LUGANO-MADRID – Thanks to DNA sequencing, patients with rare cancers for which no standard treatment is available could receive existing therapies that work in patients treated for different cancers, but who carry the same genetic mutations. The first results of a multi-drug and multi-tumour clinical trial (1), to be presented at the ESMO 2017 Congress, show that this kind of precision oncology trial is not only feasible, but also has the potential to identify patient subgroups who could benefit from existing drugs outside of their registered indication.
The Centre for Personalised Cancer Treatment (CPCT), a network of more than 40 hospitals in the Netherlands, systematically collects biopsies from metastatic cancer patients, which are then analysed by Whole Genome Sequencing (WGS) in order to create a database that now comprises about 2,000 individuals treated for all types of cancer.
“By sequencing the whole genome in so many patients, we found commonalities between tumours and DNA mistakes. For example, the ERBB2 gene is mainly screened for in breast cancer patients, but we know that it is also present in patients with other tumour types,” said principal study investigator Prof. Emile Voest, from the Netherlands Cancer Institute in Amsterdam, who led the trial on behalf of the CPCT.
“Now that we are able to identify these patients, the question is: How can we get them to benefit from existing, potentially active drugs? That is the basis for our Drug Rediscovery Protocol, which currently includes 19 different drugs from 10 pharmaceutical companies,” Voest reported.
Since the trial was launched in late 2016, over 250 cases have been submitted for review: of these, about 70 patients have so far been found eligible and started treatment. Adult patients with solid tumours, glioblastoma, lymphoma or multiple myeloma with no standard treatment options were enrolled in the study in multiple parallel cohorts according to tumour type and trial drug.
“We have preclinical evidence and case reports suggesting that certain drugs, which patients with a given genetic aberration and a certain type of cancer are sensitive to, could equally be active in patients with the same mutation in other tumour groups. However, we also know that the tissue background is extremely important: That’s why we create study cohorts not just according to genetic mutation, but also according to the specific tumour type,” Voest explained.
The efficacy of the treatment for each cohort is analysed in a two-stage process: “If in stage one, the first group of eight patients with the same tumour type and genetic mutation responds to the treatment, we expand the cohort to 24 patients in stage two to get a stronger indication of the clinical benefit,” said Voest. “Clinical benefit, in this case, is defined as either a complete remission, a partial response, where the tumour shrinks by more than 50 percent, or disease stability for at least 16 weeks.”
To date, a clinical benefit has been observed in 37 percent of trial participants, and six of the 20 study cohorts have graduated to stage two. “We’ve seen real success with several anticancer drugs, including immunotherapy, a PARP inhibitor and an antibody combination,” Voest reported.
“Our team is quite excited about these results, because everybody knows that developing new drugs is very expensive. With this study, we are providing a platform for expanding the indications of existing drugs and utilising them to their full potential,” he said. “Using drugs that are already available based on DNA sequencing is a truly novel approach to personalising medicine, and we are talking to regulatory authorities to see how new findings in this area can be translated to the clinic as quickly as possible for these rare subsets of patients.”
Dr. Richard Marais, from the Cancer Research UK Manchester Institute, commented on the study: “What makes this trial so exciting is that it could change the way we stratify patients for treatment, that is to say match their genetic profile with a treatment option. The team looks for mutations, some of which will have drugs to target them. If they find them, the patients are treated based on their genetics, rather than their indication: This is incredibly powerful. Beyond identifying new indications for existing drugs, this study is about finding treatments for patients for whom there is currently no standard of care,” he said.
“Gene sequencing is starting to become standard practice in cancer care: For example, we know that about half of all melanoma patients have a so-called BRAF mutation, so we look for it and give the relevant individuals a BRAF drug. However, for these rare types of cancer or rare mutations, we need to sequence hundreds of genes to find the specific mutations that therapies can target. The CPCT has the ability to find those targets because it sequences the entire genome,” Marais explained.
“This is very expensive, so the trial needs to show that it can be cost-effective and work for patients. Stratifying even 10 percent of trial participants could make the process cost-neutral: for health systems around the world, this would mean that despite a high upfront investment, the downstream benefits to patients and potential reduction of the cost of treating them would be enormous,” he said. “In this context, the numbers being presented here are very impressive. They have definitely shown a proof of principle.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract LBA59_PR ‘Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)’ will be presented by Dr. Emile Voest during the Proffered Paper and Poster Discussion Session, ‘Translational Research’, on Saturday, 9 September 2017, 09:00 to 10:45 (CEST) in Pamplona Auditorium.
