Jennifer R. Brown, MD, PhD, on CLL/SLL: New Findings on Zanubrutinib vs Ibrutinib for Relapsed or Refractory Disease
2022 ASH Annual Meeting and Exposition
Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, discusses phase III findings of the ALPINE study, which showed that zanubrutinib is more efficacious and better tolerated than ibrutinib as a treatment for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this first head-to-head comparison of the two BTK inhibitors, the superior progression-free survival of zanubrutinib was observed across all major subgroups, including high-risk patients (Abstract LBA-6).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
The Alpine study is a randomized phase-three trial comparing zanubrutinib to ibrutinib in relapsed/refractory CLL patients. As a reminder, ibrutinib is our first-in-class BTK inhibitor, which has been transformative for CLL therapy but has significant adverse events. Zanubrutinib is a next-generation drug, which is more specific for BTK and also maintains drug levels throughout the dosing interval, potentially allowing greater BTK occupancy. Alpine was designed to assess the efficacy and safety of zanubrutinib in comparison to ibrutinib. The population was an all-comer relapsed/refractory population with a median of one prior therapy, which was chemoimmunotherapy by and large. The randomization was stratified by age, geographic area relapsed/refractory disease, and deletion 17p or TP53 aberrancy. The findings that I presented at ASH this year demonstrated that zanubrutinib has a superior progression-free survival compared to ibrutinib in this setting with a hazard ratio of 0.65 and a two-year landmark of 79% progression-free survival for zanubrutinib versus 67% for ibrutinib, so a 12% improvement.
This was seen across all subgroups of disease, but in particular, the high-risk deletion 17p/TP53 aberrant patients had a 22% improvement in their two-year landmark PFS. The median PFS with ibrutinib was reached at 36 months, but not reached with zanubrutinib. In addition to this, zanubrutinib continues to have a higher overall response rate than ibrutinib, which was actually the primary endpoint of the study, but PFS was a key secondary endpoint that we reported here. It was event-driven after 205 events.
In terms of safety, zanubrutinib was also safer than ibrutinib. There were fewer drug discontinuations, fewer drug holds, fewer drug interruptions for toxicity. Perhaps most importantly, the cardiac safety was significantly improved with fewer cardiac serious adverse events. Only one drug discontinuation for a cardiac adverse event with zanubrutinib versus 14 for ibrutinib, and perhaps most notably, no cardiac death with zanubrutinib versus six with ibrutinib.
In terms of other toxicities, the most common toxicity was neutropenia, which was 23% grade three or higher with zanubrutinib versus 22% with ibrutinib, so pretty comparable, although there were fewer associated infections with zanubrutinib at 9% versus 13% with ibrutinib. COVID-19 was the next most common adverse event and the most common adverse event leading to death at about 4% in zanubrutinib and 5% in ibrutinib. Hypertension was balanced between the arms.
So in summary, the Alpine study demonstrated that zanubrutinib has a superior progression-free survival to ibrutinib in relapsed/refractory CLL patients and is also better tolerated with a particularly better cardiac profile, which is one of our key points we worry about with BTK inhibitors. The results of this study are potentially practice-changing, demonstrating that zanubrutinib is a new standard of care for CLL.
Are there any follow-up studies you want to mention?
Although this was the final analysis of progression-free survival, there will be ongoing analysis and we'll certainly be interested in more mature data as this is about 30 month follow up. We're also interested in studies that are evaluating combination of zanubrutinib and venetoclax, or zanubrutinib and other Bcl-2 inhibitors looking potentially at time limited therapy similar to what's been done with other BTK inhibitors, mostly ibrutinib to date, but also acalabrutinib.
Mark R. Litzow, MD, of the Mayo Clinic, discusses phase III results from the ECOG-ACRIN E1910 Trial, which show that adding blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival in adult patients aged 30 to 70 years with newly diagnosed B-lineage acute lymphocytic leukemia (ALL) who were measurable residual disease–negative after receiving intensification chemotherapy. The authors believe this may represent a new standard of care for this population (Abstract LBA-1).
Tycel J. Phillips, MD, of the City of Hope National Medical Center, discusses data that showed fixed-duration glofitamab monotherapy induced high and durable complete response rates in patients with mantle cell lymphoma (MCL) who received obinutuzumab pretreatment. This is one of the largest data sets and longest follow-ups reported with a CD20/CD3 bispecific monoclonal antibody for patients with relapsed or refractory MCL (Abstract 74).
Paolo F. Caimi, MD, of the Taussig Cancer Institute, Cleveland Clinic, discusses new findings showing that patients with diffuse large B-cell lymphoma (DLBCL) who achieve a complete response after salvage therapy with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) can achieve long-term disease control, regardless of the time to relapse from initial therapy, particularly if they proceed to autologous stem cell transplant (ASCT). These results suggest that second-line chemotherapy followed by ASCT and/or CAR T-cell therapy for chemosensitive and chemorefractory patients may maximize patient outcomes, regardless of time to relapse (Abstract 156).
Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, discusses preliminary results from the dose-expansion phase of the CC-92480-MM-001 Trial, which showed promising efficacy in patients with relapsed and refractory multiple myeloma, including those with prior BCMA-targeted therapies. Patients in these two groups had an overall response rate of 40% and 50%, respectively. The results support the development of mezigdomide, currently being evaluated in combination with standard therapies in multiple myeloma as part of a large, ongoing phase I/II trial (NCT03989414) and planned phase III studies (Abstract 568).
Kathryn R. Tringale, MD, of Memorial Sloan Kettering Cancer Center, discusses an assessment of 559 patients with primary central nervous system (CNS) lymphoma and the factors associated with consolidation therapy selection, outcomes after consolidation therapy accounting for patient factors, and patterns of disease failure. The initial treatment response was prognostic and predictive of relapse patterns (Abstract 557).