BTK Inhibitors Transform Waldenström Macroglobulinemia Management

Steven P. Treon, MD, PhD

BTK inhibitors have transformed the treatment of patients with Waldenström macroglobulinemia, according to Steven P. Treon, MD, PhD, who added that with 4 agents under examination in the space, selection will depend on availability, toxicity, convenience, and cost.

“In the Waldenström macroglobulinemia treatment armamentarium, we have never seen agents as active and safe as BTK inhibitors. We’re very blessed because, if we choose to stop administering 1 BTK inhibitor due to a toxicity concern, patients can be switched to a different BTK inhibitor,” said Treon.

The 3 key agents in the United States are ibrutinib (Imbruvica), zanubrutinib (Brukinsa), and acalabrutinib (Calquence). In Japan, another agent has been under active investigation: tirabrutinib hydrochloride (Velexbru). In August 2020, the BTK inhibitor received a supplemental approval for the BTK inhibitor in Japan for use in patients with Waldenström macroglobulinemia and lymphoplasmacytic lymphoma. The decision was based on data from a single-arm phase 2 trial which demonstrated an overall response rate of 88.9% (95% CI, 51.8-99.7) as assessed by an independent review committee.

“When I first started in the field, a young patient presented with a bad case of this disease. The patient died shortly after his first cycle of therapy due to severe complications from chemotherapy,” Treon added. “As I reflect back on other past cases, I wish we discovered BTK inhibitors in this space much sooner because they have completely changed the playing field for the disease.”

In an interview with OncLive, Treon, the director of Bing Center for Waldenström Macroglobulinemia who is also a professor of medicine at Harvard Medical School and senior physician at Dana-Farber Cancer Institute, discussed the role of BTK inhibitors in Waldenström macroglobulinemia.

OncLive: What is the role of BTK inhibitors in Waldenström macroglobulinemia?

Treon: It’s been a very exciting time for Waldenström macroglobulinemia and BTK inhibitors lie at the center of the progress that has been made for this disease. The reason why we became interested in BTK inhibitors has to do with the discovery of the MYD88 mutation; this is found in about 95% to 97% of all patients with the disease. What's important about this mutation is that it activates Bruton’s tyrosine kinase through a protein called HCK. Both HCK and BTK are targeted by ibrutinib, zanubrutinib, and acalabrutinib. All 3 agents have shown great clinical activity.

We also now know about another BTK inhibitor, tirabrutinib hydrochloride, largely due to the research efforts being conducted in Japan; this agent ishighly active in this disease. Thus, we now have 4 BTK inhibitors in the space that are all are showing response rates greater than 90% and, across the board, major response rates around 80% in this population.

Notably, when you look at the activity in previously treated patients, whether they're relapsed or refractory; have had 1, 2, 3, or more lines of prior therapy; or they are treatment-naïve; the[se] drugs [are] active, and almost at the same level. This shows that we have a real targeted therapy, which is right on point with what we would have expected based on the whole genomic analysis that allowed us to discover MYD88 mutations in this disease.

It's really a new era; we're no longer just pulling agents off the shelf that our colleagues in myeloma and lymphoma have generated. We would borrow agents used in other diseases; that used to be the main approach for treatment in Waldenström, a hand-me-down approach. Whole genome sequencing really has given us a playbook that has allowed us to rationally develop drugs.

Now, CXCR4 is the second most common mutation that we discovered in Waldenström macroglobulinemia thanks to whole genome sequencing. We see mutations in CXCR4 in about 30% to 40% of patients. These are activating mutations that have a very important role in the presentation of patients with this disease. Typically, the patients with these mutations come in with high immunoglobulin M deficiency (IgM) levels and symptomatichyperviscosity syndrome. Additionally, these mutations have been very important in terms of understanding the drug activity in Waldenström macroglobulinemia because they were associated with drug resistance.

When you look at a few of these BTK inhibitor studies where CXCR4 mutation status has determined, you see that the time to get to a major response, the depth of response, and progression-free survival are adversely impacted by the presence of these mutations. These patients don't have the same robust activity that we have seen in patients with MYD88-mutated wild-type disease. Even so, CXCR4 mutations are targetable and there are a number of CXCR4 antagonists. One is plerixafor ​(Mozobil), which is commonly used for stem cell mobilization; however, it’s not practical. The agent has to be administered subcutaneously and it has a short half-life, so it has to be given a couple of times a day.

