Opinion | Published:

Equal access to innovative therapies and precision cancer care

Nature Reviews Clinical Oncology volume 13, pages 385393 (2016) | Download Citation

Abstract

Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013. This programme is designed to make treatment decisions or recommendations on the basis of the presence of relevant biomarkers for malignancies with no targeted therapies available and also aims to improve safety, and evaluate the efficacy of targeted drugs used outside of their approved indications. Patients across France have access to molecular testing in 28 molecular genetics centres and to targeted therapies within phase II trials provided no other trials exist in which they could reasonably be included. Trials include patients below the age of 18 if safe dosing data are available. As of January 2016, 183 French clinical sites and over 7,000 patients are participating in AcSé led trials. Proof of concept is being demonstrated through trials designed to investigate the effectiveness of crizotinib and vemurafenib in a wide variety of cancers.

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References

  1. 1.

    Institut National du Cancer. Situation sur la chimothérapie des cancers: rapport 2014.

  2. 2.

    , & Drug repurposing in oncology — patient and health systems opportunities. Nat. Rev. Clin. Oncol. 12, 732–742 (2015).

  3. 3.

    et al. Unsupported off-label chemotherapy in metastatic colon cancer. BMC Health Serv. Res. 29, 481 (2012).

  4. 4.

    , , & Rare cancers in Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann. Oncol. 26, 300–306 (2015).

  5. 5.

    , & Tumour molecular profiling for deciding therapy — the French initiative. Nat. Rev. Clin. Oncol. 9, 479–486 (2012).

  6. 6.

    SIOPe. The SIOP-Europe strategic plan: a European cancer plan for children and adolescents. , (2015).

  7. 7.

    US National Library of Science. ClinicalTrials.gov , (2016).

  8. 8.

    US National Library of Science. ClinicalTrials.gov , (2015).

  9. 9.

    US National Library of Science. ClinicalTrials.gov , (2015).

  10. 10.

    US National Library of Science. ClinicalTrials.gov , (2015).

  11. 11.

    US National Library of Science. ClinicalTrials.gov , (2016).

  12. 12.

    et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem. 54, 6342–6363 (2011).

  13. 13.

    et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

  14. 14.

    ALKoma: a cancer subtype with a shared target. Cancer Discov. 2, 495–502 (2012).

  15. 15.

    & Mossé, Y. P. Targeting ALK in neuroblastoma-preclinical and clinical advancements. Nat. Rev. Clin. Oncol. 9, 391–399 (2012).

  16. 16.

    , , & Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).

  17. 17.

    , , & ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway. Expert Rev. Anticancer Ther. 12, 447–456 (2014).

  18. 18.

    et al. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J. 13, 3524–3532 (1994).

  19. 19.

    , , , & The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat. Rev. Cancer 8, 11–23 (2008).

  20. 20.

    , , & Tyrosine kinase gene rearrangements in epithelial malignancies. Nat. Rev. Cancer 13, 772–787 (2013).

  21. 21.

    et al. Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications. J. Clin. Oncol. 30, 308–315 (2012).

  22. 22.

    et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47, 1025–1037 (2008).

  23. 23.

    ALK gene amplified in most inflammatory breast cancers. J. Natl Cancer Inst. 104, 87–88 (2012).

  24. 24.

    et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16, 68–73 (1997).

  25. 25.

    et al. MET gain in diffuse astrocytomas is associated with poorer outcome. Brain Pathol. 23, 13–18 (2013).

  26. 26.

    et al. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37, 58–71 (2003).

  27. 27.

    et al. Lack of GOPCROS1 (FIGROS1) rearrangement in adult human gliomas. Eur. J. Cancer 50, 2364–2366 (2014).

  28. 28.

    et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363, 1727–1733 (2010).

  29. 29.

    et al. Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov. 4, 889–895 (2014).

  30. 30.

    et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase I consortium study. Lancet Oncol. 14, 472–480 (2013).

  31. 31.

    , & Is the European pediatric medicine regulation working for children and adolescents with cancer? Clin. Cancer Res. 19, 1315–1325 (2013).

  32. 32.

    US National Library of Science. ClinicalTrials.gov , (2016).

  33. 33.

    et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

  34. 34.

    & BRAF mutations: signalling, epidemiology, and clinical experience in multiple malignancies. Cancer Control 21, 221–229 (2014).

  35. 35.

    et al. Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr. Blood Cancer 61, 1101–1103 (2014).

  36. 36.

    US National Library of Science. ClinicalTrials.gov , (2016).

  37. 37.

    et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

  38. 38.

    et al. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanomas: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br. J. Dermatol. 167, 987–994 (2012).

  39. 39.

    Optimal two-stage designs for phase II clinical trials. Control Clin. Trials 10, 1–10 (1989).

  40. 40.

    The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J. Chron. Dis. 13, 346–353 (1961).

  41. 41.

