Targets & therapies for colorectal cancer

Transcription

1 Targets & therapies for colorectal cancer Jan Schellens Werkgroep "MOLECULAIRE DIAGNOSTIEK IN DE PATHOLOGIE

2 Current treatment options for advanced colorectal cancer (CRC) First line: - CAPOX (+ bevacizumab) -FOLFOX (+ cetuximab/panitumumab) -FOLFIRI (+ cetuximab) Second line: - Irinotecan -FOLFIRI (+ cetuximab/panitumumab) Third line: -Cetuximab KRAS wildtype or -Panitumumab KRAS & NRAS wildtype rapporten]

3 Molecular pathway and incidence of KRAS and BRAF mutations Mutations in key proteins De Roock et al. Lancet Oncol 2010;11: Allegra et al. J Clin Oncol 2009;27(12): Di Nicolantonio et al. J Clin Oncol 2008;26(35):

4 Prognosis KRAS mutant vs KRAS wildtype CRUMS study n = 414 Eklöf et al. Br J Cancer 2013;108: Phipps et al. Br J Cancer 2013;108:

5 Influence of KRASmon effectiviness of EGFR inhibitors cetuximab / panitumumab Cetuximab + chemotherapy in KRASm vs KRASwt mcrc Panitumumab + best supportive care vs best supportive care only in KRASwt vs KRASmt mcrc Lièvre et al. Cancer Res 2006;66: Amado et al. J Clin Oncol 2008;26:

6 Overall survival panitumumab + FOLFOX4 vs FOLFOX4 in KRAS wt (exon 2) mcrc Proportion alive, % Events n/n (%) Median months (95% CI) Pani + FOLFOX4 256/325 (79) 23.8 ( ) FOLFOX4 alone 279/331 (84) 19.4 ( ) HR 0.83 (95% CI ) p= Months Exploratory analysis at 82% of OS events (KRAS wt) Douillard J-Y, et al. ASCO 2013 (Abstract No. 3620)

7 Overall survival panitumumab + FOLFOX4 vs FOLFOX4 alleen in KRASm (exon 2) mcrc 100 Events n/n (%) Median months (95% CI) Pani + FOLFOX4 193/221 (87) 15.5 ( ) FOLFOX4 alone 195/219 (89) 19.2 ( ) Proportion alive, % HR 1.16 (95% CI ) p= Months Exploratory analysis at >80% of OS events (KRAS mt) Douillard J-Y, et al. ASCO 2013 (Abstract No. 3620)

8 Influence of BRAFm on effectiveness of EGFR inhibitors cetuximab / panitumumab Response rate BRAFwt vs BRAFm OS BRAFwt vs BRAFm Yuan et al. PLoS ONE 2013;8(6):e65995

9 Vemurafenib response rate in BRAFmutant melanoma versus colon cancer Vemurafenib response rate in BRAFm melanoom vs colon cancer Unresponsive to BRAF inhibition despite BRAF mutation Flaherty et al. N Engl J Med 2010;363: Chapman et al. N Engl J Med 2011;364: Kopetz et al. ASCO 2010 (Abstract 3534)

10 Why are some tumors unresponsive to targeted therapy against specific mutated proteins? Bernards. Cell 2012;151:465-8

11 Negative feedback regulation of EGFR disappears upon BRAF inhibition in BRAFm CRC EGFR-inhibitor BRAF-inhibitor Proliferation Cell survival (anti-apoptosis) Angiogenesis Cell death Prahallad et al., Nature 2012

12 Translation of preclinical concept to the clinic

13 What about KRASm tumors? BRAF mutations: 10-15% in CRC KRAS mutations: 35-45% in CRC ±20% in NSCLC ± 90% in pancreatic cancer Is there a critical feedback mechanism in KRASm cells as well? Could a combination therapy also be effective for these tumors?

14 Targeting KRASm with downstream inhibition of MEK Low response rate upon MEK inhibition in KRASm xenograft models Migliardi et al. Clin Cancer Res 2012;18:

15 Translation of preclinical concept to the clinic Combining dacomitinib and PD in patients with KRASm tumors

16 Conclusions UnmetmedicalneedforpatientswithBRAFmandKRASmCRC Currently available therapies are rarely effective BRAFm CRC is unresponsive to BRAF inhibitor monotherapy Concomitant BRAF plus EGFR inhibition results in synergy in vitro and in vivo First evidence of effectiveness in the clinic KRASm CRC is unresponsive to MEK inhibitor monotherapy Concomitant MEK plus dual EGFR/HER2 inhibitor results in synergy Clinicalstudyduetostart January2014

17 Acknowledgement Rene Bernards Robin van Geel Annemiek Cats Monique van Leerdam Cecile Grootscholten Henk Boot Petra Nederlof Ferry Eskens Stefan Sleijfer Martijn Lolkema Emile Voest