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Entospletinib Plus Obinutuzumab Brings Favorable Outcomes in R/R CLL
Findings of a single arm, open-label, phase 1/2 clinical trial on the safety and efficacy of SYK inhibitor entospletinib in combination with obinutuzumab, a glycoengineered monoclonal anti-CD20 antibody, in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL); this data was presented at the 2021 American Society of Hematology (ASH) Annual Meeting.
“Therapeutic resistance and intolerance of Bruton tyrosine kinase (BTK) inhibitors is an emerging need in CLL. SYK is integral to the activation of BTK, and the B-cell receptor (BCR) signaling cascade and is overexpressed in CLL,” explained Alexey Danilov, MD, PhD, City of Hope Comprehensive Cancer Center, Duarte, California, and co-researchers.
Researchers have demonstrated that BAFF-mediated SYK activation triggered BCR signaling and rendered protection of CLL cells from spontaneous apoptosis in vitro. Further, the single agent small molecule SYK inhibitor entospletinib was effective in the treatment of patients with R/R CLL.
The recommended phase 2 dose was established in the phase 1 portion of the study, with the dose level being entospletinib 400 mg twice daily in combination with obinutuzumab. Overall, 21 patients with CLL were enrolled. In the phase 1 portion, out of 6 patients who received entospletinib 200 mg, 1 patient experienced a dose-limiting toxicity (DLT). However, no DLTs were observed among 6 patients who received 400 mg.
The primary endpoint of the trial was complete response (CR).
The median age of all patients was 66 years old. Out of 21 total patients, 13 patients (62%) had TP53 aberration (n=9), complex karyotype (n=6), or NOTCH1 or SF3B1 mutation. The median number of prior therapies was 2, with 7 receiving prior ibrutinib (4 discontinued due to intolerance, and 2 due to progression). The median follow-up time was 31 months.
“Among the 21 efficacy-evaluable patients with CLL, the ORR was 67% (95% CI, 43% to 85%). Three patients (95% CI, 3% to 36%) achieved a CR, and 11 patients (53%) had a partial response (PR). Patients with confirmed CR had undetectable minimal residual disease (MRD) in bone marrow,” continued Dr Danilov and co-authors.
The median event-free survival (EFS) time was 27.5 months (95% CI, 16 months-NR), treatment duration was 31 months (95% CI, 27-40 months), and 13 patients with high-risk CLL had an ORR of 54 percent (5 PRs and 2 CRs). Among the 8 patients who received prior kinase inhibitors, the ORR was 62.5 percent (all PRs).
Treatment-related adverse events (AEs) were reported in 96% of patients. Grade ≥3 AEs occurred in 65%. Neutropenia (43.5%; included 4 patients [17%] who had transient grade 4 neutropenia attributed to obinutuzumab) was the most common grade ≥3 hematologic activity. The median onset of neutropenia was 7 days after the first obintuzumab infusion, with the median duration at 28 days.
“Thus, the combination of entospletinib and obintuzumab shows an acceptable safety profile. Efficacy of this combination (EFS 27.5 months in predominantly high-risk population) compares favorably with obinutuzumab in R/R CLL (13 months), warranting continued exploration of the regimen,” concluded Dr Danilov, et al.—Alexa Stoia
Danilov A, Lam V, Thurlow B, et al. Final Results of a Phase ½ Study of SYK Inhibitor Entospletinib in Combination with Obintuzumab in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 2643.
