Dr Melani Shares Impressive Results of the ViPOR Regimen for MCL

Christopher Melani, MD, Research Physician, Lymphoid Malignancy Branch, National Cancer Institute, Bethesda, Maryland, discusses a phase 1b/2 study on the safety and efficacy of VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide) in relapsed/refractory (R/R) and untreated mantle cell lymphoma (MCL).

Transcript

My name is Dr. Christopher Melani. I'm one of the assistant research physicians as part of the Lymphoid Malignancy Branch of the National Cancer Institute.

A lot of the data that leads to the background of the ViPOR regimen has been done in other aggressive B-cell lymphomas, most commonly diffuse large B-cell lymphoma (DLBCL).

We did the original studies using the BTK inhibitor ibrutinib and showed preferential activity in the activated B-cell subtype of DLBCL. Despite activity, progression-free survival (PFS) was very short, in the matter of only a few months.

We did synergy testing and showed that two of the most synergistic agents that were effective in killing DLBCL cell lines in the lab were the combination of BTK inhibitors with the BCL2 inhibitor venetoclax as well as immunomodulatory agents, such as lenalidomide.

All of these agents are active in monotherapy in various types of lymphoma, and especially, all of them are probably most active in mantle cell lymphoma (MCL).

We initially started the ViPOR regimen in other types of lymphoma, again, like DLBCL, follicular lymphoma (FL), and because of the significant clinical efficacy as monotherapy in MCL, we did add a separate safety and efficacy cohort of MCL, which was presented at the ASH meeting in December 2021.

ViPOR is a combination targeted therapy regimen that gives 5 agents. It's an acronym—venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide. It's given similar to cytotoxic chemotherapy, where patients receive 2 weeks of study drug, 1-week break for six cycles, or 18 weeks, and then stop. There's no maintenance therapy.

The first finding in both the non-mantle cell as well as the mantle cell cohort was safety. We wanted to determine the safest dose of venetoclax when given in combination with the other ViPOR agents.

In the phase I portion, in the mantle cell cohort, we went up to a dose of venetoclax as high as 400 mg and showed that that was safe to give in combination with the other ViPOR agents in MCL.

We did not see any clinical tumor lysis syndrome, which is the biggest concern with venetoclax and MCL using a 12-day ramp-up of venetoclax on cycle 2. The most common toxicities we observed were very similar to the non-mantle cell cohort with cytopenia. We saw most commonly neutropenia, thrombocytopenia, less-degree anemia.

Given the cyclic nature of the regimen and the universal use of growth factors, such as Neulasta (pegfilgrastim), we did not see any clinically significant persistent neutropenia. We did not see any febrile neutropenia. Most patients (received full dose drugs on schedule with dose reductions or delays in <10% of cycles.)

We did expand that now into the phase 2 portion in both untreated and relapsed/refractory (R/R) patients. In the R/R patients, we presented at ASH, remarkably, 100% of patients achieved a complete remission (CR) by negative end-of-treatment PET scan as well as bone marrow biopsy.

We have looked at markers of minimal residual disease (MRD) using Adaptive's clonoSEQ platform, and 100% of patients who completed therapy as well were MRD negative using circulating tumor DNA.

With the original ViPOR study, giving 5 agents at once, everyone thought the patients would explode, and there'd be horrible toxicity, which, the first surprising finding was the significant lack of toxicity we observed.

In the non-mantle cell cohort, which we've now treated almost 100 patients, about 400 or so cycles, we really didn't see any significant toxicity. About a quarter of our cycles had grade 3 or 4 neutropenia or thrombocytopenia. We only had 3 episodes of febrile neutropenia that were uncomplicated in the non-mantle cell cohort.

The non-hematologic toxicities are very mild and manageable. We've seen some hypokalemia, some diarrhea, low-grade skin rash, which are very manageable with supportive medications and rarely require dose reductions or dose delays in the medication.

Our first surprise was how well tolerated it was, at least compared to other types of combination chemotherapy. We did expect a high response rate in R/R patients. There's been several studies looking at doublet or triplet therapy in MCL showing complete responses up to 70%, 80% or so, 60%, 70% MRD negativity.

Unlike those doublet and triplet therapy regimens, the ViPOR regimen is only given, as I mentioned, for 6 cycles, or 18 weeks, little over 4 months, and then stopped. Most of those regimens that have been studied in the doublet or triplet setting are given indefinitely until progression or unacceptable toxicity.

There are some studies now that are giving a maintenance therapy that's about a year or 2 years. Again, this is only 4 months and stopped. It was pretty impressive so far, especially in these R/R patients, that we were getting a complete response rate and undetectable MRD rate of 100 percent.

The other surprising finding was 44% of these R/R patients had failed prior BTK therapy, either ibrutinib or acalabrutinib. There's several studies now showing that these patients have a very aggressive course, even with a median overall survival of only about 6 months.

The fact that we have about half of these patients achieving remission, and we need additional follow-up, but we do have our furthest patient out past a year and a half. It does look very promising, but again, the data is still very early. We need longer follow-up for our data to show that these are durable remissions and, hope, eventual cure.

At this point in time, these targeted therapies have not thought to cure any patients with MCL or other aggressive lymphomas.

We know, at least as monotherapy, these targeted agents, several of them are approved. There are several BTK inhibitors, including ibrutinib, that are approved for R/R MCL. Lenalidomide is also approved for R/R MCL.

When given as monotherapy, as I mentioned, especially in the relapse setting, it rarely leads to a deep and durable remission. Now, we are showing with doublet, triplet, and even the 5 agents used in ViPOR, that we can get quick and very deep remissions.

The unanswered question at this point in time is how durable those remissions are going to be, especially with time-limited therapy, and whether we are potentially curing any patients.

If we get deep and durable remissions with ViPOR in the frontline setting that's comparable to some more standard regimens, such as combination chemo-immunotherapy, even combination chemo-immunotherapy with consolidated autologous stem cell transplant, this would be a potentially very safe, non-toxic, chemotherapy-free, and effective regimen that could even be used in the frontline setting for MCL.

In mantle cell lymphoma, we presented the phase I portion, and we're now expanding into both untreated and R/R MCL with ViPOR to assess the true efficacy of the regimen and the durability of responses.

In non-mantle cell patients, we've completed the phase 2 expansion into DLBCL, and I'm working on publishing those data at this point in time.

We do have a follow-up study combining another novel agent, polatuzumab, which is an antibody-drug conjugate, in combination with ViPOR in order to try to improve on the efficacy seen in some of these more resistant tumors, mainly GCB DLBCL and transformed lymphoma. That will eventually lead to a randomized phase 2 study looking at ViPOR +/- polatuzumab in various subgroups of DLBCL.

In MCL we're trying to find the efficacy and the durability of responses at this point in time. ViPOR has been shown to be a very safe and effective platform. There's always potential for the addition of future novel targeted agents for that regimen as well, but we need to get a better sense of the efficacy and durability of responses before we move on to some newer types of therapies and trial designs.