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1567 Acalabrutinib Plus Rituximab with or without Lenalidomide in Patients with Follicular Lymphoma: A Multipart, Open-Label, Phase 1b Trial

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, adult, Non-Biological therapies, non-Hodgkin lymphoma, Lymphomas, B Cell lymphoma, Clinical Research, Combination therapy, indolent lymphoma, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, Monoclonal Antibody Therapy, Study Population, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Paolo Strati, MD1, Beth Christian2, Peter Martin, FRCPC, MD, MS3, Becky Champion4*, Morton Coleman, MD5*, Richy Agajanian, MD6*, Sonali M. Smith, MD7, Parameswaran Venugopal, MD8, Izidore S. Lossos, MD9, Robert Kridel, MD10, Roser Calvo11*, Kara Higgins12* and Deborah M. Stephens, DO13

1The University of Texas MD Anderson Cancer Center, Houston, TX
2The Ohio State University Comprehensive Cancer Center, Columbus, OH
3Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY
4Norton Cancer Institute, Louisville, KY
5Clinical Research Alliance/Weill Cornell Medicine, New York, NY
6The Oncology Institute of Hope & Innovation, Downey, CA
7The University of Chicago Medical Center, Chicago, IL
8Rush University Medical Center, Chicago, IL
9University of Miami - Miller School of Medicine, Miami, FL
10Princess Margaret Cancer Centre, Toronto, ON, Canada
11AstraZeneca, Gaithersburg, MD
12AstraZeneca, South San Francisco, CA
13University of Utah Huntsman Cancer Institute, Salt Lake City, UT

Background: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) have limited treatment options. FL becomes more aggressive and resistant with subsequent lines of therapy (LOT). Bruton tyrosine kinase (BTK) inhibition increases the anti-tumoral phenotype of tumor-associated macrophages, favoring its combination with rituximab or rituximab + lenalidomide (R2). Due to its specific and potent BTK inhibition and lack of interleukin-2–inducible T-cell kinase inhibition, acalabrutinib (A) is more likely to increase R2 efficacy without increasing T-cell–mediated toxicity. We report the first results from a phase 1b trial (NCT02180711) evaluating A alone and combined with rituximab or R2 in FL.

Methods: The study enrolled pts with FL grade 1–3a who were R/R to ≥1 prior therapy or who were treatment naive (TN). In part 1, R/R pts received A alone (arm A) or A + rituximab (arm A+rituximab-R/R); TN pts received A + rituximab (arm A+rituximab-TN). A was dosed at 100 mg twice daily. Part 3 was a dose-finding study for lenalidomide and enrolled R/R FL pts; these pts received A + R2 (arm A+R2) as follows: A daily until disease progression or unacceptable toxicity; rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2–6, followed by 10 additional maintenance doses every other cycle, and lenalidomide 15 mg or 20 mg on days 1–21 of each 28-day cycle up to cycle 12. Primary objective was to characterize the safety of A alone or in combination with rituximab in pts with R/R FL (part 1) and safety of A+R2 in pts with R/R FL (part 3). Secondary objectives included safety (part 1, TN cohort) and efficacy (all cohorts). Response assessment was based on Lugano criteria. Data cutoff was March 11, 2022.

Results: In part 1, 25 pts with R/R FL (arm A, n=12; arm A+rituximab-R/R, n=13) and 13 pts with TN FL (arm A+rituximab-TN) were enrolled. Median age in the R/R and TN cohorts was 67 y and 57 y, respectively. Pts had median 2 (range, 1–5) prior LOT in arm A (25.0% refractory to an anti-CD20 therapy regimen) and median 1 (range, 1–5) prior LOT in arm A+rituximab-R/R (38.5% refractory to an anti-CD20 therapy regimen). In the TN cohort, 46.2% had high tumor burden per Groupe d’Etude des Lymphomes Folliculaires criteria. Median follow-up was 8.1 mo (arm A), 8.8 mo (arm A+rituximab-R/R), and 49.5 mo (arm A+rituximab-TN). Median duration of exposure was 7.0 mo (arm A), 6.0 mo (arm A+rituximab-R/R), and 27.6 mo (arm A+rituximab-TN). The safety profile is summarized in the Table. Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥2 patients were hypertension (HTN; 16.7%; also present at baseline) in arm A and diarrhea, increased alanine aminotransferase, and increased aspartate aminotransferase (15.4% each) in the A+rituximab-TN arm. AEs led to discontinuation of A in 25.0% (arm A), 46.2% (arm A+rituximab-R/R), and 7.7% (arm A+rituximab-TN). Among events of clinical interest (ECIs), atrial fibrillation (grade 2) was reported in 1 pt in the A+rituximab-R/R arm. Any-grade hemorrhage was reported in 33.3% (arm A), 46.2% (arm A+rituximab-R/R), and 53.8% (arm A+rituximab-TN), with highest severity grade 2; no major hemorrhage events were reported. All except 1 pt (A+rituximab-R/R arm) were evaluable for response. Overall, 1 pt died due to progressive disease (A+rituximab-R/R arm; best response: partial response). Efficacy results are provided in the Table.

