From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer

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Abstract

Improvements in the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have lagged behind advances made in the treatment of many other malignancies over the past few decades. For most patients with PDAC, cytotoxic chemotherapy remains the mainstay of treatment. For patients with resectable disease, modified 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) is the standard-of-care adjuvant therapy, although data from several randomized trials have shown improved outcomes with neoadjuvant treatment strategies. For patients with advanced-stage or metastatic disease, comprehensive genomic profiling has revealed several potentially actionable alterations in small subsets of patients and the feasibility of implementing such strategies is beginning to be confirmed. Novel therapies targeting certain aberrations, most notably BRCA1/2 mutations, mismatch repair (MMR) deficiencies or NTRK1–3 fusions, have shown considerable activity in clinical trials, and larotrectinib, entrectinib and pembrolizumab have received FDA approval for the treatment of patients with tumours harbouring NTRK fusions and MMR deficiencies, respectively, regardless of primary tumour histology. In this Review, we describe the available data on the activity of these and other agents in patients with PDAC. Our discussion is structured according to the acronym ‘PRIME’ to organize the various treatment strategies currently undergoing evaluation in clinical trials: Pathway inhibition, alteration of DNA Repair pathways, Immunotherapy, cancer Metabolism and targeting the Extracellular tumour microenvironment.

Key points

  • The outcomes of the PRODIGE-24 trial have led to the modified 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) regimen becoming a new standard-of-care treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC).

  • Comprehensive genomic profiling has the potential to enable the identification of small subsets of patients with targetable alterations, who might benefit from targeted therapies.

  • Routine testing for mismatch repair deficiencies is required to identify patients who are likely to benefit from immune checkpoint inhibition.

  • Novel therapeutic agents targeting the extracellular tumour microenvironment or tumour metabolism have shown promise and are likely to have a role in the future management of patients with PDAC.

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Fig. 1: PRIME therapies for patients with advanced-stage pancreatic ductal adenocarcinoma.

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Acknowledgements

We thank Jonathan Martinez for his assistance in creating Fig. 1.

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Correspondence to Ignacio Garrido-Laguna.

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Competing interests

M.H. is a member of the Scientific Advisory Board of the Pancreatic Action Network, is a member of the Executive Committee of the Pancreatic Research Team, and is the Chair of the Arm Selection Committee for Precision Promise. I.G.-L. is a member of the scientific advisory boards of Array, Glycyx and Ignyta. C.N.-P. declares no competing interests.

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Nevala-Plagemann, C., Hidalgo, M. & Garrido-Laguna, I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol (2019) doi:10.1038/s41571-019-0281-6

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