Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study
Authors: Wang Michael , Rule Simon , Zinzani Pier Luigi , Goy Andre H. , Casasnovas Rene-Olivier , Smith Stephen D. , Damaj Gandhi Laurent , Doorduijn Jeanette K. , Lamy Thierry , Morschhauser Franck , Panizo Carlos , Shah Bijal , Davies Andrew , Eek Richard , Dupuis Jehan , Jacobsen Eric , Kater Arnon P. , Le Gouill Steven , Oberic Lucie , Robak Tadeusz , Jain Preetesh , Brock Graham , Patel Priti , Tao Lin , Dlugosz-Danecka Monika 
Published: November 2020

Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. The efficacy and safety of acala in relapsed/refractory (R/R) MCL pts was demonstrated in a single-arm phase 2 study (ACE-LY-004; NCT02213926) after a median follow-up of 26 mo (Wang M, et al. Leukemia. 2019;33:2762-6). Here, we present results after an additional year of follow-up.
Methods: Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1-5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral acala 100 mg twice daily until progressive disease (PD) or toxicity. Overall response rate (ORR; investigator-assessed partial response [PR] or better per Lugano classification), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Minimal residual disease (MRD) was analyzed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5x10-6) in pts with available paired samples.
Results: 124 pts were included (median age, 68 [range: 42-90] y; ECOG PS ≤1, 93%; bulky lymph nodes ≥10 cm, 8%; extranodal involvement, 72%; intermediate-/high-risk simplified MCL International Prognostic Index score, 44%/17%; median number of prior therapies, 2 [range: 1-5]; refractory disease, 24%).
After a median follow-up of 38.1 mo (range: 0.3-59.5), 24 (19%) pts remain on treatment and an additional 31 pts (55 total; 44%) remain in follow-up for survival. Of the 31 pts in post-acala follow-up, 6 remain PD-free (4 received post-acala treatment: anticancer treatment combinations and allogeneic stem cell transplant [n=3]; radiotherapy [n=1]). ORR was 81% (95% CI: 74, 88); 48% (95% CI: 39, 57) achieved complete response (CR). Median DOR was 28.6 mo (95% CI: 17.5, 39.1) and the estimated 36-mo DOR rate was 41.9% (95% CI: 31.7, 51.8). Median PFS was 22.0 mo (95% CI: 16.6, 33.3; Figure); estimated 36-mo PFS rate was 37.2% (95% CI: 28.2, 46.1). ORR and PFS were not significantly different between subgroups divided by Ki-67 index (≤50%, &gt;50%); PFS also did not differ significantly by prior treatment regimen (bendamustine/rituximab [BR]-based, non-BR) or prior therapy line (1, 2, ≥3). Median OS was not reached; estimated 36-mo OS rate was 60.5% (95% CI: 51.1, 68.7). Of 30 MRD-evaluable pts, 6 (20%) achieved CR and undetectable MRD (uMRD) and maintained uMRD at last assessment.
The adverse event (AE) profile was largely unchanged with an additional year of follow-up. The most frequent AEs (≥20%) of headache (39%), diarrhea (37%), fatigue (30%), cough (23%), myalgia (22%), and nausea (22%) were primarily grade 1/2. Grade 3/4 AEs (≥5%) were neutropenia (11%), anemia (10%), and pneumonia (6%). Overall, 16 pts (13%) had cardiac AEs (11 with prior cardiac risk factors); 3 of the 16 pts had cardiac AEs in the last year of follow-up (grade 3/4: n=2). Overall, 6 pts (5%) had grade 3/4 cardiac AEs (acute coronary syndrome, acute myocardial infarction, complete atrioventricular block, cardiac failure, cardiorespiratory arrest, coronary artery disease, sinus arrest; n=1 each). One pt had grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total grade 3/4, n=2 [2%]). Five pts had bleeding AEs in the last year (n=46 [37%] total) including 2 with grade 3/4 AEs of gastrointestinal hemorrhage (n=2 total) and 1 with grade 3/4 subdural hematoma (n=1 total). Three pts had grade 3/4 infections in the last year (n=21 [17%] total).
Treatment discontinuation was primarily due to PD (n=74; 60%) and AEs (n=14; 11%). Seventeen AEs led to discontinuation in 14 pts; each AE occurred in only 1 pt. There were 57 deaths (46%), most commonly due to PD (n=38; 31%) or AEs (n=6; 5%); 14 deaths (11%) occurred in the last year of follow-up (PD, n=9; other, n=1; unknown, n=4). There were 6 deaths due to AEs (bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, non-small cell lung cancer); none were related to acala.
Conclusion: Extended follow-up demonstrates no emerging safety concerns for acala in R/R MCL pts. After a median of 38.1 mo, 19% of pts remain on acala. Overall, an estimated one-third of pts remain progression free at 36 mo, with median OS not yet reached. These data support long-term use of acala in R/R MCL pts.

Disclosures
Wang: Dava Oncology: Honoraria; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; OncLive: Honoraria; Molecular Templates: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; BioInvent: Research Funding; Acerta Pharma: Research Funding; VelosBio: Research Funding; Targeted Oncology: Honoraria; Lu Daopei Medical Group: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding. Rule:Celgene: Consultancy; Celltrion: Consultancy; Roche Pharma AG: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Goy:Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Celgene: Honoraria, Research Funding; CALBG: Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Karyopharm: Research Funding; Xcenda: Consultancy; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; RCCA/OMI: Current Employment; PracticeUpdate Oncology: Consultancy; Infinity Verastem: Research Funding; AbbVie: Research Funding; Morphosys: Research Funding; Genentech/Roche: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Bayer: Research Funding; Infinity: Research Funding; Constellation: Research Funding. Casasnovas:Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Smith:Ignyta: Research Funding; Genentech: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy; Acerta Pharma BV: Research Funding; Incyte: Research Funding; Karyopharm: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Beigene: Consultancy. Doorduijn:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Panizo:Bristol-Myers Squibb, Kyowa Kirin: Speakers Bureau; Clínica Universidad de Navarra: Current Employment; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Shah:Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Jazz, Incyte: Research Funding; Moffitt Cancer Center: Current Employment; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Davies:Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Jacobsen:Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. Kater:Roche: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Oberic:Roche, Janssen: Consultancy; Roche: Honoraria; Roche, Janssen: Other: Travel, Accommodations, Expenses. Robak:Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UCB: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Acerta: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; GSK: Research Funding; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; UTX-TGR: Research Funding; Takeda: Consultancy; Morphosys: Research Funding; BioGene: Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Pfizer: Research Funding; Momenta: Consultancy. Brock:Jazz Pharmaceuticals Inc: Current Employment; Acerta Pharmaceuticals: Ended employment in the past 24 months; Astra Zeneca: Current equity holder in publicly-traded company. Patel:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Tao:Clindata Insight inc: Ended employment in the past 24 months; Acerta Pharma, LLC: Current Employment.