Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Clinical Oncology volume 17, pages 108–123 (2020)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Roser, M. & Ritchie, H. Cancer. Our World in Data https://ourworldindata.org/cancer (2018).

  2. Kalager, M., Zelen, M., Langmark, F. & Adami, H. O. Effect of screening mammography on breast-cancer mortality in Norway. N. Engl. J. Med. 363, 1203–1210 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Lauby-Secretan, B. et al. The IARC perspective on colorectal cancer screening. N. Engl. J. Med. 378, 1734–1740 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vasen, H. et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. J. Clin. Oncol. 34, 2010–2019 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Canto, M. I. et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 155, 740–751.e742 (2018).

    Article  PubMed  Google Scholar 

  6. Conroy, T. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 379, 2395–2406 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  CAS  Google Scholar 

  9. Aung, K. L. et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin. Cancer Res. 24, 1344–1354 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 8, 1112–1129 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hyman, D. M., Taylor, B. S. & Baselga, J. Implementing genome-driven oncology. Cell 168, 584–599 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dreyer, S. B., Chang, D. K., Bailey, P. & Biankin, A. V. Pancreatic cancer genomes: implications for clinical management and therapeutic development. Clin. Cancer Res. 23, 1638–1646 (2017).

    Article  PubMed  Google Scholar 

  13. Neoptolemos, J. P. et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389, 1011–1024 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Uesaka, K. et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388, 248–257 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Tempero, M. A. et al. APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 4000 (2019).

    Article  Google Scholar 

  16. Jang, J. Y. et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann. Surg. 268, 215–222 (2018).

    Article  PubMed  Google Scholar 

  17. Reni, M. et al. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. Lancet. Gastroenterol. Hepatol. 3, 413–423 (2018).

    Google Scholar 

  18. Unno, M. et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05). J. Clin. Oncol. 37, 189–189 (2019).

    Article  Google Scholar 

  19. Tienhoven, G. V. et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial [abstract]. J. Clin. Oncol. 36 (Suppl. 18), LBA4002 (2018).

    Article  Google Scholar 

  20. Strobel, O., Neoptolemos, J., Jager, D. & Buchler, M. W. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 16, 11–26 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Ghaneh, P. et al. The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma. Ann. Surg. 269, 520–529 (2019).

    Article  PubMed  Google Scholar 

  22. Neoptolemos, J. P. et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann. Surg. 234, 758–768 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lowery, M. A. et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin. Cancer Res. 23, 6094–6100 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Pishvaian, M. J. et al. Molecular profiling of patients with pancreatic cancer: initial results from the Know Your Tumor initiative. Clin. Cancer Res. 24, 5018–5027 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Subbiah, V. et al. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov. 8, 836–849 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Drilon, A. et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov. 9, 384–395 (2019).

    Article  PubMed  CAS  Google Scholar 

  27. Drilon, A. E. et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 102 (2018).

    Article  Google Scholar 

  28. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. McCormick, F. KRAS as a therapeutic target. Clin. Cancer Res. 21, 1797–1801 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e517 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Fakih, M. et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 3003 (2019).

    Article  Google Scholar 

  32. Waters, A. M. & Der, C. J. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med. 8, a031435 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eser, S., Schnieke, A., Schneider, G. & Saur, D. Oncogenic KRAS signalling in pancreatic cancer. Br. J. Cancer 111, 817–822 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vena, F. et al. The MEK1/2 inhibitor pimasertib enhances gemcitabine efficacy in pancreatic cancer models by altering ribonucleotide reductase subunit-1 (RRM1). Clin. Cancer Res. 21, 5563–5577 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Van Cutsem, E. et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int. J. Cancer 143, 2053–2064 (2018).

    Article  PubMed  CAS  Google Scholar 

  37. Chung, V. et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 3, 516–522 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kinsey, C. G. et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bryant, K. L. et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 25, 628–640 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Blasco, M. T. et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell 35, 573–587.e576 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Kheder, E. S. & Hong, D. S. Emerging targeted therapy for tumors with NTRK fusion proteins. Clin. Cancer Res. 24, 5807–5814 (2018).

