Venetoclax Demonstrates Promising Responses in Waldenstrom Macroglobulinemia

Jorge J. Castillo, MD

Jorge J. Castillo, MD

Currently, the only FDA-approved treatment for patients with Waldenström macroglobulinemia isBTK inhibitor ibrutinib (Imbruvica) plus rituximab(Rituxan). However, new phase II findings presented at the 17th International Myeloma Workshop demonstrated promising responses with venetoclax (Venclexta) in the relapsed/refractory patient population.

Overall, 30 patients were enrolled to the prospective phase II trial, in which the first 6 patients received oral treatment of 200 mg venetoclax daily for the first week, 400 mg daily for the second week, and 800 mg daily for 2 years, while the 7th patient and on received an initial starting dose at 400 mg daily for 1 week followed by 800 mg daily for 2 years. Investigators aimed to find if not only could this agent improve responses but also help patients get off therapy and continue to receive benefits long-term.

Results showed that 90% of patients responded in some way, while 80% of patients achieved a partial response (PR), and 20% of patients achieved a very good PR (VGPR).

“Seeing that about 1 in 5 patients with Waldenstrom macroglobulinemia could get exposed to venetoclax and get to a VGPR, which is 1 of the deepest responses you can aim for, makes me hopeful that once we stop treatment, those patients will sustain that response and hopefully for years to come,” said Jorge J. Castillo, MD.

These results are encouraging because patients in this trial received up to 10 prior treatments before the study. Additionally, half of the patients were previously exposed to the standard of care, ibrutinib. Treatment with ibrutinib is indefinite, which makes the fixed-duration of venetoclax appealing in this space.

In an interview withTargeted Oncology, Castillo, clinical director of the Bing Center for Waldenström Macroglobulinemia at the Dana-Farber Cancer Institute, discussed the findings from the prospective phase II trial evaluating venetoclax in patients with Waldenström macroglobulinemia. He also addressed the unmet needs in this patient population and the next steps for research in the field.

TARGETED ONCOLOGY: What was the rationale for this trial?

Castillo:This is a prospective phase II clinical trial, in which we are exposing patients to a BCL2 inhibitor called venetoclax. About 30 patients were previously treated while Waldenstrom macroglobulinemia are included. The reason we felt it was a good idea is because BCL-2 is overexpressed in patients with Waldenstrom macroglobulinemia. BCL-2 is a protein that allows malignant cells or any cells to survive, so malignant cells, in terms of Waldenstrom macroglobulinemia, for example, have more BCL-2 than they should have. These mechanisms actually immortalize those cells, so it does make sense that providing a BCL2 inhibitor therapy will deplete that BCL-2 in those cells, and then, therefore, allow those cells to die.

TARGETED ONCOLOGY: What were your findings?

Castillo:The findings from our study are very interesting and encouraging. We have been able to enroll 30 patients, which is a collaborative effort between the Dana-Farber Cancer Institute and Weill Cornell, as well as the Stanford Cancer Institute and the City of Hope. We accrued about 30 patients and exposed the patients to venetoclax at an initial dose of 200 mg by mouth once a day for a week, then 400 mg daily by mouth for another week, and then 800 mg daily for 2 years. We did this for the first 6 patients, and for patient 7 on, we actually stopped the 200 mg dose to start with 400 mg by mouth once daily for a week, followed by 800 mg a week daily for 2 years. The idea of this study is 2-fold. The first is to show that there is efficacy, such as in making patients feel better and improving blood counts, but also we [wanted] to stop therapy to see if the therapy we gave is finite in duration and can have a long-term effect.

The results of this study have been encouraging in the sense that when we looked at response rates, which in Waldenstrom macroglobulinemia is at 25% decrease at the serum immunoglobulin M protein (IgM) levels, we have been able to see that in 90% of patients, meaning 9 out of 10 patients treated will benefit from this therapy. When we go a little deeper into PRs, which means at least a 50% decrease in the IgM, 80% of patients got to that level. When we go even deeper, to about a 90% decrease in IgMs, we call that a VGPR. About 20% of patients got there.

This is very encouraging because these patients have already been treated, and we saw patients [receive] up to 10 treatments prior to exposure of venetoclax, so they can see this benefit. Not only that, but about half of the patients were previously exposed to ibrutinib. Ibrutinib is an agent that is FDA-approved for the treatment of patients with Waldenstrom macroglobulinemia and also an oral agent that is indefinite, so patients can be on it for several years. We really do not know what happens or how we can best treat patients who are failing ibrutinib. There is very limited data on that. Seeing an agent, in this case, venetoclax, producing responses in those patients is very exciting.

TARGETED ONCOLOGY: Could you expand more on the patients that had a VGPR?

Castillo:It is very important to know that the deeper the response, at least in our experience, has correlated with a longer duration of response. Seeing that about 1 in 5 patients with Waldenstrom macroglobulinemia could get exposed to venetoclax and get to a VGPR, which is 1 of the deepest responses you can aim for, makes me hopeful that once we stop treatment, those patients will sustain that response and hopefully for years to come. However, for that component of the study to be more comparable providing more insights in that sense, we need more follow up. I think with this study, we have been able to show that we have a new treatment option that is effective. I want to know if this treatment can be stopped and know the efficacy remains in these patients.

TARGETED ONCOLOGY: What is standard treatment for these patients?

