Dr Lee Reviews Cirmtuzumab and Ibrutinib in MCL/CLL

Hun Ju Lee, MD, Assistant Professor of Medicine, Department of Lymphoma & Myeloma, University of Texas MD Anderson Cancer Center, reviews a phase 1b/2 study of cirmtuzumab and ibrutinib for patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

Transcript:

Dr Lee: Hi, my name is Dr. Lee. I'm an associate professor here at the Department of Lymphoma & Myeloma at the MD Anderson Cancer Center.

I am the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research. My special interests lie in MCL, Hodgkin's lymphoma, T-cell lymphoma, rare section of our lymphoma department focusing on novel targets and creative medical education.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Lee: This is very interesting compound. Cirmtuzumab, now it has a trade name zilovertamab. This is a ROR1, Receptor Orphan Receptor 1 antibody. This target, the ROR1 is an onco-embryonic tyrosine kinase receptor that is highly expressed in many malignant, solid tumors and blood cancers, such as MCLs and CLL.

That observation originally with Dr. Kipps’ group at UCSD, and the antibody was developed, and has been going through phase 1, and it has done excellent tolerability and safety. Now, we're seeing some of the efficacy signal that's coming out.

The biological mechanism, we know that the ROR1 plays a key role in tumor growth, tumor survival, metastatic abilities, and stemness that allows for this leukemic or lymphoma stem cells to persist and grow.

We're hoping and we're proving some of the fundamental concepts of blocking ROR1 with zilovertamab and showing some of the safety and efficacy side in our abstracts and the data that is coming out.

OLN: Could you briefly describe the study and its findings?

Dr Lee: This has been a phase 1/2 study. It's looking at the safety, and then followed by the efficacy part, in the relapse/refractory (R/R) mantle cell and CLL.

The part 1 was the dose escalation, we're trying to figure out what dose of cirmtuzumab or zilovertamab will be the best in combination with ibrutinib, which have shown to be synergistic in animal models that have shown that the combination does very good, not only in terms of safety, in terms of efficacy.

The part 2 was the dose expansion. Once we found the recommended phase 2 dose, we were able to expand the patients being treated with cirmtuzumab or zilovertamab plus ibrutinib.

Then part 3 was the CLL arm of the study where they were randomized to zilovertamab plus ibrutinib versus ibrutinib alone.

The safety side of the phase 1 was very exciting because we really saw no significant toxicity of the zilovertamab.

In terms of the toxicity, it was in line with what we have seen with single-agent ibrutinib. We were very fortunate and pleased with the safety signal that it was very safe in combination with a BTK inhibitor.

In terms of the efficacy, and I know that many people are interested in the efficacy data, the real interesting data for interest of time, it came from the mantle cell side. The objective response from the phase 1/2 dose expansion group was that we were able to see 81% overall response rates (ORR) and very heavily pretreated MCL. It compares very favorably to the single-agent that was published here, from MD Anderson Dr. Wong, and his seminal New England Journal paper showed about 60+%, and the complete remission or complete response (CR) rates of 35% compare favorably to the historical 20% with ibrutinib monotherapy.

With that efficacy data, with the signal from the safety side saying that this was very well tolerated and I had many of my less young patients get on and they were able to tolerate this, we were very pleased.

]The median progression-free survival (PFS) was 36 months, which is almost tripling the ibrutinib monotherapy of about 12 to 13 months. We were very pleased with these signals that we were seeing with the phase 1/2 studies.

OLN: Were any of the outcomes particularly surprising?

Dr Lee: The real surprise came with the longer follow-up, the PFS.

The medium PFS was 36 months, which for the price you pay, because I grew up in a time where there's no such thing as a free lunch.

That means every benefit you get, you have to really pay a price, but with this combination of ibrutinib plus the zilovertamab, we were able to almost get a free lunch. As you know, there's no such thing as a free lunch.

We were able to get a significant improvement in the PFS without paying so much price in terms of toxicity.

That was really surprising and beneficial for many of our less young patients.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Lee: I'm hoping, obviously, and the phase 3 study is coming up in the second quarter of 2022. You guys will be on the lookout for this combination.

Obviously, in the MCL paradigm, there are so many agents that are coming out, CAR-Ts, bispecifics, antibody drug conjugates that are coming out that are so exciting, but obviously this combination of ibrutinib, BTK plus a zilovertamab, is a very interesting combination that I think deserves to be studied.

This will be a great option for many of those patients who are frail, less young. This combination has really worked well for many of my patients.

I look forward to the phase 3 study which will be starting in the second quarter of this year. I think that once we get a readout from that, that will be a knock-your-socks-off type of data that will get this into clinical practice.

OLN: Do you and your coinvestigators intend to expand upon this research? If so, what will be your next steps?

Dr Lee: It's going to be a global phase 3 trial for R/R MCL patients. This will be tough in terms of the logistics and the landscape of MCL, especially in the relapse setting. There's so much competition that's going on. This will be very exciting for many of our patients.

They have so many options now compared to when I started practicing almost 20 years ago, overall survival (OS) was 3 years.

Now I am here talking to you, telling you the medium PFS—PFS, not OS, this is PFS—of 3 years.

You can clearly see the improvements that we are doing for the lives and the quality of lives. Not only are we making them live longer, we are able to give quality of life. Obviously, everybody understands quality of life sometimes trumps quantity of life. We want to give both.

With this combination, I do believe that we are trying to achieve both.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

Dr Lee: Yes, MCL, obviously MD Anderson is one of the leaders in the field with Dr Wong.

For any patients who are interested in the trials and second opinions, obviously MD Anderson has the largest portfolio of clinical trial options and expertise. We have the Mantle Cell Excellence Groups that have a key partners in transplant cellular therapies, all of the treatment options that you can possibly get, cutting edge science that is being performed. Please be on the lookout for many of the trials here at MD Anderson, and many other institutions throughout the country.