Nemtabrutinib: Jennifer Woyach, MD ASH 2022 – BELLWAVE-001 Study
By Jennifer Woyach, MD
What did the BELLWAVE-01 study on Nemtabrutinib reveal in patients with relapsed refractory CLL and SLL? So we presented follow up from the phase 1/2 BELLWAVE-001 study of nemtabrutinib in patients with relapsed refractory CLL and SLL. So nemtabrutinib is a non-covalent BTK bruton tyrosine kinase inhibitors (BTKis). It was designed to be able to bind BTK outside of the C481 site, which is where the covalent BTK inhibitors bind. So the idea is that this will be an effective agent, even if patients develop resistance mutations to the covalent BTK inhibitors (which may lead to disease progression). So with this follow up, we have 57 patients now treated at the recommended phase 2 dose of 65 milligrams once daily. We see very nice efficacy with this drug. We have a relatively short follow-up, only about 5 months follow-up. So some patients are very early in treatment but we do have an overall response rate right now of a little bit over 50%. And we generally see these response rates deepen over time as more patients resolve their lymphocytosis and those lymph node responses get better and better over time.
We do have a median follow or medium progression-free survival right now for patients of 26 months estimated, and we’ll of course be able to refine that further when we have more patients who are treated for longer periods of time. The toxicity of the agent continues to look very promising.
It’s been very well tolerated in the majority of patients and most of the side effects are grades one and two. In terms of side effects, That we see most commonly. We see things like dysgeusia, fatigue some cytopenias, and then some GI symptoms just related to the oral medication. In terms of the adverse events of special interests like we generally see with BTK inhibitors, we actually see that these are very uncommon with nemtabrutinib.
We have only a few patients who have developed atrial fibrillation. I think that’s 4% at this point. Many of these patients had been on ibrutinib prior, so it’s unclear the relationship to the nemtabrutinib. So overall, we see promising early safety and clinical efficacy of this compound, and we look forward to further follow-up of this study.
What is the current standard of care in CLL, and why is this study important?
So the standard of care for our patients Chronic lymphocytic leukemia in the frontline setting is either going to be a continuous BTK inhibitor or a BCL2i inhibitor, venetoclax given in combination with an antibody.
Then, depending on the choice of frontline therapy, these can be swapped out for second-line treatment. We do know, however, that patients who are treated with BTK inhibitors, which is the majority of CLL (chronic lymphacytic leukemia) patients treated over time, and who progress will do so by developing a mutation at the drug’s binding site, usually an assist sustainer mutation at position 481.
That prevents these covalent inhibitors from binding. And so that’s why a drug like nemtabrutinib, which is a non-covalent inhibitor that binds to a distinct site on BTK, is an exciting agent.
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Could you please tell us about the trial design and why it was set up this way?
This is a phase 1 trial, so we initially examined escalating doses of nemtabrutinib not only in CLL but in other B-cell hematologic malignancies that have responses to BTK inhibitors in general. What we’re presenting data on this time is specifically the CLL/SLL cohort. So we escalated doses up to over 65 milligrams, came down to 65 milligrams for the recommended phase 2 dose, and then expanded the number of patients treated at that dose.
Can you please give us any significant data from this trial that you think is important?
I think these non-covalent inhibitors are of great clinical interest, and we’re seeing very good safety and preliminary efficacy of this drug in patients with highly relapsed, refractory CLL (chronic lymphocytic leukemia), definitely justifying future studies of this agent.
Did this trial have a primary endpoint, and if so, has it been met?
This study is designed as a phase 1 trial, and the primary endpoint is to determine the recommended phase 2 dose, and so, yes, it has been achieved.
What are the most common questions you get from your colleagues and other oncologists about this data?
A lot of people want to see or want to know what the differences in similarities are between nemtabrutinib and pirtobrulinib, which is another non-covalent BTK inhibitor. So nemtabrutinib is a very non-selective compound.
It’s a Pan-Src kinase inhibitor, whereas pure ibrutinib is very selective for BTK. And so that leads to some side effect differences between the two agents. We don’t know yet whether the alternative targets of nemtabrutinib may actually help efficacy of this agent, especially in patients who develop mutations in like PLCG2, which is immediately downstream of BTK, where you would think maybe a non-selective inhibitor might be better than a selective inhibitor for those patients. We also think that the non-selective nature of this compound may actually help it expand to other diseases a little bit easier, where the genetic landscape is a little bit more complicated than we see in CLL.
What are the takeaways you’d like to leave our oncologist with?
So I think that nemtabrutinib continues to be an exciting compound and clinical development. The company is pursuing phase 3 studies with this drug. So be on the lookout for the opportunity to enroll your patients in some of these trials of nemtabrutinib and CLL. And we look forward to seeing results for the study and results of those phase 3 trials in the future.
Jennifer Woyach, MD – About The Author, Credentials, and Affiliations
She is a doctor of internal medicine, specializes in treating patients with blood cancers, particularly chronic lymphocytic leukemia (CLL) and B-cell lymphomas as a hematologist-oncologist. I also serve as a professor in The Ohio State University’s Division of Hematology.
Their approach to patient care at the OSUCCC – James (Ohio State University) is truly unique. They work in teams of specialists, subspecialists, and super subspecialists to treat specific cancers more effectively, never losing sight of the power and value of personalized, patient-centered care. In 2019, she was named to Castle Connolly’s list of “Regional Top Doctors,” and in 2017, she was ranked among the top 10 percent of physicians nationwide for patient satisfaction.
She is a part of the OSUCCC-James (Ohio State University) Leukemia Research Program, and her research focuses on targeted therapies for CLL and ways to overcome resistance to targeted therapies. She led the collaborative effort that identified the mechanism of resistance to the BTK inhibitor ibrutinib in CLL, as well as the preclinical and clinical research that identified drugs that can overcome ibrutinib resistance.
Recently, she directed a multi-institutional phase III clinical trial that revealed older patients with CLL have a significantly lower rate of disease progression when treated with ibrutinib as opposed to bendamustine plus rituximab — a regimen that was previously considered one of the most effective therapies for this group of patients. This was the first direct comparison of the two therapies. Results were simultaneously published in the New England Journal of Medicine (NEJM) and presented at the 2018 Annual Meeting of the American Society of Hematology (ASH).
She was awarded the Young Physician-Scientist Award by the American Society for Clinical Investigation in 2015. Her work has appeared in a number of medical journals, including Journal of Clinical Oncology, Lancet Oncology, and Blood and Cancer Discovery, and she has presented her research at a number of conferences, including ASH, the American Society of Clinical Oncology (ASCO) Annual Meeting, and the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
She recognizes at The James (Ohio State University) that there are no routine cancers. As a result, she maintains her expertise in her field by participating in several professional associations. She serves on a number of subcommittees for the American Society of Clinical Oncology, the American Association for Cancer Research, and the American Society of Hematology. She is also a member of the Leukemia Committee and the Cancer in the Elderly Committee for the Alliance for Clinical Trials in Oncology, a consortium of cancer centers that designs and conducts clinical trials to improve the care of CLL patients nationwide. By collaborating with other specialists across the nation, we can increase our understanding of the biology and treatment of CLL, and she as a doctor of internal medicine and clinical oncology, can use this information to improve the lives of the patients we see at the James.