ViPOR Regimen Signals Benefit in Patients With Mantle Cell Lymphoma

Christopher Melani, MD

Treatment with the ViPOR regimen consisting of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, and lenalidomide (Revlimid), has thus far appeared safe for use in patients with mantle cell lymphoma (MCL) and has demonstrated preliminary activity.

Results from the phase 1 portion of the ViPOR study (NCT03223610) were presented during the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition. Of the 11 patients who were treated, the ORR was 100% and the complete remission (CR) rate was 80%. Nine patients were evaluable for safety and no dose-limiting toxicities were observed. There were few grade 3 and 4 adverse events (AEs), but the hematologic grade 3/4 AEs included neutropenia (13%), anemia (11%), and thrombocytopenia (9%). The non-hematologic grade 3/4 AEs included hypokalemia (33%) along with fatigue, hypomagnesemia, elevated bilirubin, atrial fibrillation, lung infection, and syncope occurring in 11% of patients each.

Finding from the study also showed no cases of tumor lysis syndrome. Dose reductions were required in 5% of the cylices and delays occurred in 15% of cycles.

The phase 2 portion of the ViPOR study aims to further assess the safety and efficacy of the regimen in 130 patients with B-cell lymphoma including a cohort of patients with MCL. The primary end point of the study is safety determined by the number of patients with AEs. The study’s secondary end points included progression-free survival, overall survival, and objective response rate.

In an interview with Targeted Oncology™, Christopher Melan, MD, assistant research physician, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, discussed the ongoing ViPOR study exploring a Bruton’s tyrosine kinase (BTK) inhibitor and BCL2 inhibitor, and NF-κB survival pathway activating combination.

Can you first provide an overview of the ViPOR study in MCL?

Melani: I presented the data recently during the ASH meeting. ViPOR is a novel combination targeted therapy regimen that simultaneously hits multiple key survival pathways utilized by B-cell lymphomas for growth and survival. It’s an acronym and it includes the BCL2 inhibitor, venetoclax, which works on apoptosis and BCL2 is an anti-apoptotic protein, so it induces apoptosis in the cells. We included ibrutinib, which is an inhibitor of Bruton’s tyrosine kinase, an enzyme in the B-cell receptor signaling pathway and is important for mantle cell lymphoma. P is prednisone, which is a corticosteroid, which is often in many regimens such as R-CHOP [Rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, prednisone], which is a combination chemo regimen, which is a mechanism of genotoxic stress for the lymphoma cells.

Obinutuzumab (Gazyva] is the CD20. It's a type-2 novel glycoengineered CD20 antibody similar to rituximab [Riuxan], promoting innate immunity towards the B-cell lymphoma. The ‘R’ is Revlimid, or lenalidomide, which through its effect on transcription factors, also leads to decreased signaling in certain pathways.

So, the NF-κB pathway also promotes interferon-mediated cell death. So, we showed that this combination of 5 drugs was very synergistic in killing lymphoma in the lab, in cell lines, and xenograft models. And this is the first study that's actually combining all 5 of these targeted agents, which are all active in B-cell lymphomas given in humans.

We initially started with a non-mantle cell cohort, and then we've expanded that into phase 2 testing in diffuse large B cell lymphoma and follicular lymphoma. And this is a separate cohort on the study for mantle cell lymphoma that I presented.

Why was this combination investigated for the treatment of patients with relapsed/refractory or untreated MCL?

A lot of the data that led to the development of this regimen was done in the activated B-cell subtype of diffuse large B cell lymphoma. So, we did a lot of the original studies using single-agent ibrutinib, and we showed that ibrutinib is effective in relapsed/refractory large cell lymphoma, and it was more active with a response of about 37% to 38%. In patients with the activated B-cell subtype versus the germinal center subtype, there was only about a 5% response rate.

We did just recently present data using a newer BTK inhibitor called acalabrutinib in untreated large cell disease and we are finding that other types of diffuse large B-cell lymphomas such as the germinal center do have activity and double-hit and diffuse large B-cell lymphoma. There is activity of BTK. But historically, we thought it to be more active in the ABC [activated B-cell]

subtype. So, building on that study, we did a lot of preclinical testing and we worked with a collaborator to do high synergy screening of BTK inhibitors with multiple molecules of all different types and some of the key agents that were shown to be the most synergistic with ibrutinib or BTK inhibitors was BCL2 inhibitors, so venetoclax as well as immune-modulatory agents such as lenalidomide. So, those 3 key components were very synergistic together meaning that the effect was not just additive, it was a greater effect than would be expected with just an additive benefit of both.

We initially combined ibrutinib, and lenalidomide with chemotherapy, in EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] in the relapsed/refractory setting of diffuse large B-cell lymphoma. Building upon that, because many of these relapsed/refractory lymphoma patients are resistant or refractory to chemotherapy, we ended up taking out the chemotherapy keeping the steroid and the CD20 antibody, and then added in venetoclax, which again was very synergistic. We originally did that in diffuse large B cell lymphoma, follicular lymphoma, and other non-Hodgkin lymphomas, because there is a risk of tumor lysis that is higher with either chronic lymphocytic lymphoma [CLL] or mantle cell lymphoma.

