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Clinical Study

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

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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.

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Fig. 1: Kaplan–Meier survival curves.
Fig. 2: Clinical outcome by neutrophil to lymphocyte ratio change.
Fig. 3: Clinical outcome by KRAS mutation status.

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Acknowledgements

We thank all the patients who agreed to participate in this trial.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Dae Won Kim, Elaine Tan, Maria Martinez, Estrella Carballido, Rutika Mehta, Jonathan Strosberg, Iman Imanirad & Richard D. Kim

  2. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

    Jun-Min Zhou & Michael J. Schell

  3. Department of Internal Medicine, Advent Health, Orlando, FL, USA

    James Yu

Authors
  1. Dae Won Kim
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  2. Elaine Tan
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  3. Jun-Min Zhou
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  4. Michael J. Schell
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  5. Maria Martinez
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  7. Estrella Carballido
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Contributions

Study concept: R.K. Study design: D.K. and R.K. Acquisition, analysis, or interpretation of data: D.K, E.T., J.Z., M.S., M.M., J.Y, E.C. R.M., J.S., I.I. and R.K. Statistical analysis: M.S. and J.Z. Manuscript preparation: D.K. and R.K. Manuscript editing and revision: D.K, E.T., J.Z., M.S., M.M., J.Y, E.C. R.M., J.S., I.I. and R.K. Manuscript review and approval: D.K, E.T., J.Z., M.S., M.M., J.Y, E.C. R.M., J.S., I.I. and R.K.

Corresponding author

Correspondence to Richard D. Kim.

Ethics declarations

Ethics approval and consent to participate

The protocol and informed consent forms were approved by the Institutional Review Boards at Moffitt Cancer Center (IRB# 00000790). Informed consent was obtained from all subjects prior to participating in the study. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Consent to participate

Not applicable.

Data availability

All authors had access to the data published in this paper. The anonymised dataset may be available from the corresponding author on reasonable request.

Competing interests

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.

Funding information

This work was supported by Janssen Oncology and Merck.

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Kim, D.W., Tan, E., Zhou, JM. et al. A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer. Br J Cancer 124, 1803–1808 (2021). https://doi.org/10.1038/s41416-021-01368-z

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