Cirmtuzumab Plus Ibrutinib Shows Activity and Tolerability in MCL and CLL

Hun Ju Lee, MD

The combination of the first-in-class humanized monoclonal antibody cirmtuzumab and the BTK inhibitor ibrutinib (Imbruvica) was found to be an active, well-tolerated regimen for patients with relapsed/refractory mantle cell lymphoma (MCL) and treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 1b/2 study (NCT03088878).

The trial enrolled patients with relapsed/refractory MCL, or relapsed/refractory or treatment-naïve CLL or small lymphocytic lymphoma (SLL) who had measurable disease and had either limited or no prior treatment with BTK inhibitors. The trial is comprised of 3 parts: a phase 1 dose-escalation phase with cirmtuzumab (part 1), an expansion cohort (part 2), and phase 2 randomization of the cirmtuzumab/ibrutinib combination versus ibrutinib alone (part 3).

As of January 29, 2020, 12 patients with relapsed/refractory MCL were enrolled onto part 1 of the trial. All patients had stage III/IV disease at diagnosis and 25% had bulky tumor at the time of study entry. Fifty-eight percent of these patients had Mantle Cell Lymphoma International Prognostic Index risk scores of intermediate or high, and 83% had received ≥2 prior regimens. Additionally, a total of 34 patients with CLL were enrolled onto either part 1 of the trial (n = 18) or the part 2 expansion phase (n = 16).

Results presented during the 2020 ASCO Virtual Scientific Program by lead author Hun Ju Lee, MD, showed a high tumor response rate with the combination in those with MCL, with an objective response rate (ORR) of 83% and a complete response (CR) rate of 58%. The initial median progression-free survival with the regimen was 17.5 months. Those who had received 1 to 10 months of prior ibrutinib also responded well to the combination; 2 patients achieved CRs and 2 achieved partial responses (PRs).

In patients with CLL/SLL, treatment with the combination led to an overall best response rate of 88% and a clinical benefit rate of 100%. One patient experienced a CR and has since remained in remission for over 8 months and off all CLL treatment. Three other patients achieved PRs with the regimen.

With regard to safety, the most common adverse effects (AEs) potentially related to the combination were fatigue, diarrhea, and contusion. One patient with MCL and 8 patients with CLL reported treatment-related severe AEs. However, the events were thought to be related to ibrutinib or the combination rather than cirmtuzumab alone. Grade 3 or higher AEs included atrial fibrillation (n = 5), pneumonia (n = 3), pericardial hemorrhage, pleural effusion, pyrexia, hyperkalemia, gastrointestinal hemorrhage, and staph infection (n = 1, each).

“In terms of medium follow up, it's very short so I don't want to get too excited. The median follow-up was 8 months and the median PFS is 17 months,” said Lee. “We are very happy with the results we have, and we look forward to building on top of this. There are ways to get rid of MCL but some of the ways that you take have a lot of toxicities involved. It is really exciting that all of my patients did not have any toxicity.”

In an interview with OncLive, Lee, an assistant professor of medicine in the Department of Lymphoma & Myeloma and the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research at The University of Texas MD Anderson Cancer Center, further discussed the interim results of the study examining cirmtuzumab plus ibrutinib and the next steps with this research in MCL and CLL/SLL.

OncLive: Could you provide some background on cirmtuzumab and the rationale to explore it in combination with ibrutinib in this setting?

Lee: As you know, the holy grail of cancer therapy is to find a target on the cancer cell that is not expressed on normal cells. Ideally, with lymphomas we're looking for a target on the lymphoma cell that is different from the proteins expressed on the surface of normal B cells. We would like to treat the lymphoma without harming normal B cells. Preclinical studies have examined ROR1, a family of proteins that are expressed in embryonic protein during early life and [then] disappear. [Investigators have] found [that these proteins] were expressed on the lymphoma cells and leukemia cells. [Investigators thought that] if [ROR1] was expressed on malignant lymphoma and leukemia cells and not expressed on normal cells, then it would serve as a great target [for therapy].

Rituximab (Rituxan) was developed in the early 90s and it targets CD20, which is expressed on normal cells. As such, when you give treatments like rituximab, even though the agent is well-tolerated, it does have some collateral damage. Rituximab decreases lymphocyte counts and we do have patients who require intravenous immunoglobulin therapyfollowing prolonged rituximab maintenance [if they have] lowlymphocyte counts.When they observed this finding, investigators questioned whether this is something that can be targetable. However, before we can develop a treatment [we have to understand] what it does.

What they found was that it is 1 of the proliferative survival signals, that are complementary to another system of proteins called immunoglobulin and that is the B-cell receptor. We know that B-cell receptor targeting has been tremendous with the targeting of BTK with ibrutinib and idelalisib (Zydelig). In all these pathways, targeting has generated great treatment options for many of our patients. However, we know that the difficulty with ibrutinib, idelalisib, the PI3K inhibitors, and BTK inhibitors, is that they don't [lead to an] 100% complete remission.

Where is it? How are these B cells surviving? What about the patients who are primary refractory? What about the patients who respond initially and then relapse? Where are these cells coming from and where's the survival? We're almost trying to play chess with these lymphoma cells because we know that they're using biological mechanisms to achieve a survival advantage.

