Ibrutinib + bortezomib + R‐CHOP for higher‐risk DLBCL: Feasibility, efficacy and molecular predictors

Introduction: Most recent phase III trials investigating single targeted treatment additions to R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL) failed, at least in part, due to the high heterogeneity of this disease. While re-analyses of negative trials (e.g. PHOENIX R-CHOP ± ibrutinib or REMoDL-B R-CHOP ± bortezomib) unveiled molecular subgroups that strongly benefitted, we pursued in our explorative single-arm open-label phase I/II ImbruVeRCHOP (ibrutinib + bortezomib + R-CHOP) investigator-initiated study (IIS) a proximal and distal BCR/NF-κB double-targeting strategy for higher-risk all-comer patients (i.e., independent of any molecular pre-selection) that utilizes repeated lymphoma biopsies for multi-omics profiling in the course of therapy to identify molecular signatures indicative of lasting responsiveness. Methods: 37 IPI ≥2 newly diagnosed DLBCL patients 61–80 years of age were enrolled in the ImbruVeRCHOP multi-center IIS (EudraCT number 2015-003429-32, ClinicalTrials.gov identifier NCT03129828). Patients received six 21d-cycles of R-CHOP plus ibrutinib (420 mg/d p.o.) and bortezomib (1.3 mg/m2 s.c. d1 + 8) followed by two subsequent applications of single-agent rituximab. Patients underwent lymphoma and liquid biopsies prior to, acutely under the first treatment cycle and, in case of a residual and reasonably accessible tumor manifestation, once again at interim CT imaging prior to cycle 3. Results: The study enrolled patients at 12 German and Austrian centers until April 2022. Workup of the multi-omics analyses started at the end of 2022. Based on 34 patients completing all treatment cycles, the median follow-up is 11.5 months and the CT-based overall response rate is 44% (15 CR, 19 PR—with no mandatory PET/CT certainly underestimating metabolic CR). Median 2-year progression-free-survival, the primary endpoint, has not been reached yet. R-CHOP dose adherence was high (91%—compared to 73% in patients over 60 years in the PHOENIX trial), and toxicities—under strongly recommended quadruple prophylaxis (G-CSF, ciprofloxacin, acyclovir, cotrimoxazole)—beyond those expected from R-CHOP were moderate and mostly grade 1 + 2 (71%, compared to 29% grade 3 + 4). No grade 5 toxicities were observed during treatment and within 30 days after end of therapy. First results from whole exome and RNA sequencing analyses are currently being obtained. Conclusions: The ibrutinib + bortezomib extension of R-CHOP is feasible and effective in this elderly higher-risk all-comer first-line population. Our meeting report will give an updated analysis of treatment outcome, first insights into candidate molecular response signatures, and shed light on potential underlying modes of biological action. With two years of median follow-up, we will be able to compare the cohort with prior study populations (RICOVER-60, REMoDL-B and PHOENIX). The research was funded by: The ImbruVeRCHOP trial is an investigator-initiated study, which was partly funded by Janssen-Cilag. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. U. Keller Other remuneration: reports personal fees from Janssen Cilag, outside the submitted work (Advisory board fees, speakers honorary, and travel support) R. Marks Consultant or advisory role: participated in an Advisory board with Janssen-Cilag C. A. Schmitt Honoraria: receives honoraria for medical advice from Roche and Janssen-Cilag Research funding: coordinates clinical research (namely the ImbruVeRCHOP trial) partly funded by Janssen-Cilag