The phase I/II CIRLL study, which is evaluating the combination of the monoclonal antibody cirmtuzumab (UC-961) plus ibrutinib has opened an expansion cohort to include patients with mantle cell lymphoma.
Hun Ju Lee, MD
The phase I/II CIRLL study (NCT03088878), which is evaluating the combination of the monoclonal antibody cirmtuzumab (UC-961) and ibrutinib (Imbruvica), has opened an expansion cohort to include patients with mantle cell lymphoma (MCL).1
The goal of the trial, which was previously exclusive to patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, is to show that adding a tyrosine-protein kinase transmembrane receptor-1 (ROR1) antibody to ibrutinib, can increase the rate of complete remissions, said Hun Ju Lee, MD. Evidence suggests that targeting ROR1 results in better responses compared with targeting CD20 or other proteins, because ROR1 is a target that is only expressed in malignant cells.
“It's just like antibiotics. Penicillin targets cell wall formation. We don't have a cell wall, but penicillin was such a good drug because it was targeting something that the human Mammalian cells did not express. If ROR1 is only expressed in CLL, MCL, Ewing sarcoma, and breast cancer, etc., this will be a golden target that we can go after,” said Lee, an associate professor of medicine, Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center.
The combination of cirmtuzumab and ibrutinib has shown promise in CLL. Results that were presented at the 2019 ASCO Annual Meeting showed that, in patients with CLL, the overall response rate (ORR) was 91.7% after 16 to 48 weeks of treatment. Among the responders, there were 6 partial responses (PR), 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, and 4 cases of stable disease. No patient with CLL progressed during the combination treatment.
As the trial continues to accrue patients, Lee believes that there will soon be some promising data from the MCL expansion cohort in this trial. Updated findings will reportedly be presented at the 2019 ASH Annual Meeting.
“I think that we will be able to show that we will get deeper remissions with the combination…. [Cirmtuzumab is] a complementary drug that has no overlapping toxicity and will be able to offer our patients a deeper remission and a longer duration of response,” Lee explained.
In an interview with OncLive, Lee discussed the phase I/II study of cirmtuzumab plus ibrutinib in patients with B-cell lymphoid malignancies and the MCL expansion cohort that was recently added to the trial, and adds how the combination can fit into the MCL treatment paradigm MCL.
OncLive: What makes ROR1 a good target for lymphomas?
Lee: ROR1 is a neoantigen that's expressed only on abnormal cells. It is a marker that's shown in embryogenesis when an organism develops and goes through the fertilization process. It's an important protein in organ formation. Then, it disappears after the embryo completes fertilization, and it loses the ROR1 expression. Fortunately for us, the expression is found in malignant cells, especially in CLL and MCL. It's interesting because everybody [who treats] lymphoma knows that rituximab (Rituxan) is targeting CD20 but, unfortunately, CD20 targets normal B cells as well as abnormal malignant clone B cells. If we can find a target that is only expressed by malignant cells, then we will be able to target that without causing collateral damage to normal B cells. That's the holy grail of what we call targeted medicine—the target is only expressed by the neoplastic malignant cells and not the normal cells.
In all of our treatment modalities, like from the start of mustard gas in World War II, all of them targeted DNA replication and transcription; unfortunately, all of that machinery is also expressed in normal cells. When you try to block that, you're going to have toxicity, and that's why there's such a narrow therapeutic index with these chemotherapy agents. It's just like antibiotics. Penicillin targets cell wall formation. We don't have a cell wall, but Penicillin was such a good drug because it was targeting something that the human Mammalian cells did not express.
If ROR1 is only expressed in CLL, MCL, Ewing sarcoma, breast cancer, etc., this will be a golden target that we can go after. If patients have CLL or MCL, they're not going through embryogenesis so this will not have an impact on the biological function of ROR1.
What was the rationale for studying cirmtuzumab and ibrutinib in MCL?
Once they found out that MCL was expressing ROR1, they screened a bunch of peptides and antibodies and were able to get a chosen antibody that had a good affinity to ROR1 and they were able to hit the target. Once they were able to hit the target, [they knew they could use this therapeutically]. It's just like rituximab. If you block these protein targets, you will increase what we call complement-activated cytotoxicity, and you'll have macrophages come in and clear the cancer cells. In terms of getting rid of MCL, this makes clear sense. Just like rituximab, which has been a superstar in the lymphoma world, ROR1 could be a superstar trying to clear MCL.
There's also a biological side to this because we know that ROR1 is a proliferating signal. It's like an antenna on top of the cell. It's going to send proliferative signals and cause activation of the Wnt signaling pathway, which causes proliferation. If you block with cirmtuzumab, the ROR1 antibody, the microenvironment will not be able to activate ROR1 and hence, you will kill off that survival switch.
