Anita Kumar, MD, Assistant Attending, Regional Care Network Medical Site Director, Memorial Sloan Kettering Cancer Center, Basking Ridge, New Jersey, highlights preliminary safety and efficacy data from a multicenter, investigator-initiated phase 2 study on zanubrutinib, obinutuzumab, and venetoclax for untreated patients with mantle cell lymphoma (MCL) expressing a TP53 mutation. These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hi. My name is Anita Kumar. I'm an assistant attending at Memorial Sloan Kettering Cancer Center and a lymphoma specialist. I'm also the medical director for one of our regional care network sites in Basking Ridge, New Jersey.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Kumar: There was a very important study published by Eskelund that was published reporting on outcomes for patients with p53 mutant MCL who were treated with intensive chemoimmunotherapy.

In this study, patients who were enrolled on the Nordic studies, which included intensive chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT), which is among the best treatment options for patients with MCL who are young and fit.

What they found was that the patients who had a p53 mutation, unfortunately, despite this optimal chemoimmunotherapy program, had dismal outcomes in terms of progression-free survival (PFS) and overall survival (OS), despite this intensive therapy.

This patient population who harbors a p53 mutation, unfortunately, despite standard-of-care therapies that benefit many patients with MCL, there exist no good treatment options for this subset of patients. That was the reason why we designed this study to address this unmet need for this specific biologic subset of MCL.

OLN: Could you briefly describe the study?

Dr. Kumar:  This is a phase 2 study, in which we specifically enrolled patients with MCL who had presence of a p53 mutation of any variant allele frequency.

Patients who were enrolled received treatment with 3 drugs. These are novel biologically targeted therapies—one, the BTK inhibitor zanubrutinib, two, obinutuzumab, which is an anti-CD20 monoclonal antibody, and three, venetoclax, the BCL2 inhibitor.

The way the study is designed is that patients initially receive, for the first 2 cycles, obinutuzumab and zanubrutinib alone, which facilitates initial cytoreduction, before initiating venetoclax therapy. We designed it in this way to mitigate the risks of tumor lysis syndrome that we see in patients when they initiate on venetoclax.

During the third cycle, patients are, in standard fashion, ramped up on the venetoclax dosing. Then, by cycle 4, patients are on all drugs, the zanubrutinib, obinutuzumab as well as venetoclax. After 8 cycles of obinutuzumab therapy, patients no longer receive obinutuzumab and just continue on the zanubrutinib and venetoclax oral drugs.

The way we designed BOVen for this high-risk subset of MCL was that patients would continue on treatment for a total of 2 years.

Then, at the end of 2 years, we plan to assess their response, both using standard response criteria—like a PET scan, bone marrow biopsy, if they had prior GI tract involvement, we would do endoscopic evaluation.

In addition, we plan to assess minimal residual disease using the Adaptive clonoSEQ Assay. If patients are both in a complete remission as well as MRD negative, then they'll no longer receive any further treatment after that 2-year time period. However, if patients have any evidence of residual disease, then they can be continued on the zanubrutinib and the venetoclax.

OLN: Could you describe the study’s findings?

Dr Kumar: We enrolled 17 patients with untreated MCL. These patients, not surprisingly, had many high-risk features. Over 70 percent had an elevated proliferation rate, over 30%. Most patients had high-risk MIPI. In addition to presence of the p53 mutation, we found that in 35% of patients, they also harbored a 17p deletion. This was a high-risk patient population.

In terms of the results, we found that, overall, the treatment program was well tolerated. Most of the side effects were grade 1 to 2, the most common being infusion-related reactions and neutropenia. However, these toxicities were generally manageable and reversible. Some of our patients did receive growth factor support. There were two grade 3 or higher adverse events (AEs). One patient who had profound tumor lysis syndrome after initiation of therapy, this patient had autolysis before even starting treatment and required management in the ICU as well as some hemodialysis and intubation. However, the patient did recover after this marked tumor lysis syndrome. Then there was 1 patient who had a grade 3 pneumonia, a Nocardia lung infection.

In terms of the efficacy, we presented preliminary efficacy data. There were 14 patients of the 17 who were valuable for efficacy. Encouragingly, the overall response rate (ORR) was 86%. So, 12 out of 14 patients responded, and 64% of these were complete responses. When looking at the peripheral blood flow cytometry, we found that all patients who had presence of disease initially did clear their peripheral blood of circulating mantle cell lymphoma.

In addition, we did highlight in our ASH poster some notable cases, which demonstrated the remarkable efficacy of the initial treatment with zanubrutinib and obinutuzumab. Even after just a week of therapy, we saw in many patients rapid reduction in disease burden, which in some cases was quite pronounced when patients initially presented.

