Phase 2 study of ibrutinib with temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (teddi‐r) for secondary cns lymphoma

Introduction: PCNSL has BCR signaling that responds to BTKi but the molecular profile of SCNSL is heterogeneous. TEDDi-R was developed to achieve therapeutic CNS levels of potentially curative agents. We present results of ibrutinib with TEDD-R in SCNSL to characterize the molecular correlates of BTKi response and overall treatment efficacy (NCT03964090). Methods: Pts with untreated or recurrent B-cell lymphoma with CNS ± systemic involvement were eligible. Pts first received ibrutinib 560 mg × 14d in a window. Pts with ≥20% reduction after ibrutinib received TEDDi-R; those with <20% reduction received TEDD-R. Therapy was 4 cycles × 21d with IT therapy (no maintenance) and mostly outpatient. All pts received isavuconazole. Response was assessed after cycles2, 4. CR was confirmed with PET brain/body and CSF. Results: 49 pts enrolled; 17 (35%) were female with median age 62 (range 26–89) and 15 (31%) aged ≥70. 27 (55%) had DLBCL including 20 (41%) non-GCB, 5 (10%) GCB, 1 (2%) PMBL, and 1 (2%) unknown. 16 (33%) had HGBL including 10 (20%) with MYC-R and BCL2-R and 6 (12%) with MYC-R and BCL6-R. 2 (4%) pts each had MCL and EBV-LPD, while 1 pt each had plasmablastic (2%) and BL (2%). 28 (57%) had synchronous CNS/peripheral dz while 21 (43%) had isolated CNS. 5 (10%) were untreated while 44 (90%) had a median of 2 (range 1–4) prior therapies. Of rel/ref pts, 44 (100%) had anthracycline, 28 (64%) had HD-MTX, 19 (43%) had CNS prophylaxis, and 8 (18%) had CAR-T. Of 42 pts who completed the ibrutinib window, 24 (57%) were ibrutinib-responsive and 17 (43%) were ibrutinib-resistant (Figure A). After TEDDi-R (N = 26), the ORR was 92% and CR rate was 77%. After TEDD-R (N = 18), the ORR was 45% and CR rate was 28%. G3/G4 neutropenia occurred in 29% and 40% of cycles, while FN occurred in 10%. G3/G4 thrombocytopenia occurred in 30% and 12% of cycles. 30 (63%) pts received blood and 18 (38%) received platelet transfusion. Other G3 AEs included UTI (21%), hypokalemia (21%), sepsis (15%), diarrhea (15%), hypotension (11%), anorexia (11%), and adrenal insufficiency (11%). No opportunistic infections were observed. 14 (30%) pts had hand-foot syndrome and 4 (9%) had G3 afib. After a median follow-up of 23m, the 1-year PFS and OS was 36.7% and 60.8%. 15 (83%) deaths were due to progression while 1 (2%) was related to treatment. A landmark analysis after the window showed the 1-year PFS and OS for pts with ibrutinib-responsive versus ibrutinib-resistant tumors was 54.7% versus 17.6% (p < 0.002) (Figure B) and 76.7% versus 47.1% (p = 0.08). 88% of ibrutinib-responsive tumors were CD10 neg. Pts with CD10 neg tumors had an ORR of 83%, and a 70% rate of CR. The 1-year PFS and OS for pts with CD10 neg tumors was 48.0% and 64.7% The research was funded by: The Intramural Research Program of the National Institutes of Health Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, molecular targeted therapies Conflicts of interests pertinent to the abstract K. Dunleavy Consultant or advisory role: Astra Zeneca, Amgen, Beigene, Kite, ADC Therapeutics, Cellectar Research funding: ONO Pharmaceuticals, Genentech, Kymera