SAKK 36/13 ‐ IBRUTINIB PLUS BORTEZOMIB AND IBRUTINIB MAINTENANCE FOR RELAPSED AND REFRACTORY MANTLE CELL LYMPHOMA: FINAL REPORT OF A PHASE I/II TRIAL OF THE EUROPEAN MCL NETWORK (2021)

Introduction: Mantle-cell lymphoma (MCL) remains incurable with frequent relapses, limited treatment options and progressively shorter disease-free survival with every relapse. The Bruton's tyrosine kinase inhibitor ibrutinib (IBR) and the proteasome inhibitor bortezomib (BOR) have single agent activity and regulatory approval in MCL. IBR and BOR lead to a downregulation of NF-κB activity via different targets. IBR resistance involves mutations in genes of the NF-κB pathway. In vitro, the combination of both drugs provides synergistic cytotoxicity in BOR-sensitive and refractory MCL. Methods: In this investigator-initiated trial, we included patients (pts.) with histologically confirmed MCL, refractory/relapsed after ≤2 lines of a non-BOR-containing chemotherapy (incl. high-dose chemotherapy), and excluded pts. with prior BOR or IBR therapy, with CNS disease, in need of anticoagulation, or active Hepatitis B, C or HIV infection. Pts. received 6 21-days cycles of IBR + BOR, followed by IBR until progression or unacceptable toxicity. The dose of the combination was established with 9 pts. in the phase I part: BOR s.c. 1.3 mg/m2, days 1, 4, 8, 11 q3w, and IBR continuously at 560 mg/day. The primary endpoint of the phase II was the overall response rate (ORR) based on CT/MRI (Cheson, 1999). The null hypothesis was an OR ≤ 65%. Data on secondary endpoints were collected until January 18, 2021. Results: Since August 2015, 58 pts. received IBR+BOR (9 in phase I (4 Swiss sites), and 49 in 11 additional sites in Switzerland, Germany and Italy). The median age was 71 (47-90), 78% were male. The ORR in 55 pts. (including those that received 560 mg IBR in phase I) to the combination was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.9%). With continued IBR (median 6 months (M)), the ORR increased to 87.3% (90% CI 77.4, 93.9%, CR(u) 43.7%). 31/55 pts. (56.4%) had at least one high-risk feature. In these, IBR+BOR was also effective (ORR 79% (90% CI 62, 90%), n = 28) for Ki-67 >30%, ORR 73% (90% CI 44, 92), n = 11) for p53 overexpression by immunohistochemistry (>50%, suggestive for mutations), and 67% (90% CI 34, 90%), n = 9) for the blastoid/pleomorphic variants), and not different in terms of time to best response from pts. with low risk features. With a median follow-up of 24.4M, the median duration of response was 22.7M (95% CI 12.3, NA), and the median PFS was 18.6M (95% 12.4, NA). All pts. had at least one adverse event (AE), which was grade (G)3 in 67.3%, and G4 in 21.8%. G3 infections (25%) and G4 hematotoxicity (16.4%) were the most frequent AEs during the combination. Neurotoxicity, mostly G1&2 occurred in 14.5%. Conclusions: The combination of Ibrutinib and Bortezomib shows significant and durable efficacy in relapsed mantle-cell lymphoma, importantly also in patients with high-risk features. In this setting, this regimen is a rational comparator regimen for a future phase III trial. (ClinicalTrials.gov Identifier: NCT02356458) The research was funded by: Janssen-Cilag Keywords: Combination Therapies Conflicts of interests pertinent to the abstract U. Novak Consultant or advisory role: Janssen-Cilag, Celgene (BMS), Takeda, Astra Zeneca, Roche, Novartis, Gilead, Pierre Fabre Honoraria: Celgene (BMS), Novartis M. Dreyling Consultant or advisory role: Astra Zeneca, Bayer, Beigene, Celgene, Gilead, Janssen, Novartis, Roche Honoraria: Bayer, Celgene, Gilead, Janssen, Roche Research funding: Abbvie, Bayer, Celgene, Janssen, Roche U. Mey Consultant or advisory role: Janssen-Cilag S. Ferrero Consultant or advisory role: Janssen Honoraria: Janssen Research funding: Janssen S. Böttcher Honoraria: Roche, AbbVie, Janssen, Astra- Zeneca, Sanofi Research funding: Janssen-Cilag Neuss, Becton Dickinson Heidelberg C. Renner Consultant or advisory role: Janssen-Cilag Honoraria: Janssen-Cilag