In part 3, 29 patients with R/R FL received A+R2 (lenalidomide dose: 15 mg, n=7; 20 mg [recommended dose], n=22). Median age was 64 y. Median time on study was 16.9 mo and median duration of exposure was 16.6 mo. Grade 3/4 TEAEs occurring in ≥2 patients were neutropenia (34.5%), and rash, thrombocytopenia, COVID-19, COVID-19 pneumonia, and febrile neutropenia (6.9% each). Five patients discontinued ≥1 study drug due to an AE. Among ECIs, atrial fibrillation (grade 2) was reported in 1 patient (3.4%), and any-grade hemorrhage was reported in 13 (44.8%) pts; no major hemorrhage events were reported. Three pts died due to AEs (septicemia, tumor lysis syndrome, aortic aneurysm). Efficacy results are provided in the Table. Of the evaluable pts, all but 1 had tumor reduction (Figure); overall response rate was 81%.

Conclusions: The combination of A+rituximab was well tolerated in TN FL and R/R FL. The addition of lenalidomide 20 mg suggests improved overall response rate in R/R FL compared with A alone; further studies of this regimen in FL are needed.

Disclosures: Strati: Hutchinson MediPharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; TG Therapeutics: Consultancy; Kite Gilead: Consultancy; Astrazeneca Acerta: Research Funding; ALX Oncology: Research Funding; Sobi: Research Funding; Roche Genentech: Consultancy. Christian: Genmab: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene/Bristol-Myers Squibb: Research Funding. Martin: ADCT: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; BMS: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Consultancy. Champion: Bristol Myers Squibb: Speakers Bureau; Abbvie: Speakers Bureau. Coleman: Arcus Biosciences, AstraZeneca, Acerta Pharma, BeiGene, BMS, Lily, EMD Serono, Genentech/Roche, Genfleet, GSK, Hutchison MediPharma, Incyte, Ipsen, MEI Pharma, Merck, Napo Pharmaceuticals, Novartis, Pfizer, Seattle Genetics: Research Funding; BMS: Consultancy. Smith: Bayer: Consultancy; TGTX: Consultancy; Genentech: Consultancy; Kite Pharma: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; BMS: Consultancy; Morphosys: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Portola: Research Funding; Gamida Cell: Consultancy; Bantam: Consultancy; Karyopharm: Consultancy; Chair, Lymphoma Research Foundation SAB: Membership on an entity's Board of Directors or advisory committees. Venugopal: AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria. Lossos: Adaptive: Honoraria; NCI: Research Funding; LRF: Membership on an entity's Board of Directors or advisory committees. Kridel: Abbvie: Research Funding. Calvo: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Higgins: Rocket Companies: Current equity holder in publicly-traded company; AstraZeneca: Current Employment; Palantir Technologies: Current equity holder in publicly-traded company. Stephens: AbbVie: Consultancy; Karyopharm: Research Funding; Mingsight: Research Funding; AstraZeneca: Consultancy; Novartis: Research Funding; CSL Behring: Consultancy; Acerta: Research Funding; Epizyme: Consultancy; Celgene: Consultancy; Beigene: Consultancy; Arqule: Research Funding; Lilly: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; JUNO: Research Funding; Newave: Research Funding.

*signifies non-member of ASH