Michael Wang, MD from The University of Texas MD Anderson Cancer Center discusses the ASH 2020 abstract – Acalabrutinib Monotherapy in Patients with Relapsed/Refractory MCL: Long-Term Efficacy and Safety Results from a Phase 2 Study.
Context:
Acalabrutinib (acala) is a highly selective, covalent, next-generation inhibitor of Bruton tyrosine kinase (BTK) approved for patients (pts) with mantle cell lymphoma (MCL) who have undergone approximately 1 prior therapy. In a single-arm phase 2 analysis (ACE-LY-004; NCT02213926), the efficacy and protection of acala in relapsed/refractory (R/R) MCL pts was demonstrated following a median follow-up of 26 mo (Wang M, et al. Leukemia. 2019;33:2762-6). Here, after an extra year of follow-up, we present the findings.
Methods: Adults with MCL and ECOG PS ⇠2 who had relapsed or were refractory to 1-5 previous medications, had no previous exposure to BTK/BCL-2 inhibitor, and did not need warfarin/vitamin K antagonists, received oral acala 100 mg twice daily before progressive disease (PD) or toxicity. Overall response rate (ORR; Lugano classification investigator-assessed partial response [PR] or better), length of response (DOR), progression-free survival (PFS), overall survival (OS) and protection were evaluated. In formalin-fixed, paraffin-embedded samples and peripheral blood, minimal residual disease (MRD) was analyzed by next-generation sequencing (5×10-6) in pts with usable paired samples.
Outcomes:
124 pts were included (median age, 68 [range: 42-90] y; ECOG PS ⇠1, 93%; bulky lymph nodes ⇠10 cm, 8%; extranodal involvement, 72%; simplified intermediate/high-risk MCL International Prognostic Index ranking, 44%/17%; median number of prior therapies, 2 [range: 1-5]; refractory disease, 24%).
Following a median follow-up of 38.1 mo (range: 0.3-59.5), 24 (19%) pts remain on care and an additional 31 pts (55 total; 44%) remain on survival follow-up. Of the 31 post-acala follow-up pts, 6 remain PD-free (4 post-acala treatment received: combinations of anticancer treatment and allogeneic stem cell transplantation [n=3]; radiotherapy [n=1]). ORR was 81% (95% CI: 74, 88); total response was obtained by 48% (95% CI: 39, 57) (CR). The median DOR was 28.6 months (95 percent CI: 17.5, 39.1) and 41.9 percent was the estimated 36-mo DOR rate (95 percent CI: 31.7, 51.8). The median PFS was 22.0 months (95% CI: 16.6, 33.3; figure); the estimated 36-month PFS rate was 372% (95 percent CI: 28.2, 46.1). ORR and PFS were not substantially different between the Ki-67 index-divided subgroups (approximately 50 percent, >50 percent); PFS was also not significantly different from the previous treatment regimen (bendamustine/rituximab [BR]-based, non-BR) or prior treatment line (1, 2, ⇠3). There was no median OS; the estimated 36-mo OS rate was 605% (95 percent CI: 51.1, 68.7). 6 (20 percent) of 30 MRD-evaluable pts achieved CR and undetectable MRD (uMRD) and retained uMRD at the last review.
For an additional year of follow-up, the adverse event (AE) profile remained essentially unchanged. The most common AEs (about 20%) for headache (39%), diarrhea (37%), fatigue (30%), cough (23%), myalgia (22%), and nausea (22%) were mainly grade 1/2. Neutropenia (11 percent), anemia (10 percent), and pneumonia were Grade 3/4 AEs (almost 5 percent) (6 percent ). Overall, 16 pts (13 percent) had cardiac AEs (11 with previous cardiac risk factors); in the last year of follow-up, 3 of the 16 pts had cardiac AEs (grade 3/4: n=2). Overall grade 3/4 cardiac AEs (acute coronary syndrome, acute myocardial infarction, full atrioventricular block, cardiac insufficiency, cardiorespiratory arrest, coronary artery disease, sinus arrest; n=1 each were 6 pts (5 percent). In the previous year, one pt had grade 3/4 hypertension (max of either grade, n=5 [4%]; total grade 3/4, n=2 [2%]). In the previous year, 5 pts had bleeding AEs (n=46 [37 percent] total), including 2 with gastrointestinal hemorrhage grade 3/4 AEs (n=2 total) and 1 with subdural hematoma grade 3/4 (n=1 total). In the last year (n=21 [17 percent] total), three pts had grade 3/4 infections.
The discontinuation of treatment was mainly attributed to PD (n=74; 60 percent) and AEs (n=14; 11 percent). Seventeen AEs in 14 pts resulted in discontinuation; each AE occurred in just 1 pt. There were 57 deaths (46 percent), most often due to PD (n=38; 31 percent) or AEs (n=6; 5 percent); in the last year of follow-up, 14 deaths (11 percent) occurred (PD, n=9; other, n=1; unknown, n=4). Six deaths (bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, non-small cell lung cancer) were recorded due to AEs; none were associated with acala.
The Conclusion:
No emerging safety issues for acala in R/R MCL pts are illustrated by extended follow-up. 19 percent of pts remain on acala, after a median of 38.1 mo. Overall, with the median OS not yet achieved, an estimated one-third of pts remain progression-free at 36 mo. These data endorse the use of acala in R/R MCL pts for long-term use.