Acalabrutinib does not boost pembrolizumab activity in metastatic UC
medwireNews: Adding the BTK inhibitor acalabrutinib to the PD-1 inhibitor pembrolizumab does not improve outcomes in previously treated patients with metastatic urothelial cancer (UC), results of the phase 2 RAPID CHECK (KEYNOTE 143) study show.
Tian Zhang (Duke University Medical Center, Durham, North Carolina, USA) and colleagues hypothesized that BTK inhibition could deplete myeloid‐derived suppressor cells (MDSCs), which are thought to promote T‐cell suppression and support an immunosuppressive tumor microenvironment needed for tumor growth. This in turn could enhance the antitumor effects of anti PD-1 monotherapy.
Yet, they found that there was no significant difference in the objective response rate between the 40 patients who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks in combination with oral acalabrutinib 100 mg twice daily and the 35 patients assigned to receive pembrolizumab alone, at 20.0% versus 25.7%. Of these, 10.0% and 8.6%, respectively, achieved a complete response.
The researchers also found no significant difference between the combination and monotherapy arms in median progression-free survival (2.2 vs 1.6 months) or overall survival (6.3 vs 11.4 months).
In terms of safety, 75.0% of patients in the combination arm and 54.3% of those in the pembrolizumab arm experienced a grade 3 or 4 adverse event (AE), 57.5% and 42.9%, respectively, experienced a serious AE, and 40.0% and 22.9%, respectively, discontinued treatment due to a treatment-emergent AE.
Fatigue was the most common AE in both groups but occurred more frequently with combination therapy versus monotherapy (85.0 vs 48.6% for all grades). Grade 3–4 increased alanine aminotransferase and aspartate aminotransferase occurred in 22.5% and 10.0%, respectively, of patients receiving combination therapy, but were not reported with monotherapy.
In contrast to their hypothesis, Zhang and team found that baseline peripheral MDSC levels did not correlate with a clinical response, but they note that one patient in the combination therapy group with a high MDSC level at baseline showed a substantial decrease at week 7. They also observed an increase in some CD8+ T-cell subsets in the combination therapy group.
Nonetheless, the authors conclude in Cancer that “the absolute MDSCs at the baseline or changes on treatment were not sufficient as biomarkers to predict a treatment response.”
They add: “Future studies are needed to carefully subtype T cells and MDSCs to evaluate their clinical utility as circulating, real-time biomarkers for monitoring patients treated with immune checkpoint inhibitors.”
In an accompanying editorial, Petros Grivas (University of Washington, Seattle, USA) and co-authors say: “Although the study findings were negative, the trial reported valuable translational biomarker data, especially with regard to circulating MDSCs and T cells, that expand and deepen our understanding.”
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