BTK Inhibitor Acalabrutinib Plus STAT3 Inhibitor Danvatirsen for R/R DLBCL

Final Results from the Phase 1 PRISM Trial

Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib plus signal transducers and activators of transcription 3 (STAT3) inhibitor danvatirsen combination therapy yielded safe and tolerable outcomes among patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but demonstrated limited efficacy outcomes, according to final results of the phase 1 PRISM trial published in Clinical Cancer Research. 

Mark Roschewski, MD, National Cancer Institute, Bethesda, Maryland, and coauthors stated, “BTK inhibitors have demonstrated safety and activity in subsets of patients with R/R DLBCL, including those with non-germinal B-cell and [activated B-cell] (ABC) DLBCL, but remission durations are short.” They noted, “STAT3 inhibition has suppressed the growth of DLBCL xenografts in preclinical models,” indicating the potential value of using STAT3 inhibitors in the treatment of R/R DLBCL. 

The PRISM trial aimed to assess the outcomes of combining acalabrutinib, a BTK inhibitor, and danvatirsen, a STAT3 inhibitor, for treatment among patients with R/R DLBCL. The primary end points included safety and tolerability, and the secondary end points were efficacy, pharmacokinetics, and immunogenicity. A total of 17 patients with R/R DLBCL were included in this study. Danvatirsen was administered at 200 mg on days 1, 3, and 5 of cycle 1, followed by weekly infusions starting on day 8 of cycle 1 plus acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity occurred. 

Final results from the phase 1 PRISM trial showed 1 case of grade 3 liver transaminase, a dose-limiting toxicity. Progressive disease, which occurred in 65% of patients, was the most common cause of treatment discontinuation. The objective response rate was 24% and the median duration of response was 1.9 months. 

All patients who had a response with available DLBCL cell-of-origin data were either activated B-cell or non-germinal center B-cell subtype, and the genetic subtype was not associated with response. Patients who did not have a response to treatment had higher baseline and longitudinal plasma cell-free DNA concentrations. Patients who responded to treatment also had higher pretreatment circulating B-cell levels. 

As end points were met, Dr Roscewski et al concluded, “Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.” 

Source: 

Roschewski M, Patel MR, Reagan PM, et al. Phase I study of acalabrutinib plus danvatirsen (AZD9150) in relapsed/refractory diffuse large B-cell lymphoma including circulating tumor DNA biomarker assessment. Clin Cancer Res. Published online: September 1, 2023. doi: 10.1158/1078-0432.CCR-22-2483