Targeting the Ras-Raf-Mek-Erk pathway Egbert F. Smit MD PhD Dept. Pulmonary Diseases Vrije Universiteit VU Medical Centre Amsterdam, The Netherlands K-Ras signalling in NSCLC Sun et al. Nature Rev. Cancer 7,738,2007 1
Driver Genes in Lung Adenocarcinoma Mutated Gene Frequency Drugs Classes Under Study KRAS mutations EGFR mutations BRAF mutations EML4-ALK translocation MEK mutated FGFR4 mutated PIK3CA KRAS/ NRAS 25% 1% ARQ197+erlotinib GSK MEKi EGFR 23% OSI906+erlotinib MM121+erlotinib NRAS 1% GSK MEKi HER2 2% BIBW 2992 EML4/ALK 7% BRAF 6% PF-02341066 (crizotinib) GSK1026 for V660E GSK MEKi for PI3K/AKT 5% BIM120 Ding L, et al. Nature. 2008;455:1069-1075. Yamamoto H, et al. Cancer Res. 2008;68:6913-6921. MET ampl 5% Crizotinib K-Ras is not a prognostic factor Long term follow up of JBR10 Test for interaction p=.97 N=451/482 K-Ras mutant 117 (24%) K-Ras WT 334 (69%) Butts et al. J. Clin. Oncol. 28,29,2010 2
K-Ras mutation is predictive for survival following chemotherapy. 2005 meta analysis HR for survival 1.40 (1.18-2.65). Mascaux et al. Br. J. Cancer. 92,131,2005 K-Ras Mutations are not predictive for survival following platinum based chemotherapy G60D Q61L 1,89% 1,89% G13V 3,77% 1,89% G12F 1,89% G12S 9,43% G13C G12V 22,64% soortkras G12V G12C G12A G12D G13C G12F G13V G12S G60D Q61L 9,43% G12D 5,66% G12A G12C 41,51% Dingemans et al. WCLC 2011 3
K-Ras Mutations are not predictive for response to EGFR TKI s. Brugger et al. J. Clin. Oncol. 29,4113,2011. K-Ras dependent and independent cell lines Singh et al. Cancer Cell 15,489,2009 4
Not all K-Ras is created equal. Secondary analysis from BATTLE Ihle et al. J. Natl. Cancer Inst. 104,1-12,2012 The Spectrum of Ras Mutations 5
K-Ras mutations confer different sensitivity to commonly used drugs in advanced NSCLC Garassino M C et al. Ann Oncol 2011;22:235-237 K-Ras directed trials - Completed Drug K-Ras mutant K-Ras WT DCR Median survival Salirasib 30/33 3/33 33% >9 months Sorafenib 57/57 53% 5.3 months Sorafenib 14/14 79% NR Tipifarnib NR NR 16% 7.7 months 6
A Phase II study of sorafenib in patients with locally advanced and/or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) with a K-Ras mutation Study objective To investigate the use of sorafenib in NSCLC with K-Ras mutation Study type/design Single arm Phase II study Inclusion criteria: stage IV NSCLC with proven K-Ras mutation; progression after 1 platinum doublet; ECOG 0-2; asymptomatic brain metastasis allowed All patients were treated with sorafenib (400 mg, bid) Primary endpoint: rate of no progression at 6 weeks Secondary endpoint: PFS Patients 57 patients with stage IV NSCLC received at least one dose of sorafenib Mean age 58.5 years; 28% male; 21/77% former/current smokers ECOG PS 0/1/2: 40/53/7% 2 nd /3 rd / 4 th line of treatment: 54/28/18% 81% adenocarcinoma Median duration of treatment 9 weeks (range 0-61 weeks) Dingemans et al. EJC: 2011; (suppl; abstr 27LBA) Primary endpoint: No progression at 6 weeks Key Results 1.0 Secondary efficacy endpoint: PFS 08 0.8 Median PFS: 2.3 months (95% CI: 1.6-3.0) Efficacy Partial response 9 (16%) Stable disease 21 (37%) Cumulative survival 0.6 0.4 Progressive disease 27 (47%) 0.2 No progression at 6 weeks 53% Primary endpoint was achieved 0.0 0 5 10 15 PFS (months) Sorafenib treatment was associated with a PFS of 2.3 months Dingemans et al. EJC: 2011; (suppl; abstr 27LBA) 7