    Article  PubMed  CAS  Google Scholar 

  42. Okamura, R. et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis. Oncol. 2018 (2018).

  43. Pishvaian, M. J. et al. Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions. J. Clin. Oncol. 36, 521–521 (2018).

    Article  Google Scholar 

  44. Drilon, A. et al. Efficacy of larotrectinib in trk fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Russo, M. et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 6, 36–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Drilon, A. et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann. Oncol. 27, 920–926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Drilon, A. et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 7, 963–972 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin, J. J., Riely, G. J., Shaw, A. T. & Targeting, A. L. K. Precision medicine takes on drug resistance. Cancer Discov. 7, 137–155 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Singhi, A. D. et al. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J. Natl Compr. Canc. Netw. 15, 555–562 (2017).

    Article  PubMed  Google Scholar 

  50. Heining, C. et al. NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov. 8, 1087–1095 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF v600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Aguirre, A. J. et al. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov. 8, 1096–1111 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen, S. H. et al. Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120. Cancer Discov. 6, 300–315 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Johnston, S. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5, 5 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 e113 (2017).

    Article  CAS  Google Scholar 

  60. Chou, A. et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut 67, 2142–2155 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Lowery, M. A. et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur. J. Cancer 89, 19–26 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. de Bono, J. et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 7, 620–629 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Shroff, R. T. et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis. Oncol. 2, 1–15 (2018).

    PubMed  Google Scholar 

  66. Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Golan, T. et al. Phase II study of olaparib for BRCAness phenotype in pancreatic cancer. J. Clin. Oncol. 36, 297–297 (2018).

    Article  Google Scholar 

  68. Drean, A., Lord, C. J. & Ashworth, A. PARP inhibitor combination therapy. Crit. Rev. Oncol. Hematol. 108, 73–85 (2016).

    Article  PubMed  Google Scholar 

  69. Bendell, J. et al. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann. Oncol. 26, 804–811 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yarchoan, M. et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget 8, 44073–44081 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Jiao, S. et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin. Cancer Res. 23, 3711–3720 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Robillard, L. et al. Preclinical evaluation of the PARP inhibitor rucaparib in combination with PD-1 and PD-L1 inhibition in a syngeneic BRCA1 mutant ovarian cancer model [abstract]. Cancer Res. 77 (Suppl. 13), 3650 (2017).

    Google Scholar 

  73. Higuchi, T. et al. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol. Res. 3, 1257–1268 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sun, C. et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci. Transl. Med. 9, eaal5148 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Chan, N. & Bristow, R. G. “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin. Cancer Res. 16, 4553–4560 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Liu, J. F. et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 15, 1207–1214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cremona, C. A. & Behrens, A. ATM signalling and cancer. Oncogene 33, 3351–3360 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Russell, R. et al. Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition. Nat. Commun. 6, 7677 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Randon, G. et al. Prognostic impact of ATM mutations in patients with metastatic colorectal cancer. Sci. Rep. 9, 2858 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Klumpen, H. J. et al. mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome. J. Clin. Oncol. 29, e150–e153 (2011).

    Article  PubMed  Google Scholar 

  81. Harder, J. et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br. J. Cancer 106, 1033–1038 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Helsten, T. et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin. Cancer Res. 22, 259–267 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Javle, M. et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol. 36, 276–282 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Loriot, Y. et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 381, 338–348 (2019).

    Article  PubMed  CAS  Google Scholar 

  85. Cuneo, K. C. et al. Dose escalation trial of the WEE1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J. Clin. Oncol. https://doi.org/10.1200/jco.19.00730 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Humphris, J. L. et al. Hypermutation in pancreatic cancer. Gastroenterology 152, 68–74.e2 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sohal, D. P. S. et al. Metastatic pancreatic cancer: ASCO clinical practice guideline update. J. Clin. Oncol. 36, 2545–2556 (2018).

    Article  PubMed  Google Scholar 

  93. Eroglu, Z. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347–350 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Poschke, I. et al. Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1240859 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Hiraoka, N. et al. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112, 1782–1790 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl Acad. Sci. USA 116, 1692–1697 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kinkead, H. L. et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight 3, 122857 (2018).

    Article  PubMed  Google Scholar 

  99. 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): late-breaking abstracts. J. Immunother. Cancer 5, 89, (2017).