Castillo:There is not an actual standard therapy currently. The only FDA-approved medication is ibrutinib, but there are so many different options. We have chemoimmunotherapy options, in which we combine cyclophosphamide (Neosar) or bendamustine (Bendeka) with rituximab. We have treatment with agents such as proteasome inhibitors (PIs) like bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro) that we also combine with rituximab. Then we also have ibrutinib alone or in combination with rituximab, so there are multiple treatment options.

The reason there is not a standard, in my mind, is because there is not 1 treatment that fits everybody well. First, there are no randomized studies comparing say bendamustine/rituximab and ibrutinib/rituximab. There is no way to know which 1 is actually better. When you look at all these treatments, the efficacy rates are very similar. Response rates are between 80% and 90%, and response rates are anywhere between 70% to 80%. Even in the VGPR population, the rate is about 20% to 30%. All of those numbers are quite similar, to put it that way. We tend to now select treatments not based on efficacy but rather on the side effects the medications can have, the patient presentation and have that in mind, as well as genomic profiling. We know now that about 90% of patients have mutations in MYD88, and about a third of the patients have another mutation in a gene called CXCR4. These medications can actually affect how ibrutinib works, for example. If a patient thinks that ibrutinib is a good option for them and I feel the same way, I will look at the genomic profiling before making that recommendation in terms of treatment. We do have a lot of points of data to take into account when making decisions. The best treatment for a patient is personalized treatment.

TARGETED ONCOLOGY: Is genetic testing standard for patients when they initially present?

Castillo:Genomic profiling has evolved over the years in patients with Waldenstrom macroglobulinemia. The MYD88 was initially prescribed in 2012. The CXCR4 mutation was initially described in 2015. Over the years, there have been multiple independent validations for both [mutations]. Obviously, MYD88 has been more extensively validated than CXCR4 mutations have been. In the community, it is a little difficult to apply genomic profiling because of access, among other things, but I would say the MYD88 mutation has become standard testing in most practices. I think CXCR4 mutation is a little more difficult because in contrast with MYD88, CXCR4 mutations are multiple. You can have up to 30 mutations in very different spots, compared to MYD88 where most mutations, about 98%, are in 1 spot. You can develop a test that is relatively easy to perform [for MYD88], whereas for CXCR4, it’s a little more difficult. I think we are getting there, and the way I see the future is essential once these steps of testing become more widely available, we will have an impact on specific treatments.

We don’t have any data that say chemoimmunotherapy or PI therapy are effective by genomic profiling, so in those scenarios, it may not be clinically necessary. For BTK inhibitors, specifically ibrutinib and the others that are common like acalabrutinib (Calquence), it seems to me that genomic testing is going to matter, and therefore genomic testing should become more standardized.

TARGETED ONCOLOGY: How do your findings inform he current thinking of Waldenstrom macroglobulinemia?

Castillo:The major contribution of our clinical trial is in just providing patients with an additional treatment option because if patients were exposed to chemotherapy and a PI and BTK inhibitors, there are not a lot of drugs left that are effective. We have several options that are less effective and much more toxic, so I think venetoclax positions itself very nicely inaddingoption that is safe, manageable, and highly effective.

How that will be positioned in the entire setting of Waldenstrom macroglobulinemia is a little more difficult to assess at this time. There are going to be several trials in the future that will combine venetoclax with other agents. We have 1 trial at Dana-Farber that we will study by the end of the year combining ibrutinib plus venetoclax in patients who have never been treated to provide patients with that chemotherapy-free regimen that I hope will induce a depth of response and duration of response that we would like to obtain but with a finite duration of treatment, which I think is very important when we think about these newer agents.

TARGETED ONCOLOGY: Is there a sequencing protocol that you adhere to in these patients?

Castillo:Sequencing therapy for Waldenstrom macroglobulinemia is not something that we have looked very much into, and the reason is because I think chemotherapy provides a different mechanism of action than PIs. PIs have different mechanisms of action than BTK inhibitors, and now BCL2 inhibitors provide some additional mechanisms of action that are distinct from the other ones. In that sense, my feeling is that the sequencing probably doesn’t matter much. Because of the chronicity of this disease and the prolonged survival that these patients have, it is very likely they will be exposed to all these agents at some point during their course of the disease.

If you feel more comfortable starting with alkylating agents or you think an alkylating agent is the right option for your patient, you can definitely expose your patient to the PIs later, and I don’t think that will be too much of a problem, in the same way with BTK inhibitors. If you decide to start with BTK inhibitors first, in our experience that has not really been a problem with those patients with alkylating agents after. We do see the responses at very high levels, so sequencing at this time in Waldenstrom macroglobulinemia doesn’t seem to be too much of a problem. However, more research is always welcome in that setting.

TARGETED ONCOLOGY: What are the next steps as far as this research goes?

Castillo:These are several-fold. First, we need to induce deeper responses and try to get to a higher percentage of VGPRs or aiming for complete responses (CRs), which are seldom seen in patients with Waldenstrom macroglobulinemia, contrast with CLL or multiple myeloma in which we see the CRs. That is not a concept we are investigating too much in Waldenstrom macroglobulinemia because we don’t even get to a CR in most scenarios.

The second thing besides getting to that depth of response, can we sustain that response? That is the second aspect, which will hopefully transform or reflect into a prolongation of the progression-free survival. That is the idea. We are always keeping the safety of patients in mind, so can we provide patients with not only deeper responses but safer options?