Tivantinib + Erlotinib Combination in Non- Small Cell Lung Cancer NSCLC N = 154 Age 18 years Inoperable LA / metastatic disease 1 prior chemo (no prior EGFR TKI) R A N D O M I Z E Arm A: Tivantinib + (ARQ 197) 360 mg PO BID Arm B: Placebo PO BID + Erlotinib 150 mg PO QD Erlotinib 150 mg PO QD b Endpoints 1 PFS a 2 ORR, OS Subset analyses Crossover: ORR Accrual complete Archival tissue evaluated for EGFR / c-met / K-Ras status in pre-planned subset analyses a Based on investigator assessment. PFS defined by histology, molecular profile, and other prognostic characteristics. b Patients in the control arm were allowed to crossover to receive ARQ 197. Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; LA, locally advanced; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; TKI, tyrosine kinase inhibitor. Sequist LV, et al. J Clin Oncol. 2011. Submitted. 15 Progression-Free Survival in Histologic and Molecular Subgroups Median PFS (95% CI), months) n/n Tivantinib/Erlotinib Placebo/Erlotinib Squamous cell 26/24 3.2 (1.9-4.2) 2.0 (1.8-4.9) Non-squamous cell 58/59 4.4 (3.5-7.3) 2.3 (1.9-3.7) c-met FISH > 4 19/18 3.6 (1.9-5.7) 3.6 (1.7-3.8) c-met FISH > 5 8/11 5.6 (3.8 - NE) 3.6 (1.8-7.3) EGFR mutant 6/11 5.6 (1.9-7.5) 4.9 (1.9-8.4) EGFR wt 51/48 3.2 (1.9-4.2) 1.9 (1.8-2.3) KRAS mutant 10/5 2.3 (1.8 - NE) 1.0 (0.3-1.9) KRAS wt 49/45 3.6 (1.9-4.2) 2.3 (1.9-3.7) 0.18 0.45 Unadjusted HR 0.71 0.71 0.70 1.05 1.23 1.01 0 0.5 1.0 1.5 2.0 5.0 Favors ARQ 197/Erlotinib Favors Placebo/Erlotinib Abbreviations: CI, confidence interval; FISH, fluorescence in situ hybridization; HR, hazard ratio; PFS, progression-free survival; wt, wild type. Sequist LV, et al. J Clin Oncol. 2011. Submitted. 16 8
Increasing complexities B-Raf mutations in LAC vs Melanoma 3% of lung adenocarcinoma Paik et al. J. Clin. Oncol. 29,2046,2011 9
Non-V600E B-RAF mutation b/a sorafenib VUMC data on file Raf inhibitors in development 10
Raf inhibitors in NSCLC Drugs Phase B-Raf mut No patients Year GSK2118436 II V600E 40 2011 Increasing complexities 11
MEK Inhibition in Anti-Cancer Therapy RTK MEKi B-Raf Ras Tumor Type % B-Raf Mutant % Ras Mutant Melanoma 50 10 Pancreatic 90 A-Raf Colorectal 15 50 c-raf Ovarian 30 NSCLC 2 30 AML 30 Thyroid 40 70 MEK ERK 23 Cell Proliferation RP2 of AZD6244 vs Pemetrexed 3rd line NSCLC Hainsworth et al. J. Thor. Oncol. 5,1630,2010. 12
MEK inhibitors in NSCLC Drugs Phase K-Ras status No pts Year AZD6244 +/- II Mutant 100 2010 Erlotinib AZD6244 + I Mutant + WT 2010 TRT Docetaxel +/- II Mutant 87 Completed AZD6244 PD-325901 II Mutant + WT 34 Terminated due to toxicity GSK 1120212 I Mutant + WT 100 2010 + pem, carbo, nab-pac GSK 1120212 Vs Docetaxel II Mutant 141 2011 More Hurdles To Overcome 13
Paradoxal Activation Paradoxal Activation Pecker et al. Cancer Cell 20,715,2011 14
Alternative pathways Combination is Key Vertical blockade Raf + Mek inhibitors Combinations with PI3 kinase inhibitors Akt inhibitors mtor inhibitors 15
Thank You For Your Attentionti 16