  100. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kinsey, C. et al. Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer [abstract]. Cancer Res. 78 (Suppl. 13), LB-254 (2018).

    Google Scholar 

  103. Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Raj, D. et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut 68, 1052–1064 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. DeSelm, C. J., Tano, Z. E., Varghese, A. M. & Adusumilli, P. S. CAR T-cell therapy for pancreatic cancer. J. Surg. Oncol. 116, 63–74 (2017).

    Article  PubMed  Google Scholar 

  107. Le, D. T. et al. Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin. Cancer Res 25, 5493–5502 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  108. Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. O’Hara, M. H. et al. A phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. Cancer Res. 79 (Suppl. 13), CT004 (2019).

    Google Scholar 

  110. Halbrook, C. J. & Lyssiotis, C. A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer. Cancer Cell 31, 5–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Alistar, A. et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 18, 770–778 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Wolpin, B. M. et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637–638 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Erkan, M. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161 (2008).

    Article  PubMed  Google Scholar 

  119. Torphy, R. J. et al. Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precis. Oncol. 2, 1–12 (2018).

    Google Scholar 

  120. Theocharis, A. D., Tsara, M. E., Papageorgacopoulou, N., Karavias, D. D. & Theocharis, D. A. Pancreatic carcinoma is characterized by elevated content of hyaluronan and chondroitin sulfate with altered disaccharide composition. Biochim. Biophys. Acta 1502, 201–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Hingorani, S. R. et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J. Clin. Oncol. 36, 359–366 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Ramanathan, R. K. et al. A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139) [abstract]. J. Clin. Oncol. 36 (Suppl. 4), 208 (2018).

    Article  Google Scholar 

  125. Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598–610 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Begum, A. et al. The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma. PLOS ONE 12, e0180181 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Kanteti, R. et al. Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biol. Ther. 19, 316–327 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hendriks, R. W., Yuvaraj, S. & Kil, L. P. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat. Rev. Cancer 14, 219–232 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Gunderson, A. J. et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 6, 270–285 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Masso-Valles, D. et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 75, 1675–1681 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tempero, M. et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine as first-line treatment for patients with metastatic pancreatic adenocarcinoma: results from the phase 3 RESOLVE study [abstract]. Ann. Oncol. 30 (Suppl. 4), mdz154.001 (2019).

    Google Scholar 

  134. Bennewith, K. L. et al. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 69, 775–784 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Neesse, A. et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc. Natl Acad. Sci. USA 110, 12325–12330 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Picozzi, V. J. et al. Effect of anti-CTGF human recombinant monoclonal antibody pamrevlumab on resectability and resection rate when combined with gemcitabine/nab-paclitaxel in phase 1/2 clinical study for the treatment of locally advanced pancreatic cancer patients [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 4016 (2018).

    Article  Google Scholar 

  137. Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Ko, A. H. et al. A phase I study of folfirinox plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 45, 370–375 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cubillo Gracian, A. et al. YOSEMITE: A 3 arm double-blind randomized phase 2 study of gemcitabine, paclitaxel protein-bound particles for injectable suspension, and placebo (GAP) versus gemcitabine, paclitaxel protein-bound particles for injectable suspension and either 1 or 2 truncated courses of demcizumab (GAD) [abstract]. Ann. Oncol. 28 (Suppl. 5), mdx369.004 (2017).

    Google Scholar 

  141. Bekaii-Saab, T. et al. phase 1b/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabptx) in metastatic pancreatic adenocarcinoma (mpdac) patients (pts). Ann. Oncol. 28 (Suppl. 3), mdx302.001 (2017).

    Google Scholar 

  142. Sehdev, A. et al. Germline and somatic DNA damage repair gene mutations and overall survival in metastatic pancreatic adenocarcinoma patients treated with FOLFIRINOX. Clin. Cancer Res. 24, 6204–6211 (2018).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

    Christopher Nevala-Plagemann & Ignacio Garrido-Laguna

  2. Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA

    Manuel Hidalgo

  3. Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Ignacio Garrido-Laguna

Authors
  1. Christopher Nevala-Plagemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel Hidalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ignacio Garrido-Laguna
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Ignacio Garrido-Laguna.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 17, 108–123 (2020). https://doi.org/10.1038/s41571-019-0281-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0281-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer