it, and you have no idea what types of patients come through. So, when we saw that signal, we were very pleased tthat the addition of cirmtuzumab made it even better for many of my patients who are older and needed something that is gentle, so that they can maintain the quality of life they want.

TARGETED ONCOLOGY: What are the next steps with this combination?

Lee: The sponsors of the study are actively talking to the FDA to expand the database and try to see how we can get FDA approval for cirmtuzumab.

_Reference:

_{Lee HJ, Choi MY, Siddiqui T, et al. Cirmtuzumab, an Anti-ROR1 antibody, in combination with ibrutinib: clinical activity in mantle cell lymphoma (mcl) or chronic lymphocytic leukemia (cll) from a phase 1/2 study. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-141917}