Zanubrutinib Plus Obinutuzumab and Venetoclax With MRD-Driven Discontinuation Shows Promise in CLL/SLL

Andrew Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, discusses results from a phase 2 trial assessing triplet therapy with zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and exploring minimal residual disease (MRD) as a biomarker for treatment duration.

Transcript:

I'm Andrew Zelenetz from Memorial Sloan Kettering Cancer Center where I'm an attending physician on the lymphoma service, and I'm the Medical Director of Quality Informatics. Today I've been asked to talk to about our recent study, which we call BOVen, but it was a combination of zanubrutinib, obinutuzumab and venetoclax for first-line therapy of CLL administered in a MRD driven fashion.

Oncology Learning Network (OLN): What led you and your coinvestigators to conduct this study?

Dr Zelenetz: We've made dramatic advances in the treatment of CLL with the introduction of targeted therapies. The initial introduction of ibrutinib dramatically changed the treatment of relapsed and refractory disease and this treatment rapidly was shown to be active in first-line therapy. Subsequent studies have shown that venetoclax allows for time limited therapy, particularly when combined with obinutuzumab, but that study demonstrated that maybe some patients weren't treated long enough and other patients may have been treated too long.

There were some initial studies of the 3-drug combination of ibrutinib, obinutuzumab, and venetoclax. These were highly effective with very high rates of undetectable MRD; however, there was substantial toxicity and there were some theoretical concerns about this treatment because ibrutinib is probably not the ideal BTK inhibitor to combine with an anti-CD20 antibody.

OLN: Please briefly describe the study.

Dr Zelenetz: All these things together we developed our 3-drug combination. We substituted zanubrutinib for ibrutinib because it doesn't have the inhibitory effects on ITK and we don't see the in vitro inhibition of ADCC caused by anti-CD20 antibodies so we thought it would be a better combination with an anti-CD20 antibody.

The biggest change in this study was the duration of treatment was driven by the achievement of undetectable MRD. We treated patients a minimum of 6 months before they were tested. We tested in the peripheral blood. If the peripheral blood had undetectable MRD, we then repeated a CT scan and did a bone marrow. If there was undetectable MRD in the bone marrow, patients received an additional 2 months of treatment and were able to discontinue. If there were still detectable disease in the peripheral blood, then this process repeated every 2 months. That way the response of the disease determined the duration of therapy.

OLN: What were the study findings?

Dr Zelenetz: The 3-drug combination was highly effective, included a lead in of 2 months of treatment with zanubrutinib and obinutuzumab by itself. This was very effective at reducing the tumor burden so that there were very few patients who needed to be hospitalized. Out of the 37 patients, only 2 patients were hospitalized for tumor lysis risk and one of them was only because the attending physician was nervous but did not meet the criteria for admission.

The primary objective was to ask how quickly and what was the rate of undetectable MRD. MRD was achieved in 95% of patients in the peripheral blood and in 89% of patients in the bone marrow. The median time to discontinuation of treatment for all patients was 10 months suggesting that there was high efficacy of this 3-drug combination, but importantly why you saw differences in rates of discontinuation.

One of the analyses we undertook was to ask, could we predict who were the fast responders and who were the slow responders? We identified a biomarker, the reduction of the tumor burden by 400 fold within the first 4 months of treatment—we looked before treatment and then cycle 5, day 1, and if there was a 400 fold or more decrease in the disease burden, these patients were able to discontinue therapy earlier. In fact 21 patients fell into this group and all 21 of these patients were able to discontinue therapy by 8 months of treatment. The 14 patients that did not fall into this category, only 3 of them were able to clear the bone marrow of undetectable MRD by the 6 months and that group had a median duration of treatment of 13 months. Only 2 patients never achieved undetectable MRD, but we think that this biomarker, this change in disease burden of 400 fold in the first 4 months, may be able to be used clinically to identify patients who need the shortest duration of treatment.

Interestingly when we analyze with very sensitive techniques, using techniques that can detect 1 cell in a million, what we find is that the patients who are in this Delta 400 group not only had the shortest duration of treatment, but have maintained the deepest remissions over time. Patients not in the Delta 400 group, those patients are showing evidence of increasing disease at the molecular level. Only 2 patients of the 37 have shown clinical progression of their disease and have been per the protocol restarted on the zanubrutinib and venetoclax.

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

Dr Zelenetz: Obviously these data need to be confirmed in a larger study. We are hoping to launch a new cohort of patients where we'll prospectively ask, did you reduce your disease burden by 400-fold? If you did, you'll stop treatment at 10 months, if you didn't, you'll continue treatment for 24 months. That way we'll have an ability to confirm this interesting observation about this novel biomarker.

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

Dr Zelenetz: One of the things that's important is this is a small cohort of patients. Even though the results are very exciting, we really consider them preliminary. One of the things that we noticed about this 3-drug combination compared particularly to the ibrutinib, obinutuzumab, venetoclax combination is, for reasons that are unclear, it was actually somewhat better tolerated with far less neutropenia than was seen with what's called the IVO combination and why that occurred and why this turned out to be a safer combination is a little bit unclear, but again, we need larger numbers, we need more information.

One of the big questions in the field is, do we really need 3 drugs? Do we really need the anti-CD20 antibody, the obinutuzumab or is a combination of a BTK inhibitor like zanubrutinib or acalabrutinib or ibrutinib with venetoclax going to be adequate and be able to get the same results? Now obviously that's a longer range question that will require randomized study between the doublet and the triplet, but we still are trying to optimize the use of the triplet combination so that we have the right regimen to compare to a doublet combination.

Source:

Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879-e890. doi:10.1016/S2352-3026(21)00307-0.