The clinical data as monotherapy has probably been most robust in CLL and mantle cell. So, although we didn't have as much preclinical testing in mantle cell, there's significant activity with BTK inhibitors, BCL2 inhibitors, and now combinations, so we're now getting doublet therapy with BCL2 and BTK inhibitors with the venetoclax and Ibrutinib. There have been several studies now looking at triplets. So, we kind of skipped a couple of steps and went straight to the 5-drug combination which again, we showed was extremely safe in other non-Hodgkin lymphomas, and then we decided to expand the study to test it in mantle cell lymphoma.

What stood out about the findings from ViPOR?

I think the main thing that we learned from both the non-mantle cell and the mantle cell was how extremely safe this regimen is compared to standard cytotoxic chemotherapy. The most common toxicity was hematologic, so neutropenia, thrombocytopenia anemia, but grade 3 or higher toxicities was very uncommon and occurred in under 20% of cycles. Also, about 10% or less of patients required dose reductions or dose delays on that therapy. Aside from the hematologic toxicity, there really wasn't a lot of high-grade, non-hematologic toxicity. So, we 1 grade 3 and grade 4 thrombocytopenia, and we had 1 grade 3 episode of hypokalemia. But no other significant high-grade toxicities, no severe infections. Even with the slight neutropenia, we didn't have any cases of neutropenic fever in the 13 patients we treated thus far across about 67 cycles of therapy. So, the first thing was very remarkable was the lack of a significant toxicity and how well tolerated it was.

Also, as expected, it was very effective. So far, in the patients that have been treated, there's 13 patients on study, 11 of them completed therapy, and in the patients who have finished therapy, all 11 achieved a complete remission, and by a negative PET scan and negative end of treatment, bone marrow biopsy. Out of those patients, we also did do minimal residual disease analyses using circulating tumor DNA. So, we collaborated with adaptive bio technologies using their clonal seek VDJ sequencing platform, and actually found that 100% of patients were MRD negative at the end of therapy, indicating that this is a rather deep remission.

The question is now going to be how durable those remissions are because, with our study, compared to a number of the other doublet triplet studies, we give this as a fixed-duration time-limited therapy similar to chemotherapy. Dosing is 6 cycles every 3 weeks, so 18 weeks or a little over 4 months with no maintenance. Other regimens often give maintenance of a year or 2 or even 3 or an indefinite therapy. It's going to be very important now with the follow up to determine if these remissions are very durable or not, and whether we're potentially curing anyone or not. But again, it's too soon to know at this time that the follow up for this cohort of the study is still too short.

We do have our first patient out who had relapsed after 2 lines of chemotherapy as well as prior BTK inhibitor. And he's about a year and a half out from therapy and still in remission. We are finding that with other retrospective studies, patients with mantle cell who progress on BTK inhibitor often have very poor outcome. And some studies are showing a median survival only about 5.6 months in those patients. So, the fact that he's still doing well in remission at about a year and a half after treatment is pretty remarkable.

What are the next steps with this study?

So, we've we finished the phase 1 portion of it to show that it's safe, we've now expanded into both untreated as well as relapse or refractory. We added a separate cohort of relapsed /refractory mantle cell and the phase 2 expansion just from building upon the great results we saw in the phase 1 portion. So, I think we need to see what the durability of remission are for mantle cell to see if there's anyone that were potentially curing or at least leading to a very deep durable remission.

After this study, what unmet need do you hope research will address in the years to come?

MCL is still in general not curable with most therapies. We know that with high-dose chemotherapy we can get 3 or 4 years of remission. When you incorporate induction chemotherapy with autologous stem cell transplant, we're still we can get maybe out to 5 years or 6 years of remission. But again, there's still a continuous rate of relapse even after these intensive therapies. We know that patients who relapse and then go on BTK inhibitor and progress, the median progression-free survival is about 2.5 years, but I think 1 of the current unmet needs is these BTK patients who progress on BTK because again, retrospective studies have shown the median survival is very poor in patients who progress after BTK. What is the most appropriate therapy for those patients? in the ViPOR study, 44% of our patients were BTK had relapsed or refractory to BTK inhibitor. So, the fact that we're seeing CR rates, even in these patients who were exposed to prior BTK is pretty exciting. I think the BTK failures are certainly some area in that we have to work on novel therapies.

P53-mutated or deleted, patients often have very poor prognosis with standard chemotherapy, and then the blastoid mantle cell patients as well tend to have very aggressive disease and patients don't often respond well to chemotherapy. Whether some of this resistance of blastoid and p53-mutated mantle cell can be overcome from some of these newer novel combination therapy regimens, is still to be determined. We are assessing, we are sequencing our tumors and looking for those mutations to see if I may have overcome some of these negative prognostic markers.

_Reference:

_{Melani C, Lakhotia R, Pittaluga S, et al. Phase 1b/2 study of Vipor (venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide) in relapsed/refractory and untreated mantle cell lymphoma: safety, efficacy, and molecular analysis. Blood. 2021; 138 (suppl 1):3537. doi: 10.1182/blood-2021-147032}