Chronic Lymphocytic Leukemia | stock.adobe.com
Treatment with the combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) led to responses and was well tolerated in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from the phase 1/1b BGB-11417-101 study (NCT04277637) presented at the 2024 ASH Annual Meeting.1
At week 48, the combination of standard dose zanubrutinib plus 160 mg or 320 mg sonrotoclax elicited an overall response for 100% of patients. At the 160 mg dose, this consisted of 60% partial responses (PR) and 40% complete responses (CR) or CR with incomplete count recovery (CRi). In the 320-mg sonrotoclax group, 58% of patients had a PR and 42% had a CR/CRi. Responses were accompanied by rapid achievement of minimal residual disease (MRD), with 24% and 14% reaching MRD at a sensitivity of 10-4 or greater (MRD4+) or 59% and 78% reaching undetectable MRD4 (uMRD4) in the 160-mg and 320-mg sonrotoclax dose arms, respectively, by week 24.
"Substantial efficacy was observed in this all-comer treatment-naive CLL population, with higher rates of response and uMRD4 including in patients with high-risk features," lead investigator Jacob D. Soumerai, MD, Massachusetts General Hospital Cancer Center and Harvard Medical School, said during a presentation of the results. "These data support evaluation of sonrotoclax at 320 mg in combination with zanubrutinib at the approved dose in patients with treatment CLL."
Sonrotoclax is a second-generation BCL2 inhibitor with higher potency than the first-generation BCL2 inhibitor venetoclax (Venclexta), Soumerai said. Sonrotoclax has a shorter half-life with no drug accumulation. These features are thought to improve its toxicity profile. Additionally, the BTK inhibitor zanubrutinib was shown to be superior to ibrutinib (Imbruvica) for CLL,2 further boosting the efficacy potential of the combination.
"Toxicities can limit use of this BCL2/BTK combinations and there remains a need to further improve efficacy," said Soumerai. "For this reason, there's an ongoing need to develop novel combinations of next-generation BCL2 inhibitors."
In the dose-finding study, sonrotoclax was explored in several combinations and as a monotherapy. Data presented at ASH were from the expansion cohort looking at sonrotoclax and zanubrutinib. For the dosing, zanubrutinib was in an 8-to-12-week lead-in period at 320 mg every day or 160 mg twice daily (320 mg total). This dose was continued through the combination period, wherein sonrotoclax was administered at either 160 mg (n = 51) or 320 mg daily (n = 86). The study ran for a fixed duration and at 96 weeks, participants could opt to discontinue therapy. The median follow-up at the time of the analysis was 19.4 months (range, 0.4-33.3 months).
Across both dose groups, the median age of patients was 62 years, with 40.1% being over the age of 65 years. The disease was most commonly CLL (94.9%) with the remainder of patients having SLL. High-risk features included del(17p) for 9% of patients, TP53 mutations for 22.0%, and del(11q) for 17.2%. There were slightly more patients with del(17p) and TP53 mutations in the 160-mg sonrotoclax arm than the 320-mg arm (11.1% vs 7.8% and 23.4% vs 21.0%, respectively). More patients with unmutated IGHV were enrolled in the 160 mg group (68.1% vs 53.3%). Additionally, more patients had high tumor bulk at baseline in the 160 mg arm (43.1% vs 20.7%).
At week 24, 59% of those in the 160 mg dose arm of sonrotoclax had uMRD4 and 24% had MRD4+. In the 320 mg dose, the uMRD4 rate was 78% and the MRD4+ rate was 14%. By week 48, the MRD4+ rate was 13% and the uMRD4 rate was 82% in the 160 mg dose group. For the 320 mg dose, the MRD4+ rate was 9% and the uMRD4 rate was 91%. At the analysis, no cases of uMRD4 had switched to MRD4+.
"We think we are seeing more MRD because it is more potent. This of course requires additional confirmation," said Soumerai.
After a median follow-up of 19.4 months, there had been just 1 case of progression in the lower dose cohort. This progression event was a Richter's transformation at 8 months. All other enrolled patients remained alive and progression free.
The median exposure for those receiving the 160 mg dose of sonrotoclax was 18.7 months compared with 19.3 months for the 320 mg dose of sonrotoclax. Treatment-emergent adverse events (TEAEs) were experienced by 100% of those in the 160 mg dose compared with 89.5% of those in the 320 mg arm. Grade 3 or higher TEAEs were seen in 56.9% of those in the 160 mg arm compared with 45.3% of those in the 320 mg group. Serious TEAEs were experienced by 25.5% of patients treated with the 160 mg dose of sonrotoclax compared with 23.3% of patients receiving the larger dose.
TEAEs leading to discontinuation were rare, with just 5 patients discontinuing therapy. Dose reductions were also rare, with a median of 99.0% of patients receiving the full dose intensity. At the data cutoff, 19 patients were still in the zanubrutinib alone lead-in period. There were no cases of tumor lysis syndrome detected in the study.
The most observed TEAE was neutropenia, which was experienced by 50% of patients in the 160 mg group and by 29% in the 320 mg group. The rate of grade 3/4 neutropenia was 24% in the 160 mg arm and 23% in the 320 mg group. In general, Soumerai noted, the neutropenia was transient and did not result in high rates of grade 3/4 infection. Grade 1/2 COVID-19 was seen in 37% of those in the 160 mg dose and for 21% of those in the 320 mg arm. Grade 1/2 upper respiratory tract infection was seen in 20% of those in the 160 mg group and in 23% of those in the 320 mg group.
The phase 3 CELESTIAL-TNCLL trial is currently enrolling to explore the combination further in treatment-naive patients with CLL. In the study, the 320 mg dose of sonrotoclax is being combined with standard zanubrutinib compared with venetoclax plus obinutuzumab (Gazyva). The study anticipates enrolling 640 participants and anticipates a primary completion in 2032 (NCT06073821).
References
Soumerai JD, Cheah CY, Anderson MA, et al. Sonrotoclax and zanubrutinib as frontline treatment for CLL demonstrates high MRD clearance rates with good tolerability: data from an ongoing phase 1/1b Study BGB-11417-101. Blood. 2024;144(suppl 1):1012. doi:10.1182/blood-2024-199175
Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388(4):319-332. DOI: 10.1056/NEJMoa2211582