A phase 1b study found acalabrutinib, a highly selective next-generation BTK inhibitor, plus anti-STAT3 allele-specific oligonucleotide AZD9150, is safe and tolerable for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but has limited efficacy; these findings were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Patients with R/R DLBCL after prior autologous stem cell transplant (ASCT) or chimeric antigen receptor T-cell (CAR-T) therapy have poor outcomes with limited treatment options,” said Mark Roschewski, MD, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, and co-investigators. “Bruton’s tyrosine kinase (BTK) inhibitors are safe and effective agents in subsets of DLBCL with chronic active B-cell receptor (BCR) signaling, but durations of remission are short,” he continued.

Thus, Dr Roschewski reported on 1 of the arms from the phase 1 PRISM study of acalabrutinib plus AZD9150 in patients with R/R DLBCL.

In all, 17 patients with R/R DLBCL, who were ≥18 years of age (median age 72), had an Eastern Cooperative Oncology Group performance status of ≤2, and had ≥1 line of prior chemoimmunotherapy (median prior lines was 2), were enrolled. Acalabrutinib 100mg was given starting on cycle 1 day 1 twice daily until disease progression or discontinuation. AZD9150 100 mg was administered as a 1-hour intravenous (IV) infusion on day 1, day 3, and day 5 of cycle 1, followed by weekly infusions starting on day 8 and after.

The primary end point was safety. A dose-limiting toxicity analysis was completed after 6 patients completed day 28. The secondary end point was disease response assessed using Response Evaluation Criteria in Lymphoma 2017. Circulating tumor DNA (ctDNA) analysis was conducted using whole gene sequencing (WGS) and a custom next-generation sequencing panel.

The study found the overall response rate (ORR) was 24 percent with a complete response (CR) rate of 12 percent.

The most common (≥25%) adverse events of any grade included amnesia, AST/ALT elevation, thrombocytopenia, neutropenia, and fatigue. There was 1 DLT of grade 3 AST/ALT increase observed, and there were no treatment-related deaths. Total cell-free DNA (cfDNA) levels and the allele frequency of mutations within ctDNA correlated with treatment response. Just 1 patient achieved an early CR to therapy after cycle 2, which correlated with dynamic changes in ctDNA, including disappearance of copy number changes. Patients with persistent copy number changes—found as early as cycle 1 day 8—were less likely to respond to acalabrutinib plus AZD9150.

“Targeting BTK and STAT3 is safe and tolerable in relapsed DLBCL but has limited efficacy. Early clearance of copy number variations and decreased cfDNA levels were associated with clinical responses and may be a useful biomarker with targeted agents,” concluded Dr Roschewski et al.—Emily Bader

Roschewski M, Munugalavadla V, Nuttall B, et al. A phase 1 study of the combination of acalabrutinib and AZD9150 in patients with relapsed/refractory diffuse large B-cell lymphoma. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 1418.