The addition of acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, to pembrolizumab failed to improve objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) among patients with platinum-resistant metastatic urothelial cancer (mUC), according to the results of a phase 2 study published in Cancer.

Pembrolizumab and other immune checkpoint inhibitors are already approved for mUC, but only approximately one-quarter of patients respond. Acalabrutinib is a selective and potent inhibitor of BTK that may inhibit growth of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Higher levels of MDSCs are hypothesized to play a role in decreased response to programmed death-1 (PD-1) inhibition.

The purpose of this trial was to determine if suppression of MDSCs with acalabrutinib could enhance pembrolizumab activity safely in this population.

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The multicenter, open-label, phase 2 RAPID CHECK trial randomly assigned 75 patients with platinum-resistant mUC to receive pembrolizumab with or without acalabrutinib. The coprimary endpoints were ORR and safety and secondary endpoints included PFS and OS. Exploratory analyses included levels of circulating monocytic MDSCs and T cells.

At baseline, the median patient age was 67 years, and 77% of patients were male. Most patients had an Eastern Cooperative Oncology Group performance status of 1 and most patients received 1 prior treatment, with 30% and 23% receiving 2 or ≥3 prior therapies, respectively.

The ORR was similar between groups, at 20% with acalabrutinib plus pembrolizumab and 26% with pembrolizumab alone. The complete response rate was 10% and 8.6% with acalabrutinib plus pembrolizumab or pembrolizumab monotherapy, respectively.

Survival was also similar between the groups. The median PFS was 2.2 months with the acalabrutinib combination compared with 1.6 months with pembrolizumab alone, translating to a 12-month PFS of 16.4% and 20.8%, respectively. Median OS was 6.3 months with acalabrutinib plus pembrolizumab compared with 11.4 months with pembrolizumab monotherapy. At 12 months, the OS rate was 38.5% and 44.3%, respectively.

MDSC baseline levels and changes in levels during treatment were not associated with response in either group.

Grade 3 to grade 4 adverse events (AEs) occurred more frequently in the combination arm at 75% compared with 54.3% in the pembrolizumab monotherapy arm.

Discontinuation due to treatment-emergent AEs, including increased liver enzymes, pneumonia, colitis, fatigue, and vomiting, occurred in 40% of patients who received the acalabrutinib combination compared with 22.9% of patients who received pembrolizumab alone.

The authors concluded that the results from this trial “did not show improved responses with the combination.”


Zhang T, Harrison MR, O’Donnell PH, et al. A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer. Cancer. Published August 2, 2020. doi:10.1002/cncr.33067