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12 september 2017: Bron: ESMO 2017

DNA-sequencing (mutatie en receptorenonderzoek) kan nieuwe rol voor reeds geregistreerde geneesmiddelen betekenen voor patiënten met afwijkende tumoren. Zo werd de Nederlandse DRUP studie van de CPCT gepresenteerd op ESMO 2017. Daar werden de exacte resultaten van de DRUP studie gepresenteerd zoals deze in het Algemeen Dagblad al waren aangekondigd, zie hieronder.

Uit ca. 250 patiënten die vooraf werden getoetst op een aantal factoren, waaronder receptoren- en DNA onderzoek bleken er tot nu toe 73 patiënten te voldoen aan de toelastingscriteria voor een van de studies binnen de DRUP studies.

Bij 37 procent van de deelnemende patiënten (n = 73) werd een therapeutisch resultaat bereikt

"Therapeutisch resultaat betekent in dit geval: als een volledige remissie, een gedeeltelijke remissie, waar de tumor met meer dan 50 procent krimpt of de stabiliteit van de ziekte gedurende ten minste 16 weken is bereikt."

6 procent van de deelnemende patiënten bereikte een CR = complete remissie, 14 procent een PR = een gedeeltelijke remissie en 17 procent SD = stabiele ziekte.

In deze DRUP studie werden behandelingen die werden gegeven aan vooraf geselecteerde uitbehandelde patiënten met verschillende vormen van solide tumoren gebaseerd op genen- en receptorenonderzoek (DNA mutaties). Zie hier het volledige studieprotocol zoals geregistreerd in clinical trials.

Hier staan een aantal van de tot nu toe gebruikte medicijnen in de DRUP studie, maar deze zijn inmiddels al 19 verschillende medicijnen of combinaties van mediicijnen:

Het abstract van de studie staat onderaan dit artikel.

Hier de presentatie van dr. Voest op ESMO 2017:

ESMO 2017 Press Release: DNA Sequencing Could Open Up New Drug Indications for Patients with Rare Cancers

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.”

28 augustus 2017: Bron: Algemeen Dagblad

De Nederlandse DRUP studie geeft hoopvolle resultaten voor uitbehandelde kankerpatienten. Althans dat schrijft het Algemeen Dagblad vandaag waarin prof. dr. Voest (Personalized Cancer Treatment (CPCT) zegt dat zij op ESMO 2017 in Madrid (van 8 t/m 12 september 2017) hoopvolle resultaten zullen presenteren van een studie met 73 patiënten die afgelopen jaar zijn behandeld op basis van biomoleculaire kenmerken (DNA mutaties en receptorenexpressie en niet op basis van primaire tumor type. Een personalised medicine behandeling dus.

Hier meer over de CPJT studies opzet: http://www.cpct.nl/voor-onderzoekers/onderzoeksopzet/

En de DRUP studie: http://www.cpct.nl/drup-drug-rediscovery-protocol-studie/ waarin patiënten worden opgenomen als uit de CPCT studie blijkt dat er voldoende aanwijzingen zijn dat de patiënt eventueel zou kunnen profiteren van een ander medicijn, andere behandeling, die bij andere vormen van kanker goede resultaten gaf en als medicijn staat geregistreerd.

Een voorbeeld is dat soms mannen met prostaatkanker ook een BRCA 1 of BRCA 2 mutatie hebben en goed zouden kunnen reageren op olaparib, een zogeheten parpremmer die voor zowel borstkanker als eierstokkanker een geregistreerd tweedelijns medicijn is. Ook de anti-PD medicijnen (bij een P1-ligand mutatie) zoals pembrolizumab, nivolumab en atezolizumab bij blaaskanker, enz. die bij o.a. melanomen, borstkanker, longkanker , blaaskanker geregistreerde immuuntherapeutische medicijnen zijn kunnen aan andere kankerpatienten met een andere primaire vorm van kanker maar wel met een P1-ligand mutatie gegeven worden. Meestal binnen studieverband, maar soms ook per individuele patiënt.

Als ESMO start zal ik uiteraard de studieresultaten publiceren. Hier het artikel uit het Algemeen Dagblad d.d. 28 augustus 2017

medicijnenbeeld

Proef met 'vreemde' medicatie biedt hoop voor uitbehandelde kankerpatiënt

Drieëntwintig ziekenhuizen doen mee aan een studie waarin uitbehandelde kankerpatiënten medicatie krijgen die eigenlijk niet voor hen is bedoeld. De eerste successen zijn geboekt: de tumor slonk of de ziekte bleef stabiel. ,,Maar er is wél meer onderzoek nodig om vast te stellen bij wie het wel of niet werkt.”

Zeventig kankerpatiënten bij wie alle hoop verdwenen leek, zijn afgelopen jaar gestart met medicatie waar ze normaal gesproken niet voor in aanmerking komen. Zij kregen geneesmiddelen die zijn uitgevonden voor een ander type kanker, maar door dna-foutjes in hun tumor mogelijk ook voor hen heilzaam kunnen zijn.

Na een uitgebreide dna-analyse werden de patiënten opgesplitst in meer dan twintig groepjes. Bij zes groepjes zijn inmiddels successen geboekt: de ziekte bleef langer stabiel of de tumor slonk. Hoe succesvol de behandelingen precies zijn brengt het Center for Personalized Cancer Treatment (CPCT), waarin de 23 ziekenhuizen samenwerken, over twee weken naar buiten op een internationaal congres in Madrid.

Veelbelovend

,,De studie is veelbelovend,” zegt Emile Voest, internist-oncoloog van het Antoni van Leeuwenhoekziekenhuis. Maar er is volgens hem wél meer onderzoek nodig.>>>>>>>lees meer

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.

Abstract LBA59_PR

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.

DRUP studie, overzicht van personalised medicine, receptorenonderzoek, eiwitexpressie, DNA mutaties, prognosemodel, Personalized Cancer Treatment (CPCT)