Can Combo of Vemurafenib and Obinutuzumab Shake Up Hairy Cell Leukemia Paradigm?

Author(s):

The standard of care for the frontline treatment of patients with hairy cell leukemia has been purine nucleoside analogs, including pentostatin and cladribine; however, investigators are challenging this treatment in a phase II clinical trial with a targeted therapy that may provide similar benefit with fewer toxicities.

Justin Taylor, MD, attending physician at Memorial Sloan Kettering Cancer Center

Justin Taylor, MD

The standard of care for the frontline treatment of patients with hairy cell leukemia has been purine nucleoside analogs (PNA), including pentostatin and cladribine. However, investigators are challenging this treatment in a phase II clinical trial with a targeted therapy that may provide similar benefit with fewer toxicities.

The phase II trial (NCT03410875) is exploring the combination of the BRAF inhibitor vemurafenib (Zelboraf) and the anti-CD20 monoclonal antibody obinutuzumab (Gazyva) in previously untreated patients with classical hairy cell leukemia. After enrolling the first 9 patients and observing potential for the combination, investigators expanded the trial to include 24 patients.

In an interview with OncLive^®, Justin Taylor, MD, attending physician at Memorial Sloan Kettering Cancer Center (MSKCC), one of the study sites, discussed the rationale for evaluating targeted therapies in the frontline setting for hairy cell leukemia and the potential for upfront vemurafenib plus obinutuzumab.

OncLive^®: What was the rationale for evaluating the vemurafenib combination in the frontline?

Taylor: This is the first trial in hairy cell leukemia looking at targeted agents as a frontline treatment. Previously at MSKCC and also a group in Italy at the University of Perugia, completed a phase II trial in patients that had relapsed after initial therapy with vemurafenib alone and saw good response rates in that setting. The rationale is to see if treating the patients upfront before they relapse might have better outcomes.

Additionally, the group from the University of Perugia had done a clinical trial where they added the anti-CD20 antibody rituximab to vemurafenib, and they saw even higher responses than we saw with vemurafenib alone. Obinutuzumab is an anti-CD20 monoclonal antibody that is a little more potent than rituximab, so that was the reason for using this combination. We hope to see if the targeted agent vemurafenib plus anti-CD20 antibody obinutuzumab could lead to higher response rates in the frontline setting.

How was this trial designed?

It’s a phase II study, so all patients are getting active treatment. We designed it as a 2-step test. The first 9 patients were treated, and we had a cutoff that if we weren’t seeing the kinds of responses that we expected, the trial would stop. Luckily, that didn’t happen. We’ve enrolled 9 patients, and we now have more patients because we decided that we are seeing that level of efficacy that we expected. The second stage is to expand to 24 patients. We are currently treating more patients.

It’s a limited duration of vemurafenib, so patients get the agent for 4 cycles, which is approximately 4 months. This is a twice-a-day pill that they take. They then get the obinutuzumab, which is an injection, beginning in the second cycle, and they get it every month thereafter. This is a 1-time injection per month.

Which patients are being enrolled in this trial?

We’re enrolling classical hairy cell leukemia patients. There is classical hairy cell leukemia and variant hairy cell leukemia. The classical hairy cell leukemia patients have BRAF mutations, and vemurafenib targets BRAF mutations, so we are only taking patients with classical hairy cell leukemia. It can only be patients who have never received prior treatment because we are testing this as a frontline therapy. Pretty much any patients with classical hairy cell leukemia who have not received prior therapy [can enroll].

Have you looked at any data yet from the first part of this trial?

We have collected some data, but we cannot present that data publicly yet. It’s very encouraging, though, and like I said, we are now opening the enrollment to a larger number of patients. This study is open at MSKCC, as well as the Yale Cancer Center and Dana-Farber Cancer Institute.

What unmet medical needs remain in hairy cell leukemia?

Hairy cell leukemia is a bit lucky in the sense that there are some good drugs that work in the frontline. We are really challenging the current frontline, which is PNA, either cladribine or pentostatin. Those already have very high response rates with patients having long durations of remission even with just the single agent alone, but part of the challenge with that treatment and why we decided to go forward with this study is because there are side effects related to the treatment. It’s a chemotherapy and can cause neutropenia, which is low blood counts that could put patients at risk for infections during the treatment period. We don’t see that neutropenia with vemurafenib, and it’s not expected to have increased risk of neutropenia with the addition of obinutuzumab because that wasn’t seen in prior combinations with rituximab. Can we spare the neutropenic risk? That is more than just an infection. It could end in hospitalization. Some patients could die if the infection is really bad and unable to be treated. That is a challenge with the current treatment.

With this, we won’t get that side effect, but really, we have to see if it will be as long of a duration as the PNA by themselves. In the relapsed setting where we previously tested vemurafenib, the duration of response is not as long as with the chemotherapy drugs, but the hope is that the addition of obinutuzumab is going to hopefully make it a longer duration of remission. We will have to see. We are testing the response rates, but we will follow the patients to see how long the remission lasts. We expect that there will be prolonged remissions, but I think that’s the controversial area with this study.

Are there other targeted agents that appear promising for the treatment of patients with hairy cell leukemia?

We’ve heard at this meeting about BTK inhibitors [such as ibrutinib (Imbruvica)]. Those are not being used upfront. They are being used in the relapsed setting, but there are 2 different drugs being tested. None of them are approved for hairy cell leukemia, so it is a clinical trial, but they seem promising. There is also potential for adding these targeted agents together. This trial does not exist yet, but that is the future step: combination of 2 targeted agents plus or minus the CD20 antibody.

Where do you see the field headed in the next decade or so?

At MSKCC, a lot of our leukemias and hematologic cancers in general are going toward chemotherapy-free regimens. This spares the toxicity associated with chemotherapy, but chemotherapy can also be associated with risk of second cancers. We are really trying to shift everything as much as possible, in the context of evidence-based clinical trials, into a chemotherapy-free era. That is where I think the field is headed. We will have to see the results of this trial, but can we spare some of the side effects associated with chemotherapy by switching to targeted agents alone?