DP003 | COMBINATION TREATMENT WITH NOVEL BCL2 INHIBITOR SONROTOCLAX (BGB-11417) AND ZANUBRUTINIB INDUCES HIGH RATE OF COMPLETE REMISSION FOR PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA

BACKGROUND: Sonrotoclax (sonro; BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax. Zanubrutinib (zanu), a next-generation BTK inhibitor (BTKi), is approved for R/R MCL. Updated safety and efficacy of sonro + zanu in R/R MCL in the ongoing BGB-11417-101 (NCT04277637) study are reported. METHODS: Patients (pts) with ≥1 prior treatment [tx] for MCL received zanu (320 mg QD/160mg BID) 8-12 wk before sonro ramp-up to the target dose (80, 160, 320, or 640mg QD) to prevent tumor lysis syndrome (TLS) risk; tx continued until progressive disease (PD)/unacceptable toxicity. Dose expansion occurred at 160 and 320 mg. The primary endpoint was safety (CTCAE v5.0); a secondary endpoint was ORR per 2014 Lugano classification. RESULTS: As of 6 Dec 2024, 49 pts with R/R MCL were enrolled and treated (sonro 80 mg, n=6; 160 mg, n=13; 320 mg, n=25; 640 mg, n=5): 7 were in zanu lead-in; 42 started sonro. Pts had a median of 1 prior tx (range, 1-4; stem cell transplant, n=15 [1 allogeneic, 14 autologous]; CAR T-cell therapy, n=1; BTKi, n=3). Median follow-up was 16.2 mo (range, 0.6-39.7). MTD was not reached up to sonro 640mg; the RP2D was 320 mg. Overall, 20 pts (40.8%) discontinued (d/c) ≥1 tx: 7 d/c zanu only (5 PD during zanu lead-in; 2 AE [diarrhea, meningitis]); 13 d/c sonro + zanu (8 PD, 4 AE [myelodysplastic syndrome, pneumonia, diarrhea, abdominal sepsis], 1 pt withdrawal). Eight pts died due to PD (4 during zanu lead-in). Tx-emergent AEs (TEAEs) in ≥30% of pts were contusion, COVID-19, diarrhea, and neutropenia (30.6% each). The most common grade ≥3 TEAE was neutropenia (20.4%). No laboratory or clinical TLS occurred. No atrial fibrillation/flutter or ventricular arrhythmia occurred. TEAEs led to 2 deaths (4.1%; 1 pneumonia, 1 abdominal sepsis [not tx-related]). In 45 evaluable pts across doses, ORR was 77.8% (CR, n=28; 62.2%) (Figure). Median time to CR was 6.7 mo; at data cutoff, 89% (25/28) remained in CR. In the 160 and 320mg expansion cohorts (median follow-up, 16.2 and 12.9 mo, respectively), ORR was 76.9% (CR, n=7; 53.8%) and 76.2% (CR, n=13; 61.9%), respectively. Two of 3 evaluable pts with prior BTKi tx had partial responses and 1 had PD. CONCLUSIONS: Sonro + zanu was well tolerated and had encouraging antitumor activity, with a CR rate of 62.2%, and responses in pts with prior BTKi tx. A registrational phase 3 study (NCT06742996) with sonro 320mg + zanu is recruiting.