KEY TAKEAWAYS
- The phase 1 and 2 trials aimed to test the initial safety and tolerability assessment of escalating sonrotoclax doses combined with dexamethasone in R/R MM (t(11;14)) patients.
- The result demonstrated that sonrotoclax plus dexamethasone showed favorable tolerability and promising efficacy.
B-cell lymphoma-2 (BCL2) family proteins emerge as promising therapeutic targets in multiple myeloma (MM), crucial for cell survival. The previous study results demonstrated that in relapsed/refractory (R/R) MM with t(11;14) patients(pts) and failed prior therapies, the first-generation BCL2 inhibitor venetoclax displayed anti-myeloma effects.
Dexamethasone, a longstanding MM treatment, elevates BCL2 and Bim expression, heightens the reliance on BCL2 for tumor survival, and amplifies sensitivity to BCL2 inhibitors.
Sonrotoclax (BGB-11417), a potent BH3 mimetic, binds and inhibits BCL2 more than 10 times the potency of venetoclax in biochemical assays.
In the ongoing phase 1b/2 trial, Hang Quach and her research group conducted a study that aimed to assess the safety and efficacy of sonrotoclax as monotherapy, combined with dexamethasone or with dexamethasone plus carfilzomib in R/R MM pts with t(11;14). Preliminary data from the dose-escalation (DE) cohorts of sonrotoclax plus dexamethasone are reported here.
In the interventional study, pts eligible for the trial have R/R MM t(11;14) abnormality, confirmed centrally. They have undergone 1-7 prior treatments, including exposure to a proteasome inhibitor and an IMiD agent. In the DE phase, pts received daily doses of sonrotoclax at 80, 160, 320, or 640 mg along with 40 mg of dexamethasone weekly until intolerability, disease progression, or death.
In the DE cohorts, the main objectives were to evaluate the overall safety/tolerability, determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD), and establish the recommended phase 2 dose (RP2D). Adverse events (AEs) were documented according to CTCAEs v5.0. Safety assessments were conducted by a safety monitoring committee (SMC) within a 21-day dose-limiting toxicity (DLT) window for each cohort, utilizing a modified toxicity probability interval method (mTPI-2). Disease responses were evaluated based on the International Myeloma Working Group 2016 criteria.
Around 19 pts were enrolled in the dose-escalation cohorts with 3 pts each in the 80-, 160-, and 320-mg groups and 10 pts in the 640-mg group. The median age of the pts was 68 years (range, 52-81 years), and the median prior lines of therapy were 4 (range, 1-12). Among the enrolled pts, 11 (58%) had previously failed on a prior anti-CD38 antibody.
The most frequently reported AEs occurring in more than 20% of all pts included insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%). None of these events reached a severity grade ≥3. Grade ≥3 treatment-emergent AEs (TEAEs) were observed in 3 pts (16%): 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 in lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment.
COVID-19 events were reported in 3 pts, with 2 experiencing grades 1-2 and 1 experiencing grades≥3. Three pts had TEAEs leading to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No DLTs were observed across all tested dose levels. Consequently, sonrotoclax 640 mg daily was determined to be the maximum administered dose (MAD), and the RP2D in combination with dexamethasone.
In the study, 4 pts (21%) died, and none of the deaths were deemed by investigators to be associated with the study treatment. One patient died from COVID-19 while receiving study therapy, and three additional pts died more than or equal to 50 days after treatment discontinuation (due to COVID-19, progressive disease, and unknown causes; n=1 each).
Among pts treated with sonrotoclax plus dexamethasone for a median of 120 days (range 30-526 days), an overall response rate (ORR) of 58.00% was achieved: 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]). Notably, the ORR was even higher in the 640mg cohort at 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). At data cutoff, 9 pts continued treatment, with the longest ongoing response lasting 483 days (20 cycles).
The study concluded that the combination of sonrotoclax and dexamethasone demonstrated good tolerability in patients with R/R MM characterized by t(11;14) translocation, even at doses as high as 640 mg. Initial findings indicated promising safety and efficacy outcomes. Based on these results, the SMC has endorsed using 640 mg with dexamethasone as the RP2D. Ongoing recruitment is focused on evaluating the dose-finding arms of sonrotoclax in combination with dexamethasone and carfilzomib and exploring the indication expansion cohort for sonrotoclax plus dexamethasone. This study is sponsored by BeiGene.
Source: https://ash.confex.com/ash/2023/webprogram/Paper178735.html
Clinical trial: https://clinicaltrials.gov/study/NCT04973605
Quach H, Sborov D, Kazandjian D, et al. “Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose” Presented at ASH 2023. (Abstract: 1011)