[When the BTK is being blocked, these lymphoma cells] reroute the survival signal through another survival channel. We believe one of the mechanisms that this drug works by, is by blocking the ROR1, which is one of the other survival signals. When we gave ibrutinib in preclinical studies, [it was found to] increase the signaling pathway in the ROR1 pathway. If you block the BTK, the cells find an alternative route. The lymphoma and leukemia cells are very smart. They are able to take advantage of alternate sources of growth signals. That's where the idea came in, combined with the results from preclinical studies demonstrating that patients who had high levels of ROR1 had lower survival.

I'm not saying this is the only way that the lymphoma cells escape mechanism. We know that there's mutations in the BTK and so forth and so on. However, this may be one of the contributing factors that help these lymphoma and leukemia cells become resistant to BTK inhibition. Therefore, we feel that blocking this pathway will block both pathways, thus, leading to a deeper response, meaning more CRs.

Could you discuss the design of the trial and the dosing schedules that were investigated?

This was designed as an open-label, phase 1/2 study. We knew that BTK inhibition and the ROR1 works in a complimentary fashion. We already knew the dosing schedule for ibrutinib, but we did multiple-dose escalations to try to find the right recommended dose [for cirmtuzumab] in the phase 2 [portion of the] study. We had 2 mg, 4 mg, 8 mg, 16 mg, 3 kg, and a flat dosing of 300 mg and 600 mg. Ultimately, after the phase 1 study, went with the 600 mg flat dosing, and that was found to be very well tolerated.

This goes right into the safety issue. We're looking for any toxicity. One of the remarkable things about this protein is that many of the antibody-driven therapies have been very well tolerated, and cirmtuzumab has also been very well tolerated. We did not see any grade 3 toxicity for cirmtuzumab.

Do anti-ROR1 antibodies have an established toxicity profile or is it still under investigation?

That is still under investigation, but in combination with the ibrutinib, we did not have any signal in terms of dose-limiting toxicities with the doses that we gave. Here, at The University of Texas MD Anderson Cancer Center, we gave the 2 mg through 18 mg per kilograms and the high and low flat dosing, and it was found to be very tolerated.

What did we see with efficacy?

The efficacy seen with the combination was very interesting. Two histologies were studied: MCL and CLL. I am leading the MCL side and Michael Choi, MD, of the University of California, San Diego Medical Center, is leading the CLL portion of this study.

The MCL portion showed tremendous, exciting signal on phase 1 and 2 of this study. The ORRs were north of 80%, and the real kicker, knock-your-socks-off data are the CR rates. We were able to get 58% CR rates for many of these very heavily pretreated patients. We had approximately 40% of patients who had undergone autologous stem cell transplantation; we have patients who failed ibrutinib; and we have patients who had received [prior] CAR T-cell therapy and responded. Those findings gets people excited. I was surprised at how good the response was, given that usually toxicity and response go hand in hand. When you get more responses, you usually have very high toxicity. However, we really did not see any grade 3 toxicities.

Tons of CAR T-cells are being developed, but they come with fairly heavy prices. The headlines are big, but I know behind [the scenes], because I take care of these patients. It's not easy; if a patient is 70 years of age, they’re barely getting into the clinic. [When they ask for a CAR T], I get nervous; it is tough. But with this [combination], the majority of my patients [did not even feel that they were on a treatment]. This is very exciting for our patients.

The ORRs were north of 80%, and there was a 58% CR rate. We have 12 patients treated. Part 2 is open and it's accruing very nicely so we're trying to get more patients to enroll. This space is very tight; I'm sure you're aware that MCL is a tough place now because of the success achieved by Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, with ibrutinib and CAR T. We're competing against some big agents, which are very effective. However, it's [a good thing] for our patients, because they have many treatment options that are available.

In terms of CLL, we did see high response rates; however, we did not see the robust CR rates that we saw in MCL; that’s one thing to note. They're up to part 2 and that part of the trial is enrolling much faster than MCL. CLL is the most common lymphoid malignancy in North America so investigators are readily finding patients. We're hoping that the enrollment for the MCL portion can get going and will show robust data.

Is there anything that you would like to add?

There was a rapid attainment of CR rates observed. Many of these patients have had hyper-CVAD, autologous stem cell transplantation, and CAR T-cell therapies, among others. [These were not patients who had only received 1 line of prior] therapy. If you start using ibrutinib earlier in treatment, you get higher levels of CRs and higher levels of PFS. However, these are patients that are heavily pretreated with fairly aggressive histologies and behavior. If you look at the waterfall plot, you can clearly see a rapid drop in the tumor sizes of the patients with MCL.

Many more patients were included in the CLL [portion of the study] and they do have a response, but the majority of these responses were PR, so they were not able to attain CR. Although they do have a response, it is not as dramatic as the MCL population.

If you look at the PFS curves for MCL they look nice. It's a very limited population with very limited follow up, so this will need to be followed up for much longer.

This is going to be leading to a very exciting time for cirmtuzumab and ibrutinib as we enroll for part 2 [of the trial], which is going to be the efficacy signal that we will be seeing moving forward. Additionally, other agents are being developed for the ROR1 targets, but the efficacy that we saw in our study with our limited number of patients is very exciting.

Reference

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 15):8036. doi:10.1200/JCO.2020.38.15_suppl.8036