pci-32765 and Neoplasm-Metastasis

MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC.. This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS).. A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively.. Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS.. NCT03332498.

Topics: Adenine; Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA Mismatch Repair; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Piperidines; Progression-Free Survival; Treatment Outcome; Young Adult

Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear.. Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer.. Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour T. Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.

Topics: Adenine; Animals; Breast Neoplasms; Dendritic Cells; Disease Progression; Female; Humans; Mice; Myeloid-Derived Suppressor Cells; Neoplasm Metastasis; Piperidines