For example, there was a patient, a 63-year-old gentleman with non-nodal leukemic MCL, who had a baseline white blood cell count of 277,000 with predominant lymphocytosis with an absolute lymphocyte count of 263,100. After just 1 week of therapy with obinutuzumab and zanubrutinib, the patient normalized his white blood cell count to 9600. This rapid reduction in leukemic disease burden was likely driven by the obinutuzumab therapy, which appears to have remarkable efficacy in MCL.

OLN: Were any of the outcomes particularly surprising?

Dr Kumar: One of the things that was surprising, as I mentioned before, was the remarkable early efficacy of the obinutuzumab. Obinutuzumab is an anti-CD20 monoclonal antibody, which has not been FDA-approved for the treatment of MCL patients. We have more experience with this anti-CD20 in other histologic subtypes of non-Hodgkin lymphoma (NHL). Rituximab is the more common anti-CD20 monoclonal antibody that we use in MCL.

What we saw was, as I mentioned, for patients who had extensive disease burden, for example, we had a patient who had a very bulky lymph node mass in the neck that was causing extrinsic compression of his airway. The patient presented and was admitted to the ICU for airway monitoring, had marked dysphasia. Similarly, to the other case that I described, after initial treatment with the obinutuzumab and zanubrutinib, dramatically, over the course of days to even early weeks, we saw significant improvement in the patient's ability to swallow and in terms of their airway status.

Personally, what we were excited to see was that, even among these high-risk patients, oftentimes who had plastic disease and high proliferation rates, that this treatment combination was highly active and efficacious.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Kumar: The study results are too early to be practice changing. However, we are eager to see what the long-term follow-up of these patients will be as we continue to treat these patients on this study.

There is burgeoning evidence in the field that we need to use a novel therapeutic approach for this specific biologic subset of MCL, patients who have a p53 mutation. We know that existing chemoimmunotherapy does not work well in these patients.

Whether BOVen will become a new standard of care for this high-risk subset is still unknown. The results that we presented at ASH represented only a median follow-up of 4 months on study. Our primary endpoint for the study is the 2-year PFS among this patient population. We need to see how the more mature results look over time to be able to answer that question definitively.

There have been other studies that have looked at novel biologically targeted combinations in MCL. Because this is a very rare subset of an already rare disease, only about 10% to 20% of newly diagnosed MCL patients have a p53 mutation, so it's hard to specifically accrue a study that focuses only on this patient subgroup.

There have been p53-mutant patients who've been included in other studies that have included dual inhibition of Bruton's tyrosine kinase and BCL2, and we've seen similar positive results from those findings. We are hopeful that the preliminary early efficacy that we see so far will be sustained over time.

OLN: Do you and your co-investigators indent to expand upon this research? If so, what will be your next steps?

Dr Kumar: We are planning to expand the study to another site. Right now, this study is open at Memorial Sloan Kettering as well as at Mass General Hospital, and we plan to expand it to Washington University. Dr. Brad Kahl will be our site principal investigator at WashU. We plan to expand the study to include all patients who are transplant ineligible, regardless of their p53 mutation status. Because we've seen such encouraging results in such a high-risk subset of patients, we believe that this chemotherapy-free option may be a potentially exciting treatment option for patients who are not transplant eligible who have mantle cell lymphoma.

We also plan to do a number of correlative studies to try to gain further insight into the differential efficacy of this treatment program among patients with p53 mutation. We know not all patients with a p53 mutation are created equally.

Certainly, coexisting mutations or other genetic alterations may impact the responsiveness to this treatment program but also to the overall prognosis of this patient population.

One of the cases that we highlighted in our ASH presentation was a patient who had a p53 mutation, but also had a CARD11 mutation and SMARCA4 mutations. These mutations have been associated with resistance to Bruton's tyrosine kinase (BTK) inhibitors and BCL2 inhibition. Interestingly, once the patient finished the obinutuzumab, then shortly thereafter we saw that the patient began to progress, which was not entirely unexpected given the resistance mutations that the patients had that might have predicted a lack of response to ongoing zanubrutinib and venetoclax therapy.

We plan to do full mutational profiling for all of the patients who are enrolled in this study. We also plan to look at the clonal evolution of the MCL over time. In the context of this study, we're assessing minimal residual disease (MRD) by the Adaptive clonoSEQ Assay as well as by peripheral blood flow cytometry, as I mentioned.

Then we're excited about a collaboration with BostonGene, where we're going to be doing whole-exome sequencing and RNA-seq to understand the full biologic profile of these patients to try to gain as much insight as possible into this biologic subset of patients and what may drive therapeutic resistance or sensitivity in this context.