A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Gov identifier: NCT03332498.

Conflict of interest statement

Rutika Mehta reported advisory/consulting for Taiho Oncology, Bristol Myers Squibb and Eli Lilly. Jonathan Strosberg reported consulting for Novartis. Richard Kim received an honorarium from Eli Lilly, Bristol Myers Squibb and Bayer. The remaining authors declare no competing interests.

Figures

Fig. 1. Kaplan–Meier survival curves.

Kaplan–Meier survival curves of progression-free survival and overall survival and Kaplan–Meier survival curves. CI confidence interval, OS overall survival, PFS progression-free survival.

Fig. 2. Clinical outcome by neutrophil to lymphocyte ratio change.

Kaplan–Meier survival curves of progression-free survival and overall survival by change of neutrophil to lymphocyte ratio between baseline and week 3 of

Fig. 3. Clinical outcome by KRAS mutation status.

Kaplan–Meier survival curves of progression-free survival and overall survival by KRAS mutation status. CI confidence interval, HR hazard ratio, MT mutation, WT wild type.