Abstract
Introduction: R-CHOP remains the standard of care for DLBCL but fails in a proportion of patients (pts.) either through refractory lymphoma or relapse after achieving an initial remission. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome for non-germinal centre like DLBCL. However, R-CHOP-I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. Therefore, we combined A with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy.
Methods: Eligible pts. were treatment naive with histologically confirmed DLBCL. All received 6 cycles of R-CHOP on a standard 21-day schedule, with the addition of A in cycles 2-6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP-A. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R-CHOP (modified 6+6 design) with 24 months follow-up. Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the cell of origin (COO), pharmacokinetics and pharmacodynamics. COO was determined by HTG EdgeSeq transcriptome analysis. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006) and coordinated by Southampton Clinical Trials Unit.
Results: From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% >65 years old); 76% stage III/IV; 71% abnormal LDH; 29% B symptoms; 34% bulk; 24% high IPI; 32% high-intermediate IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65 at time of USM, 1 pt). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common ≥grade3 adverse events were neutropenia (34% of pts.), febrile neutropenia (16%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One of 7 eligible pts. in the first cohort (A 100mg od) progressed on therapy and subsequently died, 1 pt. not achieving mCR received additional radiotherapy. Twenty-four eligible patients received the RP2D in either dose escalation or expansion. Four pts. withdrew early from treatment (1 pt subject withdrawal, 2 pts. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The RP2D ORR was 96% (95% CI 79-100) with 79% (95% CI 58-93) of pts. achieving a mCR (4 pts. partial response (PR), 1pts. stable disease (SD)). One pt. with MYC/BCL2/BCL6 rearrangements and 1 pt. with MYC/BCL6 rearrangement achieved a mCR; neither have progressed. mCR was achieved in 9 of 12 ABC pts. (83%), 9/9 GCB pts and 1/2 unclassified pts. (PR 2, 0, 1 pts. respectively, 1/1 fail). At the RP2D with a median follow-up of 30 months, the 24 months EFS was 90% (95% CI 66-97), PFS was 95% (95% CI 68-99) and OS was 96% (95% CI 73-99) - 1 pt. progressed at 11 months and 1 double expressor patient with SD received subsequent chemotherapy prior to progression then died of PD. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented.
Conclusions: Acalabrutinib is well tolerated in combination with R-CHOP chemotherapy and may be associated with improved efficacy. This is being explored in the randomised REMoDL-A (NCT04546620) and ESCALADE (NCT04529772) trials.
Disclosures
Davies:Celgene, a Bristol Myers Squibb Company: Consultancy, Honoraria, Other: Travel grants / expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel grants / expenses, Research Funding; Kite, a Gilead company: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy; Janssen: Research Funding; GSK: Research Funding. Collins:SecuraBio: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants / expenses, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants / expenses, Speakers Bureau. Schuh:Adaptive Biotechnology: Honoraria; AstraZeneca: Honoraria, Other: Non-educational grant; SERENOx: Membership on an entity's Board of Directors or advisory committees, Other: Founder of; Gilead: Honoraria, Other: Personal fees; Oxford Nanopore Technology: Other: In kind contributions; Illumina: Other: In-kind contributions; Exact Sciences: Honoraria; Abbvie: Honoraria, Other: Personal fees; Roche: Honoraria, Other: Personal fees; Janssen: Honoraria, Other: Non-educational grant. Ardeshna:Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria. McMillan:Takeda: Honoraria, Other: Travel funding; Prosethetics: Honoraria; Roche: Honoraria; Amgen: Honoraria. Radford:The University of Manchester and Christie Hospital NHS Foundation Trust: Current Employment; BMS: Consultancy, Honoraria; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current equity holder in private company, Current holder of stock options in a privately-held company, Honoraria, Speakers Bureau; Kite Pharma: Consultancy; Astrazenca: Current equity holder in private company, Current holder of stock options in a privately-held company. Lewis:Eli Lilly and Company: Consultancy; Janssen: Consultancy, Other: Speakers fees; travel grant; Kite: Consultancy, Other: Travel grant; Roche: Consultancy; Beigene: Consultancy. Griffiths:Jannsenn-Cilag: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Astex: Research Funding; Roche: Research Funding; Heartflow: Research Funding; BMS: Research Funding; BionTech: Research Funding; Celldex: Other. Burton:Roche: Consultancy. Johnson:Novartis: Honoraria; Takeda: Honoraria; MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Celgene: Honoraria; BMS: Honoraria; Oncimmune: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy; Epizyme: Consultancy, Research Funding.
OffLabel Disclosure:
The drug is acalabrutinib, a second generation BTK inhibitor being used in combination with R-CHOP. This is not licensed for use in diffuse large B-cell lymphoma.
Author notes
Asterisk with author names denotes non-ASH members.
