Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

Abstract

Background: The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade.

Methods: This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed.

Results: A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1-6). Grade 3-4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway.

Conclusions: The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue.

Trial registration number: NCT02362048.

Keywords: CTLA-4 antigen; clinical trials, phase II as topic; immunotherapy; myeloid-derived suppressor cells; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: MO reports research funding from Merck. SN reports fees and research support from Allogene, Celgene, Kite (a Gilead Company), Merck and Unum Therapeutics; research support from Acerta Pharma, Bristol-Myers Squibb, Cellectis, Karus and Poseida and fees from Cell Medica, Incyte, Novartis, Pfizer and Precision Biosciences. NBM receives research funding to institution from Amgen, ARMO Biosciences, BMS, Genentech, Incyte, MedImmune and OncoMed and research funding from the Lustgarten Foundation. LT, VM and PP are employees of Acerta Pharma. VM owns stock in AstraZeneca and Gilead Sciences. MJ, RED, CK-S, PV, CDL, ERP and LX report no relevant conflicts of interest. AM receives royalties from Cosmos Wisdom Biotechnology for a biomarker test related to pancreatic cancer early detection.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Efficacy outcomes stratified by treatment arm (monotherapy and combination therapy). (A) Best radiographic response according to RECIST V.1.1: data show maximum change from baseline in SLD. (B) Kaplan-Meier plot for PFS based on objective tumor assessment by the investigator per RECIST V.1.1, based on the safety analysis set. (C) Kaplan-Meier plot for OS based on the safety analysis set. OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RECIST V.1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease; SLD, sum of longest diameters.

Figure 2

Exceptional responders showing CA 19–9 trend, representative radiographic images, histopathological tissue sampling and pretreatment multiplex immunohistochemistry. (A) Exceptional responder 1. (B) Exceptional responder 2. Baseline mIF images of tumor sections from exceptional responders 1 and 2 analyzed with panel 1 and 2 markers. Upper images: exceptional responder 1 showing increased number of macrophages expressing PD-L1+ and low density of total CD3+ T cells, with details of mIF showing TAMs expressing PD-L1+ (left) and high density of activated natural killer (CD57+granzyme B+CD45RO−) cells (right). Lower images: exceptional responder 2 showing similar findings to responder 1, with details of mIF again showing TAMs expressing PD-L1+ (left) and high density of CD45RO+ memory T cells (right), reflecting the variations in cell phenotypes observed in such cases. Images ×200 with high-power magnification of the positive cells. mIF, multiplex immunofluorescence; PD-L1+, programmed cell death ligand-1 positive; TAM, tumor-associated macrophage.

Figure 3

Changes in immune cell subsets and immune markers in peripheral blood mononuclear cells. Flow cytometry was performed on serial blood samples from both the monotherapy and the combination therapy arms at the indicated time points (baseline=week 1). (A–D) Percentage change in absolute number of monocytic (defined as CD3−CD20−CD56−HLA-DRlo/CD33+/CD11b+/CD14+) (A, B) and granulocytic (defined as CD3−CD20−CD56−HLA-DRlo/CD33+/CD11b+/CD15+) MDSC (C, D) in the PB in each treatment arm is shown for all samples assessed. Data shown as violin plots with median indicated by red horizontal lines and IQRs shown by blue horizontal lines. Each dot in the plot represents a sample. P values were calculated by Mann-Whitney two-tailed U test by comparing each time point with baseline. (E–H) Percentage change in MFI of CD69 on CD4 (E, F) or CD8 (G, H) memory (CD45RO+) T cells is shown as violin plots as above for each treatment arm. MDSC, myeloid-derived suppressor cells; MFI, mean fluorescence intensity; PB, peripheral blood.