The use of an antibody-blocking agent against CXCR4 called ulocuplumab (BMS-936564) was also evaluated in a phase 1 trial. In the study, this agent was combined with ibrutinib in patients with CXCR4-mutated disease and results showed that we could accelerate response, and we could achieve those deep responses that we normally see in those with CXCR4 wild-type disease.

Whole genome sequencing has discovered actionable mutations, and this is giving us a wonderful playbook for the disease that includes BTK inhibitors and other drugs that are going to help us optimize the activity of these BTK inhibitors in these patients.

How do you choose among the 4 available BTK inhibitors in this patient population?

The first factor is availability. In the United States, we still don't have access to tirabrutinib; this agent is going to largely be developed in Japan. Experience is also very important. In the pivotal trial with ibrutinib, we have a median follow up of 59 months; this gives us a sense of what the activity is going to be along with any long-term safety concerns. With a longer follow-up, we did see more atrial fibrillation and hypertension [with the agent]. Atrial fibrillation was largely managed, so most of the patients continued on ibrutinib, despite the development of this adverse effect. However, we went from about 5% of patients experiencing atrial fibrillation at 2 years to roughly 13% with a longer follow-up at 5 years. It’s important to note that, although the percentage rose, it was medically manageable. The hypertension rate went up, as well; however, I don't believe anyone came off the therapy due to the hypertension.

The toxicity profile is also important, especially since the only head-to-head BTK inhibitor study that we have data on now is ibrutinib versus zanubrutinib. We saw result from the ASPEN trial presented during the 2020 ASCO Virtual Scientific Program. This was a randomized, international study that was targeted for patients. Approximately 200 patients were enrolled on the trial. More very good partial responses (VGPR) were seen in the zanubrutinib arm, based on the data cutoff that was reported during the meeting. Although the difference was not statistically significant, it was [found to be] significant with longer follow-up. This finding did not surprise me because, as we have learned, VGPR rates do increase over time.

It’s critical to understand what VGPR actually means. It may mean nothing if you're thinking about PFS, because we still don't have the data. However, it may mean a lot for patients who have IgM-related morbidity. Many patients will present with IgM-related morbidity, whether its peripheral neuropathy or hyperviscosity. When you look at the area under the curve for IgM, it was significantly better with zanubrutinib. As we look to the future, we may identify niches of patients who benefit with one agent over the other.

In the case of zanubrutinib, I'd like to see more clinical data from the investigators affirming what we would think would be appropriate with a lower IgM. If you come across patients who you think may be more prone to atrial fibrillation, [it’s important to remember that] with zanubrutinib, the atrial fibrillation ratewas 2% with a 19-month follow-up; this rate was 15% with ibrutinib [at this same time point]. That caught me by surprise, because that's much higher than what we saw in the pivotal trial where this rate was around 5%. But this is a randomized, open-label trial so I think that tells us that there's going to be safety differences associated with the 2 agents. Slightly more bleeding events were associated with ibrutinib but there were more neutropenia events with zanubrutinib. These differences are going to be very important for clinicians to understand.

We saw exciting data with acalabrutinib in a single-arm study that enrolled just under 100 patients. Participants presented with headaches in the first few months of therapy, although this is common with acalabrutinib. With this said, this effect did not limit its use.

Convenience is also going to be part of the story; patients receive ibrutinib once a day and zanubrutinib and acalabrutinib are given twice a day. Some investigators may not believe that this has hindered the compliance of the study; however, the real-world experience may differ. Sending patients home with a diary and expecting them to show up with notes in the diary at their next visit, may help them remember to consistently take the drug. However, in the real-world setting, especially with this disease, the elderly may be a different story. Compliance needs to be factored into the decision.

Finally, cost must also be taken into consideration. We still have an issue with cost, at least in the United States, where the Medicare population has serious monthly co-pays.

Reference

ONO receives a supplemental approval in Japan for Velexbru tablet 80mg, a BTK inhibitor, for additional indication of Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma. News release. Ono Pharmaceutical Co, Ltd. August 21, 2020. Accessed September 29, 2020. https://bit.ly/2S6qFg4.