New publication from UNITO

The UNITO team (D. Oddo et al.) has just published Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer in the British Journal of Cancer (DOI: 10.1038/bjc.2017.196).

Background: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAFV600E and MET amplification. However, after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.

Methods: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.

Results: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.

Conclusions: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

 

New MErCuRIC Publication

MErCuRIC researchers have recently published a review in Nature Reviews Clinical Oncology.

Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges

Conor A. Bradley, Manuel Salto-Tellez, Pierre Laurent-PuigAlberto BardelliChristian RolfoJosep TaberneroHajrah A. KhawajaMark LawlerPatrick G. JohnstonSandra Van Schaeybroeck & on behalf of the MErCuRIC consortium

Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)–hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.

EUPATI Seminar – Patient Involvement in Ethical Review of Clinical Trials

EUPATI is hosting a webinar on Guidance for Patient Involvement in Ethical Review of Clinical Trials, 29 May 2017 – 17:00 to 18:30 CET.

You can learn more and register here.

More information on the guidance developed by EUPATI can be found here.

Cancer Core Europe Summer School

Initiated in 2011 by the EurocanPlatform and since 2016 organized under the umbrella of Cancer Core Europe, the Summer School in Translational Cancer Research will once again take place in Portugal in Albufeira, 16 – 20 October, 2017. The registration deadline is 30 June 2017.

You can learn more about the course here: https://dktk.dkfz.de/en/training/dktk-summer-school/introdution.

 

EUPATI Expert Training Course

Applications are now being accepted for the third EUPATI Expert Training Course.

The EUPATI Training Course Patient Experts in Medicines Research & Development is an exciting and unique opportunity offering patient advocates expert-level training in medicines research and development, specifically tailored for them.

The application deadline is 31 March 2017.

Special Commendation’ for Research Engagement from Cancer Research

Congratulations to Margaret Grayson, our MErCuRIC Patient Representative, who received a ‘Special Commendation’ for Research Engagement from Cancer Research UK in 2016!

grayson

MErCuRIC – Year 3 Meeting

The MErCuRIC team met at UZA in Antwerp for our Year 3 meeting (05 – 06 Dec 2016). We discussed progress in the Phase I trial from the previous year, and mapped our clinical and translational activities for the coming year. As the dose escalation phase I study draws to a close, we are planning activities to initiate the dose expansion phase I study. Samples from this study will soon be sent to the translational research partners for analysis.

 

NCRI 2016

MErCuRIC results were presented in a poster at the NCRI Cancer Conference in Liverpool, UK on 08:15-11:00). The conference ‘showcases the latest basic, translational and clinical cancer research. It brings researchers together to share ideas and develop collaborations.’

‘MErCuRIC1: A Phase Ia study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in patients with advanced solid tumours’

Abstract

RAS activating mutations occur in ~55% of metastatic (m)CRC. RASMT and >50% of RASWT mCRC patients do not benefit from anti-EGFR antibodies. c-MET is overexpressed in ~50-60%, amplified in ~2-3% and mutated in ~1-3% of mCRC. Preclinical data support the clinical evaluation of MEK1/2 and METi, particularly in RASMT tumours and RASWT with aberrant c-MET expression. The study’s primary aim was to establish the maximum tolerated dose (MTD) and assess safety/toxicity profile of PD-0325901 MEKi/crizotinib METi in patients with advanced solid tumours using NCI CTCAE V4.03.

Method: A single arm, open-label phase I trial of PD-0325901 with crizotinib in patients with advanced solid tumours, measurable disease, ECOG PS 0-1 and adequate end organ function. Patients received oral PD-0325901 (days 1-21 every 28 days) at doses of 2-8mg BD with oral crizotinib continuously at 250mg OD or 200mg BD, using a rolling-6 design.Crizotinib started after a week lead-in with PD-0325901. Blood samples forpharmacokinetics, pERK and soluble c-MET levels and skin biopsies for pERK levels were collected.

Results: Between 12/2014 and 11/2015 we enrolled 25 patients; Male(13), Female(12), who received 52 cycles in total. Median age 63yrs (range 36-78). MTD was defined at the highest dose; crizotinib: 200mg BD continuously; PD-0325901: 8mg BD days 1-21 every 28 days at which 1/6 patients exhibited dose-limiting toxicity (fatigue). Drug-related adverse events were in keeping with single agent toxicity profiles, including rash, diarrhoea, fatigue, nausea, hypoalbuminemia and visual disturbances. Best clinical response was stable disease at end of cycle 2 in 4/25 patients.

Conclusion: MEK/METi can be given together at pharmacologically active doses. MTD for the PD-0325901/crizotinib combination was 8mg BD (days1-21) and 200mg BD continuously in a 28 day cycle. The combination is now being explored further with an alternate MEKi before expansion into RASMT and RASWT CRC with aberrant c-MET expression.EudraCT: 2014-000463-40.

img_0702

MErCuRIC Patient Representative with poster at NCRI

EUPATI Oct 2016 Newsletter

The latest newsletter from EUPATI is now available. This issue covers an update on national activities in 18 countries and information on the upcoming EUPATI 2016 conference All Aboard to a Better Health Future on 14 Dec 2016.

eupati-oct2016