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Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
D. van der Velden1, L. Hoes2, H. van der Wijngaart3, H. Bloemendal4, K. Grunberg5, A. Huitema6, E. Lugtenburg7, F. De Vos8, C.M.L. Herpen9, D.J. de Groot10, P. Hamberg11, E. Smit12, E. Cuppen13, N. Steeghs14, S. Sleijfer15, H.M. Verheul16, H. Gelderblom17, E. Voest1
1Molecular Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, Netherlands, 2Molecular Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Medical Oncology, VU University Medical Center, Amsterdam, Netherlands, 4Medical Oncology, Meander Medical Center, Amersfoort, Netherlands, 5Pathology, Radboud University Medical Center, Nijmegen, Netherlands, 6Dept. of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands, 7Hematology, Erasmus University Medical Center, Rotterdam, Netherlands, 8Medical Oncology, University Hospital Utrecht, Utrecht, Netherlands, 9Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands, 10Medical Oncology, University Hospital Groningen (UMCG), Groningen, Netherlands, 11Medical Oncology, St Franciscus Gasthuis, Rotterdam, Netherlands, 12Department of Pulmonary Diseases & Thoracic Oncology, VU medical center & Netherlands Cancer Institute, Amsterdam, Netherlands, 13Genetics, University Hospital Utrecht, Utrecht, Netherlands, 14Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 15Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 16Medical Oncology, Vrije University Medical Centre (VUMC), Amsterdam, Netherlands, 17Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
Background: Once regulatory drug approval is obtained, patients and pharma would greatly benefit from identifying signals of activity in cancer subsets outside the approved indication. In the Netherlands’ precision oncology-network (), Whole Genome Sequencing (WGS) is offered to systemically treated cancer patients. This allows us to identify a spectrum of potentially actionable genetic aberrations in all types of cancer. The DRUP provides patients with such aberrations access to genetically matched treatment upon central review of the tumor profile.
Methods: Adult patients with solid tumors, glioblastoma, lymphoma or multiple myeloma, with no standard treatment options, are eligible. Patients are enrolled in multiple parallel cohorts, each defined by 1 tumor type, 1 tumor profile and 1 treatment. Efficacy is analyzed per cohort using a Simon-2-stage approach, aimed at ≥1 clinical benefit (CR, PR or SD ≥16 weeks) / 8 patients in stage I, and ≥5 / 24 in stage II (85% power, α error rate 7.8%). A fresh tumor biopsy for biomarker research is mandatory. There are currently 23 participating hospitals and 19 study drugs, supplied by 10 pharmaceutical companies.
Results: Since study launch Sep 2016, ~250 cases were submitted for review and about 1/3 of these patients have started study treatment. Clinical benefit was observed in 37% (6% CR, 14% PR, 17% SD ≥16 weeks; all CRs and 2/3 of PRs were ongoing at the time of writing and awaiting ≥30 days confirmation). About 2/3 of case submissions were rejected, due to a general protocol ineligibility (18%), b current unavailability of matching study drugs (17%), c no actionable target detected (15%), d negative evidence for target-drug-match (13%), e eligible for standard treatment (12%), f eligible for competing trials (11%), g loss to follow up (10%) or h genetic tumor profile not yet assessed (4%).
Conclusions: Execution of a national multi-drug and multi-tumor precision oncology trial is feasible. By performing WGS in many different cancer types, subgroups are identified who may benefit from existing drugs outside of their registered indication. This study hereby accelerates translation of new findings to the clinic and increases the yield of existing therapies.
Clinical trial identification: NCT02925234 (release date: 26-Aug-2016) EudraCT 2015-004398-33 (release date: 01-Oct-2015)
Legal entity responsible for the study:
- Governance: Stichting Het Nederlands Kanker Instituut – Antoni van Leeuwenhoek Ziekenhuis, whose registered office is at Plesmanlaan 121, 1066CX, Amsterdam, lawfully represented by Prof. R. Medema, Head of the Board representing the CPCT.
- Coordination and running of the study: Prof. E.E. Voest, Netherlands Cancer Institute, division of Molecular Oncology, Amsterdam, the Netherlands.
Funding: • Barcode for Life Foundation (BFL): funding • Dutch Cancer Society (KWF): funding • Hartwig Medical Foundation (HMF): sequencing • Pharmaceutical partners (Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, Roche): funding and study drugs
Disclosure: F. De Vos: I have the following conflict of interest to report: 1. Direct research support to the responsible project lead (Principle Investigator): see 2 2. Novartis, BMS, Roche/Genetech, GSK, Array, AstraZeneca, Merus, Merck
E. Cuppen: I have the following conflict of interest to report: Board of Directors Hartwig Medical Foundation (not for profit)
N. Steeghs: I have the following conflict of interest to declare: 1. Consulting or Advisory role - Lilly 2. Research Funding - AB Science; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol MS
All other authors have declared no conflicts of interest.
Keywords: whole genome sequencing (WGS), Off label use, targeted therapy, precision oncology