Ibrutinib is a superstar in treating MCL. MCL was the first lymphoid malignancy to get approval from the FDA based on data from Dr Wang at MD Anderson Cancer Center. However, ibrutinib does not lead to a high level of CR. In his pivotal New England Journal of Medicine paper, about 21% of patients were able to achieve a CR. That's very low. The majority of these patients only had a partial response, but they did have clinical benefit, and with the longer follow-up, more patients were able to stay on the drug and hence, they were able to increase the CR rates. It was a no-brainer of adding cirmtuzumab to ibrutinib because they have complementary mechanisms of action. Not only are you stopping the BTK, which is the BCR signaling for survival and proliferation, but you're also going to have the ROR1 antibody cirmtuzumab blocking the ROR1 downstream signaling pathway, which is another survival pathway. The hope is that in combining the 2, we will see synergistic activity with minimal overlapping toxicity.
The phase I data that was presented by Michael Choi, MD, from the University of California San Diego (UCSD) showed that this was fairly well tolerated. The maximum tolerated dose was not reached. Patients had no infusional reactions or cytopenias with the ROR1 antibody. This shows that this is an awesome antibody for combination therapy, just like rituximab.
Can you discuss the preliminary results for MCL with this combination?
Lee: For MCL, we had about 6 patients with 3 responses. There was 2 CRs, 2 PRs, and 1 progressive disease. It's much more preliminary than the CLL cohort. However, the first patient with MCL who went on this trial that excited me was a patient who was a post-allogeneic transplant who failed allogeneic transplant and presented to me in my clinic with about an 8-cm size mass on the chest wall. After about 2 or 3 cycles of cirmtuzumab plus ibrutinib, he was able to get into CR by Lugano criteria.
What is the overall goal for this research?
We just finished the phase I dose-finding study and we didn't have any toxicity to talk about. I think cirmtuzumab is a great drug to pursue in combination, just like rituximab. If you look at rituximab as a single agent in the relapsed/refractory setting of MCL, you're looking at about a 20% ORR with CR rates in the single digits. That is very similar. I think we're doing better than single agent, but we don't have the efficacy data that rituximab has yet because our study is phase I. We're now doing the phase II study.
The compounding variable is that we will be giving ibrutinib with cirmtuzumab. That will be one of the criticisms that I'm sure I'll be facing. I think people will say "Dr Lee, you're giving ibrutinib, a superstar, to [patients with] MCL. Why do we even need to give cirmtuzumab?"
I think that we will be able to show that we will get deeper remissions with the combination. I like to look at this like ibrutinib is Michael Jordan, and Jordan didn't win any championships until Scottie Pippen, Jr. came to the Chicago Bulls. I feel that cirmtuzumab is like Scottie Pippen, Jr. It's a complementary drug that has no overlapping toxicity and will be able to offer our patients a deeper remission and a longer duration of response.
How do you envision this combination fitting into the current treatment landscape for MCL?
Right now, frontline therapy for MCL is still chemotherapy in the community setting, and bendamustine (Treanda) plus rituximab is probably the most common outside of clinical trials. If you have a young fit patient, you might treat them like the Europeans do, or they come to MD Anderson Cancer Center and get hyper-CVAD, or a variation of the high-dose araC therapy regimens.
What I feel and what I see in my colleagues is that people are moving away from autologous transplantation and giving patients less intense regimens. We now have better salvage regimens like ibrutinib and venetoclax (Venclexta). These are very active agents along with an agent like lenalidomide (Revlimid) and bortezomib (Velcade), which has already been approved.
I like the most active single agent is venetoclax, and I think that is going to be FDA approved in the next few months. It has ORR above 70% and CR rates of 30% to 40%. It's probably better than ibrutinib. Then, in Australia, a study of ibrutinib plus venetoclax was superb, and 4 months out they were able to active double or triple the CR rate compared to single-agent ibrutinib.
How does cirmtuzumab plus ibrutinib fit in? In our faculty meetings, we often discuss what is the right sequence to give. Ibrutinib is intended to be in the second-line drug after chemotherapy because that is what insurance approves outside of the clinical trial setting. I believe that cirmtuzumab can be, theoretically, added to any regimen in combination, and that's where we’re going to end up going.
This study is going to show that ibrutinib and cirmtuzumab in a great combination regimen. We'll be able to show that as soon as this trial is rapidly enrolling. Our data will be presented at ASH 2019.
Choi MY, Wierda WG, Lee HJ, et al. Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts. J Clin Oncol. 2019;37(suppl; abstr 7527). doi: 10.1200/JCO.2019.37.15_suppl.7527.