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Next-generation BTK Inhibitors: A challenge for ibrutinib in B-cell Malignancies?
Are the next-generation Bruton’s tyrosine kinase (BTK) inhibitors acalabrutinib and zanubrutinib poised to challenge ibrutinib’s position in the management of CLL and other forms of B-cell malignancy? We didn’t get the final answer to that question at EHA25 Virtual, but there was plenty of new data to consider, including results from the first head-to-head trial of BTK inhibitors.

Meletios Dimopoulos presented the results of the phase 3 ASPEN trial, the first head-to-head comparison of BTK inhibitors in any disease. The trial compared first-in-class BTK inhibitor ibrutinib with next-generation agent zanubrutinib in 201 patients with Waldenström’s macroglobulinaemia (WM) and MYD88 mutation (MYD88MUT WM).

At median follow-up of 19.4 months, the rate of complete response + very good partial response (CR + VGPR), the primary endpoint, was higher for zanubrutinib vs ibrutinib, but the difference was not statistically significant (28.4% vs 19.2%, respectively; 2-sided P=0.0921). This meant that the trial failed to meet its primary endpoint. There was a deeper, sustained reduction in IgM levels over time with zanubrutinib vs ibrutinib (P=0.037), but major response rates were comparable for the two drugs. Rates of PFS and OS at 12 months were similar for zanubrutinib vs ibrutinib (12-month PFS 89.7% vs 87.2%; 12-month OS: 97.0% vs 93.9%).

There was some evidence that zanubrutinib has improved safety and tolerability in this population compared to ibrutinib. There were fewer AEs leading to death, treatment discontinuation or interruption with zanubrutinib vs ibrutinib. Notably, there was also a significant reduction in risk of atrial fibrillation/flutter (2.0% vs 15.3%; P=0.0008) and lower rates of bleeding (20.8% vs 31.6%) and hypertension (10.9% vs 17.3%) in zanubrutinib-treated patients vs ibrutinib. The rate of neutropenia was markedly higher for zanubrutinib vs ibrutinib (25% vs 12%), but rates of infection were generally comparable. Both drugs were associated with improvement in quality of life, but the trend in patients with deeper responses (VGPR) favoured zanubrutinib over ibrutinib.

So what does this trial tell us? It would seem that both BTK inhibitors have comparable efficacy in this setting. However, zanubrutinib may offer some safety and tolerability advantages over ibrutinib with a reduced incidence of BTK inhibitor treatment-related toxicities such as atrial fibrillation and bleeding.

Dimopoulos, M., Opat, S., et al. (2020). ASPEN: results of a phase 3 randomized trial of Zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). EHA25. Oral Presentation. Abstract # S225.

There were also promising initial results from an investigator-initiated study of zanubrutinib in combination with obinutuzumab + venetoclax (BOVen) in a small group of 39 patients with untreated CLL. Initial lead-in with zanubrutinib and obinutuzumab reduced the risk of tumour lysis syndrome and the chemotherapy-free triplet combination was generally well tolerated. The combination achieved rapid undetectable minimal residual disease (uMRD), with 84% uMRD in the peripheral blood and 73% in the bone marrow with median follow-up of 11 months. The median time to uMRD in the bone marrow was 6 months (2 months lead-in and 4 months triplet therapy). After a median of 8 months (6 months triplet therapy) 62% of patients had achieved the prespecified MRD endpoint and were able to stop therapy.


Soumerai, J., Mato, A., et al. (2020). Initial results of a multicenter, investigator-initiated
Study of MRD-driven time-limited therapy with zanubrutinib, obinutuzumab and venetoclax. EHA25. Oral Presentation. Abstract # S162.

Paolo Ghia presented final results from the phase 3 ASCEND study, one of two studies (the other being ELEVATE-TN) that supported the U.S. FDA approval of acalabrutinib in CLL. The randomised, global, multicentre ASCEND study investigated acalabrutinib monotherapy vs investigator’s choice of idelalisib + rituximab (IdR) or bendamustine + rituximab (BR) in 310 patients with relapsed/refractory CLL.

At median follow-up of 22 months, acalabrutinib monotherapy significantly prolonged PFS vs IdR/BR (median: not reached vs 16.8 months; HR: 0.27, P<0.0001). Notably, the PFS benefit with acalabrutinib vs IdR/BR extended to patients with high-risk features such as del(17p)/TP53 mutation and unmutated IGHV. Median OS was not reached in either treatment arm. The ORR was slightly lower in the acalabrutinib arm compared to IdR/BR (80% vs 84%; P=0.35).

Acalabrutinib showed a more manageable safety profile in this relapsed/refractory patient population compared to IdR, with lower incidences of grade >3 AEs, serious AEs, treatment-related AEs, drug discontinuations and dose modifications. The most common grade 3 AEs with acalabrutinib were neutropenia (17%), anaemia (12%) and pneumonia (7%). Bleeding events of any grade were more common with acalabrutinib than IdR but the incidence of major events was low in both arms (3% each).

Overall, these results confirm the efficacy and favourable safety profile of acalabrutinib vs IdR in relapsed/refractory CLL and support its use this setting, including in patients with high-risk features.

Ghia, P., Pluta, A., et al. (2020). Acalabrutinib vs idelalisib plus rituximab (IdR) or Bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. EHA25 Virtual. Oral Presentation. Abstract # S159.

There was also positive new data for acalabrutinib in first-line CLL as John Byrd presented updated results for first phase 2 study of acalabrutinib monotherapy (ACE-CL-001) in patients with treatment-naïve disease. With median follow-up of 53 months, this study provides the longest safety and efficacy follow-up to date for acalabrutinib in symptomatic patients with CLL.

The results showed that responses to acalabrutinib were durable with an overall response rate (ORR) of 97% (7% CR, 90% PR). Notably, the response rate was 100% in each of the high-risk subgroups analysed (unmutated IGHV, del(17p), TP53 mutation and complex karyotype). Median event free survival (EFS) and median progression free survival (PFS) were not reached. The 4-year EFS rate was 90%.

The majority of adverse events (AEs) were mild in severity and the incidence of AEs generally decreased over time. Serious AEs were seen in 38% of patients and clinical events of interest included infection, bleeding events, and hypertension, but no patient discontinued due to these events. Overall only 6% of patients discontinued due to drug toxicity.

Together with the results of the phase 3 ELEVATE-TN study that supported U.S. FDA approval of acalabrutinib in CLL last year, these follow-up data suggest that acalabrutinib can provide durable efficacy with no new long-term safety issues in patients with treatment-naïve CLL.

Byrd J., Woyach J., et at. (2020). Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: mature results from phase 2 study demonstrating durable remissions and long-term tolerability. EHA25 Virtual. Oral Presentation. Abstract # S163.