The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1,2,3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit—defined as complete or partial response, or as stable disease beyond 16 weeks—of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8–11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.
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All data described in this study are freely available for academic use, and can be obtained through the Netherlands Cancer Institute and the HMF through standardized procedures and request forms. These can be found at https://www.hartwigmedicalfoundation.nl/en. In brief, a data request can be initiated by filling out the standard form, which requires the applicant to provide the intended use of the requested data. Next, an independent data-access board will evaluate whether the intended use of the data is compatible with the consent given by the patients, and whether there would be any applicable legal or ethical constraints. Upon formal approval by the data-access board, a standard license agreement (which does not have any restrictions regarding intellectual property resulting from the data analysis) needs to be signed by an official representation of the organization before access to the data is granted. All WGS data, including raw data files, will be made available through a dedicated download portal with two-factor authentication, via the HMF. Clinical, outcome and safety data can be obtained at a per-patient level for all patients reported in the study, by emailing the Institutional Review Board of the Netherlands Cancer Institute (IRB@nki.nl). Both the WGS and clinical datasets have unique identifiers for individual patients, which allows a combined analysis. For any other data, correspondence should be addressed to email@example.com and requests for materials to DRUP@nki.nl.
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We thank the Barcode for Life Foundation and the Dutch Cancer Society for their financial support; Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck Sharp and Dohme, Novartis, Pfizer and Roche for their in-kind and financial support; the HMF for their in-kind support by performing sequencing and biomarker analyses on baseline biopsies; the Center for Personalized Cancer Treatment Multidisciplinary Expert Board for supporting the central case-review process; the Independent Data Monitoring Committee for their advice on cohort decisions and the monitoring of preliminary safety data; the Netherlands Cancer Institute’s Biobank Facility, Scientific Department and Pharmacy for their facilitating services; A. P. Hamberg, L. V. Beerepoot and J. M. Meerum-Terwogt for their contributions to trial recruitment; and all participating hospitals for supporting and facilitating the conduct of the DRUP trial.
E.E.V. is legally responsible for all contracts with pharmaceutical companies at the Netherlands Cancer Institute. H.M.W.V. and H.G. have, through the DRUP and other studies, received support from pharmaceutical companies that are participating in the DRUP. R.L.S serves as principal investigator for the TAPUR trial, in support of which the American Society of Clinical Oncology receives financial support from Astra-Zeneca, Bayer, Bristol-Myers Squibb, Genentech, Lilly, Merck and Pfizer. C.M.L.v.H. has received funding from AstraZeneca, BMS, Ipsen, Merck, MSD and Novartis. A.J.d.L. has served as an advisor for AstraZeneca, BMS, Boehringer, Pfizer, Lilly and MSD, and has received research grants from AstraZeneca, BMS and MSD. E.K. has served as advisor for Amgen, BMS, Eisai, Genzyme-Sanofi, MSD, Novartis and Roche. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Peer review information Nature thanks David Hyman, Christophe Le Tourneau and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Patients may be identified via regular diagnostics or by WGS performed within the context of a CPCT sequencing study. Adult patients with advanced cancers and without standard-treatment options (but with a known potentially actionable variant in their molecular tumour profile) can be submitted for review. The central review is done by two or more reviewers independently, supported by the CPCT Molecular Tumour Board, and includes review of (i) the medical history of the patient, (ii) tumour-profiling test results, (iii) available literature and (iv) potential drug-access alternatives. Patients who are eligible for standard treatments are referred back to their treating physician. Genomic variants of unknown significance (VUS) that are not likely to be actionable are not considered acceptable drug targets. Negative trials are not repeated, nor are positive or ongoing phase II or III trials, unless drug access is not (or is not yet) facilitated. Drug access via other trials or access programmes is preferred, if available. Input for stages (iii) and (iv) of the review is derived from PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), ClinicalTrials.gov and weekly automatic updates on publications that mention any drug in the study in their titles and/or abstracts. If the general selection criteria are met and the appropriate study treatment is available, the patient can be informed, screened and enrolled (if all drug-specific selection criteria are also met). Once a fresh baseline tumour biopsy is obtained, study treatment can be initiated. Patients are treated and followed according to the labelled indication for each drug. Response is evaluated once every two months. Patients can continue study treatment as long as clinical benefit is observed. Patients who discontinue study treatment can be resubmitted if their molecular tumour profile (as revealed by the baseline biopsy) contains additional actionable variants. CR, complete response, PR, partial response.
Overview of the first 642 case submissions (submitted between 1 September 2016 and 1 September 2018), as well as the reasons for not being enrolled in the study. Values are displayed as a percentage relative to these 642 case submissions, and as an absolute number per category. Cases that were erroneously submitted (owing to incomplete understanding of the study protocol and/or retraction of the submission by the treating physician) are not included in this overview (n = 58 cases).
Overview and success rate of WGS on pre-treatment tumour biopsies. The bottom panel displays the number of patients for whom WGS succeeded, and indicates whether the initial variant (on the basis of which the patient started the study treatment) was also present in the fresh baseline biopsy. Values are displayed as absolute numbers and percentages, relative to the 131 successfully sequenced biopsies. CPCT-02, the national WGS programme of the CPCT; HML, high mutational load (defined as ≥140 somatic missense variants across the tumour genome overall); WGS-MSI, microsatellite instability suspected on the basis of WGS results; ampl, amplification; mut, mutation; wt, wild type.