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Cabozantinib with or without Panitumumab for RAS wild-type metastatic colorectal cancer: impact of MET amplification on clinical outcomes and circulating biomarkers

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Abstract

Purpose

Acquired resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC) remains a hurdle for effective treatment. MET amplification has been indicated as a driver of acquired resistance. Clinical activity has been demonstrated for the combination of EGFR and MET inhibitors in mCRC. But the impact of this regimen on angiogenesis and inflammation remains largely unknown.

Methods

In this non-randomized, open-label phase Ib/II study, four patients were treated with cabozantinib alone and 25 patients received the combination of cabozantinib and panitumumab. MET amplification was detected in blood in all four patients treated with cabozantinib monotherapy and 5/25 patients treated with cabozantinib and panitumumab combination therapy. Plasma samples from 28 patients were available for biomarker analysis.

Results

A panel of circulating protein biomarkers was assessed in patient plasma at baseline and on-treatment. Baseline marker levels were analyzed for prognostic value for clinical outcomes, including MET amplification as a covariate. HGF and OPN were prognostic for both progression-free survival (PFS) and overall survival (OS), while six markers (IL-6, VCAM-1, VEGF-R1, TSP-2, TIMP-1, ICAM-1) were prognostic only for OS. In patients with MET amplification, baseline PDGF-AA, PDGF-BB, TGF-β1, and VEGF-C levels were significantly higher, whereas baseline TGFβ-R3 levels were significantly lower than MET non-amplified patients. On-treatment change of four markers (CD73, PlGF, PDGF-BB, VEGF) were significantly different between MET amplified and non-amplified subpopulations.

Conclusion

This study identified circulating HGF and several inflammatory and angiogenic proteins as prognostic biomarkers. Furthermore, MET amplification status is associated with both baseline expression and on-treatment modulation of members of angiogenesis and TGF-β pathway proteins.

Clinical trials registration number

ClinicalTrials.gov identifier: NCT02008383.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors gratefully acknowledge the invaluable contributions of the patients, their families, the clinical staff, and the Duke University Gastrointestinal Oncology Clinical Trials team. They thank Dana Warren for her data management contributions to this manuscript. Duke Cancer Center and Duke University Medical Center participated in this study.

Funding

This research was supported by Exelixis, Inc. (Alameda, CA).

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Authors and Affiliations

  1. Duke Cancer Institute, Durham, NC, USA

    Jingquan Jia, John H. Strickler & Andrew B. Nixon

  2. Duke Department of Biostatistics and Bioinformatics, Durham, NC, USA

    Lauren Howard & Donna Niedzwiecki

  3. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Jingquan Jia, Yingmiao Liu, Mark D. Starr, John C. Brady, John H. Strickler & Andrew B. Nixon

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  1. Jingquan Jia
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Correspondence to Andrew B. Nixon.

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Conflict of interest

John H. Strickler has received research funding from Abbvie, AstraZeneca, Bayer, Mereo BioPharma,Pfizer, Seattle Genetics (C/A), Bayer (H), Amgen, Seattle Genetics,Exelixis, AStar D3, Sanofi, Nektar, Abbvie, and Roche/Genentech,Daiichi-Sankyo (RF); Andrew B. Nixon has received research funding from Genentech, MedImmune/AstraZeneca, Medpacto, Seattle Genetics, HTG Molecular Diagnostics, and Promega Corporation and has received consultant/advisory compensation from Eli Lilly, GSK, Promega Corporation, Leap Therapeutics, and AdjuVolt Therapeutics. The other authors declare no potential conflicts of interest.

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Jia, J., Howard, L., Liu, Y. et al. Cabozantinib with or without Panitumumab for RAS wild-type metastatic colorectal cancer: impact of MET amplification on clinical outcomes and circulating biomarkers. Cancer Chemother Pharmacol 89, 413–422 (2022). https://doi.org/10.1007/s00280-022-04404-8

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