    , , & An optimal three-stage design for phase II clinical trials. Stat. Med. 13, 1727–1736 (1994).

  42. 42.

    , & Bayesian design and conduct of phase II single-arm clinical trials with binary outcomes: a tutorial. Contemp. Clin. Trials 29, 608–616 (2008).

  43. 43.

    Committee for medicinal products for human use (CHMP). Guideline on clinical trials in small populations. European Medical Agency , (2006).

  44. 44.

    & Bayesian sample size calculations in phase II clinical trials using informative conjugate priors. Control Clin. Trials 25, 157–167 (2004).

  45. 45.

    , , & Summarizing historical information on controls in clinical trials. Clin. Trials 7, 5–18 (2010).

  46. 46.

    & Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J. Clin. Oncol. 26, 1346–1354 (2008).

  47. 47.

    US National Library of Science. ClinicalTrials.gov , (2015).

  48. 48.

    Agence nationalle de Sécurité du Médicament et des produtis de santé. Clinical trials registry.

  49. 49.

    ASCO's Targeted Agent and Profiling Utilization Registry (TAPUR) Study. ASCO , (2016).

  50. 50.

    et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 15, 267–274 (2014).

  51. 51.

    et al. Molecular screening for cancer treatment optimization (MOSCATO 01): a prospective molecular triage trial [abstract]. Cancer Res. 74 (Suppl.), CT240 (2014).

  52. 52.

    et al. Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses. Clin. Cancer Res. 20, 4827–4836 (2014).

  53. 53.

    & Molecular analysis for therapy choice: NCI MATCH. Semin. Oncol. 41, 297–299 (2014).

  54. 54.

    et al. The Signature Program: bringing the protocol to the patient. Clin. Pharmacol. Ther. 98, 124–126 (2015).

  55. 55.

    et al. Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologsts. J. Clin. Oncol. 31, 1134–1139 (2013).

  56. 56.

    et al. Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study. Eur. J. Clin. Pharmacol. 70, 719–725 (2014).

  57. 57.

    The complexity of covering off-label use for a multitude of oncology regimens. Am. J. Manag. Care 18, SP242–SP247 (2012).

  58. 58.

    , , & Conflict of interest disclosure in off-label oncology clinical trials. J. Oncol. Pract. 8, 298–302 (2012).

  59. 59.

    et al. The off-label use of targeted therapies in sarcomas: the OUTC'S program. BMC Cancer 24, 870 (2014).

Download references

Acknowledgements

We thank Maren White (freelancer editor and medical writer) for her editorial support in the preparation of this manuscript.

Author information

Affiliations

  1. Agnès Buzyn, Natalie Hoog-Labouret and Frédérique Nowak are at the Institut National du Cancer, 52 avenue André Morizet, F-92513 Boulogne-Billancourt, France.

    • Agnès Buzyn
    • , Natalie Hoog-Labouret
    •  & Frédérique Nowak
  2. David Pérol and Jean-Yves Blay are at the Centre Léon Bérard, 28 Rue Laennec, F-69008, Lyon, France.

    • Jean-Yves Blay
    •  & David Pérol
  3. Jean-Yves Blay is at the University of Lyon, 92 Rue Pasteur, F-69007 Lyon, France.

    • Jean-Yves Blay
  4. Marta Jimenez and Christian Cailliot are at R&D Unicancer, 101 rue de Tolbiac, F-75654 Paris Cedex 13, France.

    • Marta Jimenez
    •  & Christian Cailliot
  5. Marie-Cécile Le Deley and Gilles Vassal are at Gustave Roussy, 114 rue Edouard Vaillant, F-94805, Villejuif, France and University Paris-SUD, Faculté de Médecine, 63 Rue Gabriel Péri, F-94270 Le Kremlin Bicêtre, France.

    • Marie-Cécile Le Deley
    •  & Gilles Vassal
  6. Marie-Cécile Le Deley is at INSERM CSEP Team 2, 114 rue Edouard Vaillant, F-94805, Villejuif, France.

    • Marie-Cécile Le Deley
  7. Jacques Raynaud is at the ARC Foundation for Cancer Research, 9 Rue Guy Moquet, F-94805 Villejuif, France.

    • Jacques Raynaud

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Contributions

N. H-L., M. J., F. N., M-C.L-D., D. P. and G. V. researched data for this article. M-C.L-D., D. P. and G. V. wrote the article, A. B., J.-Y. B., M-C.L-D., D. P. and G. V. made a substantial contribution to the discussion of content, and all authors review and edited the manuscript before submission and during revisions.

Competing interests

The AcSé programme is funded by INCA and ARC Foundation for Cancer Research. The clinical trials are sponsored by Unicancer. G.V. is chief-investigator of AcSé-crizotinib and J.-Y. B. is chief-investigator of AcSé-vémurafénib.

Corresponding author

Correspondence to Agnès Buzyn.

About this article

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DOI

https://doi.org/10.1038/nrclinonc.2016.31

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