Zilovertamab With Ibrutinib Provides Durable Responses in MCL and CLL

Hun Ju Lee, MD

In a phase 1 study (NCT03088878) assessing zilovertamab plus ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), promising responses were observed, including a tolerable toxicity profile with the combination.¹

In the dose-finding and dose-expansion cohorts of the study, treatment with the combination generated an overall response rate (ORRs) of 89.3% among 25 patients with MCL, and 91.2% in 31 patients with CLL, respectively. The randomized portion of the trial showed the ORR to be 93.8% in the 15 patients with CLL who received the combination vs 100.0% of patients treated with ibrutinib alone.

Moreover, the addition of zilovertamab, a fully humanized monoclonal antibody that inhibits the signaling of the ROR1 onco-embryonic kinase-like receptor, did not significantly change the number of adverse events observed in these patient populations compared with previous reports of ibrutinib monotherapy.

Overall, this combination is well-tolerated with a promising safety profile and encouraging clinical responses seen among patients with MCL and CLL.

“This makes me happy that patients are having a durable response to a tolerable treatment option. This field is changing quickly and it's an exciting time for the young folks who are doing the research, and for our patients who get exciting treatment options,” Hun Ju Lee, MD, told Targeted Oncology^TM, in an interview.

In the interview, Lee, associate professor of medicine in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, discussed the encouraging responses shown with the combination of zilovertamab and ibrutinib in MCL and CLL, and highlighted other studies making headway in the field.

Targeted Oncology: Can you discuss zilovertamab for the treatment of patients with MCL?

Lee: Zilovertamab is an anti ROR1 antibody that was developed because the ROR1 is a great target for hematologic malignancies, especially mantle cell, CLL, and marginal zone lymphoma. We have shown that in preclinical studies, there's synergistic activity between the BTK pathway and the ROR1 pathway that appears to promote tumor progression and resistance to treatment. It was a great target to go after. The ROR1 antibody has been developed and now has a real scientific name, zilovertamab. We've been doing this phase 1/2 study for the past few years.

The study design based on the preclinical studies was that we had a part 1, which was the dose-finding. We did not know how to dose this drug so in the MCL and the CLL portion, part 1 was the dose-finding part, and then part 2 was the dose-expansion to see the true efficacy in mantle cell, CLL, and marginal zone lymphoma. Then part 3, at the time of the development, was a randomization of 2:1 to zilovertamab plus ibrutinib vs ibruitinib alone. So far, we have enrolled more than 80 patients, 30 patients on the mantle cell lymphoma arm and 50 plus patients on the CLL arm. In the mantle cell arm, there's still 40% of patients continuing on treatment and responding very well. It's very well-tolerated, and the CLL arm has completed enrollment and treatment.

What were the safety findings reported in this phase 1/2 study?

So far in terms of safety, safety is a big concern for us, and for this regimen, there's a new antibody combined with ibrutinib. We're obviously concerned about making sure that this is a safe regimen for our patient population. What we saw, in summary, was that this was not significantly different from that of the ibrutinib single agent. Atrial fibrillation, which was a special AE of interest, was only in 9%, neutropenic fever was only seen in 1%. We were very, we were very pleased and optimistic about the combination being well-tolerated.

Can you discuss the efficacy data?

We saw a robust response that was rapid and durable. The initial response rates are above 80%, now closing in on 90%. Within the first 3 months, we were able to get close to 18%-19% CR rates and with more follow-up, our CR rates were as high as 43%, comparing well in terms of historically to the single agent ibrutinib data. Especially in those patient populations with high KI67 and TP53 mutations, they also did well, showing that this combination is helping our patient population. From a personal side in my clinic, you have a good product when the patients are eager to come back. One of the drawbacks is that this was designed for treatment until progression, meaning they had to come back every month to see me. This was long, and we're hoping that with a lot of the trends in the current environment to limit treatment, I think those will be the future questions that we'll be adding on to our clinical trials.

In terms of CLL, we have overall response rates of greater than 90%.

The key takeaway message was that we saw a great response in the TP53-altered population. In this high-risk population, we saw 100% PFS at 43 months. I agree the numbers are small as we have 5 patients who are treatment-naive and 5 patients who are relapsed/refractory, but we saw that this was 100% PFS. If you compare it to a lot of the new data that's coming out, like the ALPINE study [NCT03734016], we found this to be kind of a knock your socks off type of data. We do agree the numbers are small, so this will need to be verified. This makes me happy that patients are having a durable response to a tolerable treatment option. This field is changing quickly and it's an exciting time for the young folks who are doing the research, and for our patients who get exciting treatment options.

What are your future predictions for MCL research?

There is a lot of activity with the bispecifics, the CAR T space, not just the autologous CAR T but the allogeneic CAR Ts sound enticing off-the-shelf. I do not know who is going to win the race, but what I can tell you is that a lot of our patients will have many opportunities and hopefully they will be able to take advantage of some of these clinical trials that are being offered. Yes, it is difficult to choose and there's a lot of controversy on how to sequence these agents. It is tough, and patients need to sit down with their oncologist and make informed decisions because everybody has a different perspective on risk and each agent. Every treatment option will have its own independent risk which will need to be weighed against the benefit that could possibly offer. I think those discussions take a long time and it will, the oncologist who will have to spend a lot of time discussing all these new options, like BTK, BCL2, cellular therapy, bispecifics etc.

There's so much excitement, but no one really knows exactly how, or which should go first, which 1 should go after, and the permutation becomes bigger and bigger for which way you should sequence. Those things, I'm sure over time, will get some answers as to which treatment should be first, followed by next. That will be difficult, but we'll get it done.

What are some of the most practice changing data to be recently presented for MCL?

If you go by the TRIANGLE study [NCT02858258], my own opinion is that the autologous transplant, high-dose chemotherapy is on the way out. That is not groundbreaking news, but I do agree that we have much more logical and targeted treatment options that are more rational. Just because you're young, you should get intense chemotherapy and transplant, I think, is an older way of thinking, I'm not saying old is bad, but we need to adapt.

I have my own personal bias, but in terms of mantle cell lymphoma, the frontline treatment options, chemotherapy vs chemoimmunotherapy vs BTK vs BCL2, and with the CAR T's trying to creep up in earlier lines of therapy, those kinds of data are coming out and will have to be digested. The bispecifics and TRIANGLE study will have an impact in terms of a lot of patients. A lot of places are still trying to offer, just because [patients are] young, intense chemotherapy, followed by transplant. But now, this is going to be a bigger discussion. I'm not saying it's completely gone, and I don't think any option should be disregarded, but it has to be calculated as to the best interests of the patient.

What other ongoing research is interesting to you in this space?

Pirobrutinib, the non-covalent BTK inhibitors, seem the most exciting. This is going to be a real game changer for not only the frontline, but all these long-term follow-up data we thought to be in the frontline will be lifted upside down because of some of the data coming out, but I will have to digest a little more to give a more educated guess.

Where do you think research is going to be focused on next for mantle cell lymphoma?

When I was starting off, they said the median overall survival for mantle cell lymphoma was 3 years. Now, it's probably like 25-30 years given the treatment options. There are so many great treatment options. how to sequence them [is now] the key question. How to sequence these treatments, which should come first, and which one should come after that. This is going to incorporate not just the physicians, the oncologists, but you'll need the patient's input as to what adverse effects they are willing to accept. I recognize the risk is taken by the patient, so they need to be informed of the subtleties of the risk that is involved in selecting treatment options.

REFERENCE:

Lee HJ, Choi M, Siddiqi T. et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL). Blood. 2022;140(suppl 1):566-568. doi:10.1182/blood-2022-167153