Next-Gen BCL-2 Inhibitor Shows Deep Responses in Myeloma

Multiple myeloma multiplex: © LASZLO - stock.adobe.com

The next-generation BCL-2 inhibitor sonrotoclax (BGB-11417) plus dexamethasone led to safety, antitumor activity, and early responses in patients with heavily pretreated, relapsed/refractory multiple myeloma harboring t(11:14), according to updated safety and efficacy data from the phase 1b/2 BGB-11417-105 study (NCT04973605) shared at the 21st International Myeloma Society Annual Meeting.¹

The combination generated an overall response rate (ORR) of 75% (95% CI, 53%-90%) in the efficacy evaluable population (n = 24), 50% (95% CI, 29-71) of which were very good partial responses or better and 21% (95% CI, 7%-42%) of which were complete responses (CR) or stringent CRs. Additionally, 13% of patients achieved a best overall response of minor response and 13% achieved stable disease. Of the patients who achieved a CR (n = 4) or sCR (n = 1), 2 went on to demonstrate minimal residual disease negativity based on a threshold of 10-5 using a flow cytometry assay.

The median time to response (TTR) was 0.7 months and the median duration of response (DOR) was 8 months (95% CI, 4-not evaluable). Ten patients improved upon their first response and the longest DOR lasted 18 months. A total of 2 patients spent over 1 year on treatment.

Regarding safety, 87.5% of patients (n = 32) experienced any-grade treatment-emergent adverse effects (TEAE), 31.3% experienced grade 3 or higher TEAEs, 18.8% suffered from serious TEAEs, and 3.1% of patients experienced a TEAE leading to death.

“These results indicate that sonrotoclax plus dexamethasone is well tolerated in a heavily pretreated population, [as the] sonrotoclax plus dexamethasone combination provided deep and durable responses in this relapsed/refractory population,” lead study author, Abel Costa, MD, of the D'Or Institute of Research and Teaching and D'Or Oncology group, in São Paulo, Brazil, reported in an oral presentation of the data.

Patients with multiple myeloma who present with t(11:14)—which occurs in approximately 15% to 20% of patients—often exhibit high expression of BCL2, which is a therapeutic target in this disease. It is thought that due to the disease’s responsiveness to BCL-2 inhibitors, combining these agents with dexamethasone or a proteosome inhibitor have the potential to improve clinical outcomes in patients compared with treatment of a BCL-2 inhibitor alone.

Despite their potential utility, no BCL2-targeted therapies have received FDA approval for the treatment of patients with multiple myeloma. Therefore, investigators evaluated sonrotoclax in combination with dexamethasone, which has demonstrated tolerability in multiple myeloma.

Understanding the Study Design and Patient Population

The ongoing, open-label, multicenter dose-escalation study serves as the backbone for various combination therapies of dexamethasone and standard-of-care agents in patients with relapsed/refractory myeloma harboring t(11;14). Part 1a of the investigation comprises the dose-escalation portion. Treatment began at a starting dose of 80 mg of sonrotoclax (dose 1; n = 3) and was escalated to 160 mg (dose 2, n = 3), 320 mg (dose 3, n = 3), and 640 mg (dose 4; n = 10), the latter of which was recognized as the recommended dose for expansion (RDFE). Part 2b of the investigation is evaluating sonrotoclax at the 640 mg dose in combination with 40 mg of dexamethasone (n = 35).^1,2

The study’s primary end points were safety and ORR. Secondary end points included pharmacokinetics, DOR, TTR, progression-free survival, and overall survival.

As of March 25, 2024, 32 patients were treated with the RDFE of sonrotoclax plus dexamethasone (part 1, n = 10; part 2, n = 22), with a median follow-up of 4.6 months (range, 0.1-19). However, 10 patients discontinued treatment due to disease progression (n = 6), AEs (n =2), patient withdrawal (n = 1), and physician decision (n = 1).¹

The median age of patients enrolled onto the study was 69 years (range, 48-80); 46.9% of those enrolled were male, and participants had an ECOG performance status of 0 (43.8%), 1 (50%), or 2 (6.3%). Patients had a Revised International Staging System stage at diagnosis of I (15.6%), II (53.1%), III (12.5%), or unknown (18.8%) at initial diagnosis. The median time from most recent relapsed/refractory episode to first dose was 1.9 months (0.4-93.8). Notably, 28.1% of patients also had high cytogenic risk; 68.8% were not deemed high risk, and 3.1% were unknown.

The median prior lines of systemic therapy was 3 (range, 1-12), with the majority of patients being treated with 3 or more lines (65.6%). Notably, all patients had prior exposure to a proteasome inhibitor (PI) and immunomodulatory drugs (IMiDs), and 71.9% of patients had exposure to an anti-CD38 antibody. A total of 71.9% of patients were exposed to at least 1 line of all 3 treatments. Furthermore, 56.3%, 71.9%, 56.3% and 46.9% of patients were refractory to PIs, IMiDs, anti-CD38 antibodies, and all 3 treatments, respectively. Prior autologous stem cell transplant was administered to 62.5% of patients.

Additional Safety Data

Two patients died on the study, 1 of whom experienced a new diagnosis of treatment-emergent metastatic pancreatic cancer and the other who experienced non–TEAE-related death due to liver failure from hepatocellular carcinoma 5 months after study discontinuation. These deaths were not deemed related to the study drug. Serious TEAEs were reported in 19% of patients, and 31% experienced grade 3 or higher TEAEs. No dose-limiting toxicities were experienced during the first 21 days of part 1.

Furthermore, 21.9% of TEAEs led to dose interruption of either drug (sonrotoclax, 18.8%; dexamethasone. 15.6%), 31.3% led to dose reduction (0%; 31.3%), and 9.4% to treatment discontinuation (6.3%; 9.4%).

Costa added that the most common any-grade TEAEs were fatigue and insomnia (each 28.1%), diarrhea (1.9%), and constipation and nausea (each 15.6%).

Hematologic TEAEs occurred in 12.5% of patients in the form of grade 1 and 3 platelet count decrease (6.3%), and grade 3 neutrophil count decrease (3.1%), and grade 3 thrombocytopenia (3.1%). There were low rates of infection, with any infection occurring in 21.9% of patients. Common infections included COVID-19 (6.3%), upper respiratory tract infection (6.3%), influence, (3.1%), and lower respiratory tract infection (3.1%).

“The study is ongoing and other combination treatments with sonrotoclax are being investigated,” Costa concluded.

Disclosures: Dr Costa reports consultancy, travel, accommodations, and expense relationships with Janssen, as well as research funding from Janssen, AbbVie, BeiGene, Roche, Regeneron, and AstraZeneca.

REFERENCES:

1. Costa A, Dhakel B, Hultcrantz M, et al. Sonrotoclax plus dexamethasone was tolerable and demonstrated antimyeloma activity in patients with relapsed/ refractory multiple myeloma harboring t(11;14).Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-58.

2. A phase 1b/​2 study of BGB-11417 in monotherapy and in various combinations with dexamethasone and carfilzomib in multiple myeloma. ClinicalTrials.gov. Updated August 19, 2024. Accessed September 30, 2024. https://clinicaltrials.gov/study/NCT04973605