Sonrotoclax (BGB-11417)

As of Jan 20, 2025, 14 and 36 evaluable pts were enrolled in the sonro 320-mg and 640-mg cohorts, respectively; median (range) follow-up was 6.2 mo (2.6-34.5) and 12.1 mo (0.1-28.9), respectively. The median (range) prior lines of tx were 3 (1-7) in the 320-mg cohort and 3 (1-12) in the 640-mg cohort; 78.6% and 66.7% of pts were refractory to 3 tx classes, respectively. At data cutoff, 7 pts (50.0%) in the 320-mg cohort and 14 (38.9%) in the 640-mg cohort remained on tx; progression was the most common reason for discontinuation (35.7% and 41.7%, respectively). The ORR (95% CI) was 64.3% (35.1-87.2) in the 320-mg cohort and 80.6% (64.0-91.8) in the 640-mg cohort, with VGPR or better rates (95% CI) of 35.7% (12.8-64.9) and 55.6% (38.1-72.1), respectively. The median time to response was 0.7 mo in both cohorts. Median (95% CI) duration of response was 5.9 mo (1.8-not estimable [NE]) in the 320-mg cohort and 12.2 mo (8.3-18.9) in the 640-mg cohort. Median (95% CI) PFS was 6.6 mo (2.9-NE) in the 320-mg cohort and 13.3 mo (9.0-19.6) in the 640-mg cohort. IMS 2025 The most common TEAEs were fatigue (35.7%) in the 320-mg cohort, and insomnia (38.9%) and diarrhea (38.9%, all grade 1/2) in the 640-mg cohort. Grade ≥3 TEAEs occurred in 5 pts (35.7%) in the 320-mg cohort and 17 pts (47.2%) in the 640-mg cohort; serious TEAEs occurred in 3 (21.4%) and 10 (27.8%), respectively. Grade ≥3 hematologic TEAEs occurred in 1 (7.1%) and 9 (25.0%) and grade ≥3 infections in 3 (21.4%) and 4 (11.1%) pts, respectively. Two pts (14.3%) in the 320-mg cohort and 2 (5.6%) in the 640-mg cohort died during the tx-emergent part for reasons unrelated to tx (320 mg, pneumonia RSV and COVID-19; 640 mg, hypoventilation [related to pulmonary involvement with PD] and metastatic pancreatic cancer). Four more deaths occurred >30 d after the last 640-mg dose.

As of May 26, 2023, 19 patients have been enrolled in the 80-, 160-, and 320-mg (n=3 each) and 640-mg (n=10 patients) dose-escalation cohorts. The median age was 68 years (range, 52-81 years). The median prior lines of therapy was 4 (range, 1-12) and 11 patients (58%) failed on a prior anti-CD38 antibody. The most common AEs (>20% of all patients) were insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%); none of which were severity grade ≥3. Three patients (16%) experienced grade ≥3 treatment-emergent AEs (TEAEs). One patient (33%) in the 160-mg cohort had grade 3 increases in liver enzymes and diarrhea; one patient (10%) in the 640-mg cohort had a grade 3 decrease lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment. Three patients experienced COVID-19 (grade 1-2, n=2; grade ≥3, n=1). Three patients experienced TEAEs that led to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No patient, across all dose levels tested, experienced a DLTs; thus, sonrotoclax 640 mg daily was the determined to be the MAD and the RP2D in combination with dexamethasone.

Four patients (21%) died while on study; however, no deaths were determined by the investigators to be associated with study treatment. One patient died from COVID-19 while receiving study therapy; three additional patients died ≥50 days after treatment discontinuation (COVID, progressive disease, and unknown causes, n=1 each).

With a median treatment duration of 120 days (range, 30-526), ORR was 58%; 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]; Figure). The ORR for the 640-mg cohort was 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). Nine patients remained on treatment; the longest duration of response was 483 days (20 cycles) which, at data cutoff, was still ongoing.

Results: As of May 16, 2025, a total of 20 patients were enrolled and had been treated in 1 of 3 cohorts: sonrotoclax 320 mg + K56 + dex (n=11), sonrotoclax 320 mg + K70 + dex (n=7), or sonrotoclax 640 mg + K56 + dex (n=2; enrollment ongoing). The median follow-up in all patients was 7.3 months (range, 1.7-22.2 months). Across cohorts, the median age was 65 years (range, 51-77 years), 75% were male, and 50% were White. Patients had a median of 4 prior lines of therapy (range, 2-8); 65% of patients had ≥4 prior lines, 85% were triple-class exposed, and 20% were triple-class refractory. At data cutoff, 13 patients (65%) remained on study treatment; 6 patients discontinued due to disease progression, and 1 withdrew consent. The most common all-grade treatment-emergent adverse events (TEAEs) were insomnia (40%), fatigue (35%), nausea (30%), anemia (30%), and back pain (30%). Grade ≥3 TEAEs occurred in 12 patients (60%), grade ≥3 hematologic TEAEs occurred in 7 (35%), and grade ≥3 infections occurred in 5 (25%). Cardiac disorders occurred in 3 patients (15%; grade 2 arrhythmia, n=1; grade 2 atrial flutter, n=1; grade 1 tachycardia, n=1), and hypertension in 4 patients (20%; grade 1/2, n=2; grade 3, n=2). Eight patients (40%) experienced a serious TEAE; the most common serious TEAE was pneumonia (15%). Dose-limiting toxicities were reported in 2 patients (transient grade 3 thrombocytopenia and acute kidney injury). No TEAEs led to death, sonrotoclax discontinuation, or sonrotoclax dose reduction. Four patients died during the study, all for reasons unrelated to study treatment. In 19 response-evaluable patients across dose groups, the ORR was 84% (95% CI, 60%-97%), which included 32% (95% CI, 13%-57%) of patients with a complete response (CR)/stringent complete response (sCR). The median time to response was 1.0 months (range, 0.9-6.1 months). Median duration of response and median progression-free survival were not reached.

Conclusions: Sonrotoclax + K + dex combination therapy demonstrated a tolerable safety profile and encouraging antimyeloma activity, with an 84% ORR and a 32% CR/sCR rate in heavily pretreated patients with t(11;14)-positive R/R MM. Enrollment in BGB-11417-105 is ongoing, and additional treatment combinations with sonrotoclax are being investigated.