Clinical Challenges: BTK Inhibitors in Waldenstrom Macroglobulinemia

There is little question that the development of Bruton tyrosine kinase (BTK) inhibitors has changed the treatment landscape for Waldenström macroglobulinemia patients and their doctors.

The first drug ever approved by the FDA for Waldenström was the BTK inhibitor ibrutinib (Imbruvica) in January 2015. Since then, it has become a mainstay of treatment for the disease.

Ibrutinib’s approval was based on a phase II study of the drug in 63 symptomatic patients with previously-treated Waldenström macroglobulinemia. Long-term findings from that study at a median of 59 months showed overall and major response rates of 90.5% and 79.4%, respectively, with responses affected by mutated MYD88 and CXCR4 status.

Ibrutinib has also been shown to be effective in combination with rituximab (Rituxan), and in 2018 that regimen was approved for the treatment of adults with Waldenström, based on results from the phase III iNNOVATE trial.

Final results from the iNNOVATE study, which evaluated ibrutinib in combination with rituximab vs rituximab alone in 150 patients with previously untreated and relapsed or refractory Waldenström, demonstrated a 75% reduction in the risk of disease progression or death. Median progression-free survival (PFS) was not reached with ibrutinib-rituximab in the median follow-up of 50 months but was 20.3 months with rituximab alone.

That final analysis demonstrated the ongoing efficacy of the combination compared with rituximab alone, regardless of prior treatment status or MYD88/CXCR4 genotype.

While ibrutinib is an effective drug and is considered to be well tolerated, it has been associated with several side effects – with atrial fibrillation emerging as a particularly significant adverse event.

In a retrospective review of 112 Waldenström patients treated with ibrutinib for 43 months or more, 11% experienced atrial fibrillation. And in the final analysis of the iNNOVATE trial, investigators reported that 15% of patients treated with the ibrutinib/rituximab combination experienced grade 3 or 4 atrial fibrillation.

“Ibrutinib is a great drug in general, but it can be improved,” said Constantine Tam, MD, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

Thus, Tam noted, it was desirable to find more selective BTK inhibitors that could minimize the off-target effects and associated toxicity seen with ibrutinib. This has led to the clinical development of second-generation BTK inhibitors, including zanubrutinib (Brukinsa) and acalabrutinib (Calquence).

Tam and his colleagues conducted the ASPEN trial, which compared the efficacy of zanubrutinib versus ibrutinib in 201 patients with Waldenström and MYD88 mutation.

The primary endpoint of the ASPEN trial was complete response (CR) plus very good partial remission (VGPR) as assessed by an independent review committee (ICR). The ICR-assessed rate was 28.4% for zanubrutinib and 19.2% for ibrutinib (P=0.09).

“Zanubrutinib didn’t reach the P=0.05 threshold,” Tam noted. “So technically, it was a negative study. Zanubrutinib was not better than ibrutinib, but not worse.”

Tam suggested this finding was probably an effect of underpowering.

“You can look at efficacy in about six different ways, and the only way it was negative was the way we chose the primary endpoint, which was the VGPR rate at that particular time,” he said.

“However, the interesting thing about the study was zanubrutinib’s safety profile,” Tam added. “This was the first head-to-head comparison of BTK inhibitors in any disease, and in ASPEN it was very clear zanubrutinib had less atrial fibrillation.”

Specifically, the incidence of atrial fibrillation or flutter was 2.0% with zanubrutinib versus 15.3% with ibrutinib. In addition, there was less hypertension with zanubrutinib (10.9% vs 17.3%), fewer major bleeding events (5.9% vs 9.2%), and fewer side effects leading to discontinuation (4.0% vs 9.2%).

“The only price we paid with zanubrutinib in terms of toxicity was an increased risk of neutropenia, and that was not associated with an increased risk of infection,” Tam said.

Based on ASPEN’s results, zanubrutinib was approved by the FDA in August 2021 for adult patients with Waldenström macroglobulinemia.

Tam also noted that results from the ALPINE study in chronic lymphocytic leukemia (CLL) demonstrated less cardiotoxicity with zanubrutinib compared with ibrutinib in that disease, while the ELEVATE-R/R study showed acalabrutinib came with less cardiotoxicity than ibrutinib in CLL.

“So, I think it is irrefutable now across these three phase III studies that second-generation BTK inhibitors are safer,” Tam said.

Acalabrutinib was assessed in Waldenström in a phase II multicenter study of 106 patients (14 who were treatment naïve and 92 with relapsed or refractory disease).

At a follow-up of 27.4 months, 13 (93%) treatment-naive patients achieved an overall response, as did 86 (93%) of the relapsed or refractory patients. Major response, defined as a response greater than or equal to a partial response, was recorded in 11 (79%) treatment-naive patients and 72 (78%) relapsed or refractory patients.

The most common grade 3 and grade 4 adverse events included neutropenia (16%), pneumonia (7%), anemia (5%), and lower respiratory tract infection (5%). Atrial fibrillation occurred in 5% of patients, significantly lower than the rates demonstrated for ibrutinib monotherapy or with the combination of ibrutinib and rituximab.

The end result is that BTK inhibitors are all very effective drugs, Tam said. And while the second-generation drugs have a more favorable safely profile than ibrutinib, he added, “I don’t think the availability of zanubrutinib or acalabrutinib is a sufficient reason to switch someone who is doing well on ibrutinib.”

Another second-generation BTK inhibitor, tirabrutinib (GS-4059/ONO), has been evaluated in a Japanese phase II study, in which 18 patients with treatment-naïve Waldenström and nine with refractory/relapsed disease were treated with tirabrutinib monotherapy.

The major and overall response rates were 88.9% and 94.4%, respectively, among treatment-naïve patients, and 88.9% and 100% among patients with relapsed or refractory disease. PFS and overall survival were not reached with a median follow‐up of 6.5 and 8.3 months for those two cohorts, respectively.

The most common adverse events were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%).