PF , HKI 272 XL647, BIBW

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1 Targeted Therapy for Lung Cancer? Emerging Novel targets for NSCLC 11 th UCSF/UCD Thoracic Oncology Conference 11/21/29 Sarita Dubey, M.D., Medical Oncology University of California, San Francisco Cytotoxic chemotherapy is non-specific Benefit of one size fits all chemotherapy approach has plateaued Several critical pathways involved in initiation and progression of lung cancer identified viable pharmacologic targets PF 29984, HKI 272 XL647, BIBW 2992, BEZ 235 XL765 BEZ 235 ARRY 1

2 EGFR resistance Inhibition of EGFR by Gefitinib/erlotinib T79M mutation reduces ATP affinity of gefitinib/erlotinib MET amplification activated PI3K/Akt via ERBB3 OTHERS; Kras MT, PI3KCA MT MET & T79M account for 6-7% Engelman & Janne, CCR 28;14 Yun, PNAS 28; 15 2 nd Generation EGFR TKIs Overcoming EGFR resistance Other inhibitors XL 88 Eder ASCO 27 #3526 MET, VEGFR BIBW 2992 EGFR, HER2, Phase I NSCLC RR 2% HKI 272 XL 674 PF29984 EGFR, HER2,HER3, T79M EGFR, HER2, VEGFR2, T79M Irreversible Pan HER T79M Phase I 4% SD Phase II 29% RR Phase I PR1% Riley, T Thoracic Oncol 28, 3 Janne, ASCO 28, XL 184 Salgia ASCO 28, 3522 XL 765 Papadopoulos ASCO 28, # 351 BEZ 235 Engelman, Nat Med 28: 14 ARQ 197 Yap, ASCO 29, # 3523 MET, VEGFR2, RET PI3K, mtor PI3K, mtor MET 2

3 The Ras-Raf-MEK-ERK pathway Growth Factors Approach to Kras Mutation Kras driven mice adenocarcinoma B-Raf Mutations: malignant melanomas and papillary thyroid cancers, colon cancer GDP GTP RAS* Raf ligand Ras Mutations: lung, colon and pancreatic cancers Kras/BRaf mutations activate the MEK pathway Proliferation (Ki67) MEK1 MEK2 MEK Pathway ERK1 ERK2 P Cell death (Caspase 3) Migration Combined inhibition of PI3K, mtor, and MEK may efffectively treat Kras MT tumors Engelman, Nat Med, 28; 14 : 1351 Akt mtor X X PI3K PKC Ras NF-κB X Raf MEK1/2 Erk1/2 Angiogenesis inhibitors 3

4 Approaches to inhibition of VEGF signaling BEV, VEGF-TRAP Ligand sequestration: MAbs, soluble receptors Inhibitor Vatalanib (PTK787) AZD2171 Anti-anigiogenesis Receptor TKI s VEGFR 1 VEGFR 2 VEGFR PDGFR C-Kit FGFR Other Receptor blocking: MAbs TKI = tyrosine kinase inhibitor GW78634, AZD2171, vatalanib Tyrosine kinase inhibition: TKIs p85 PLCγ Transcription factor inhibition GRB2 SOS Inhibition of tyrosine phosphorylation and downstream signalling inhibition ras Pazopanib (GW78634) Sunitinib (SU11248) AG13736 Sorafenib (Bay 43-96) Zactima (ZD6474) Raf + + EGFR RET ESCAPE - Chemotherapy ± Sorafenib ESCAPE - Chemotherapy ± Sorafenib Overall Survival Stage IIIB/IV NSCLC PS -1 Stratification: Geographic region ECOG PS vs 1 Squamous vs non-squamous cell Stage IIIb (with effusion) vs Stage IV Hanna, Chest Conference, 28, Abstr # 13 Carboplatin AUC 6 d1 + Paclitaxel 2 mg/m2 d1 + Sorafenib 4 mg bid d2-19, q3w (CPS) Carboplatin AUC 6 d1 + Paclitaxel 2 mg/m2 d1 + Placebo d2-19, q3w (CPP) Sorafenib Placebo Survival Probability HR = % CI:.95, 1.43 P =.93 Hanna, Chest Conference, 28, Abstr # 13 Oct 27 Sept 28* Months CPS Median: 1.7 months 95% CI: 9.3, 13.9 CPP Median: 1.6 months 95% CI: 9.7, Survival Probability HR = % CI:.93, 1.28 P = Months CPS Median: 1.5 months 95% CI: 9.2, 11.7 CPP Median: 1.7 months 95% CI: 9.8,

5 Many Targeted Therapies Failed to Show Additional Benefit when Combined with Platinum Based CT Median Survival results in months Placebo Agent INTACT-1 CG ± gefitinib /9.9 NS INTACT-2 CP ± gefitinib /8.7 NS TRIBUTE CP ± erlotinib NS TALENT CG ± erlotinib NS SPIRIT-1 VC ± bexarotene NS SPIRIT-2 CP ± bexarotene NS Paz-Ares et al. CG ± aprinocarsen NS ISIS-3521 CP ± aprinocarsen NS AG CG ± prinomastat NS BR.18 CG ± BMS NS Study 544 CP± panitumumab NS BR.24 CbP ± cediranib Will not proceed to Phase III because of toxicity Courtesy: E. Vokes CALGB 367: Sunitinib as Maintenance Therapy in Nonprogressing Advanced NSCLC Patients Patients with untreated stage IIIB/IV NSCLC and ECOG PS 1 Four cycles of platinum-based chemotherapy* (PI: Mark Socinski) Randomization of responding patients or patients with stable disease stratified by prior treatment with/without bevacizumab Sunitinib 37.5 mg/day Placebo Continue until disease progression Planned follow-up: 1 year 1 Endpoint - PFS *Platinum-based regimen may include carboplatin/cisplatin plus paclitaxel, docetaxel, vinorelbine or gemcitabine with or without bevacizumab (bevacizumab discontinued after four cycles) At progression, patients receiving placebo may cross over to the sunitinib arm Vascular Disrupting Agents VDA s VDA Large established BVs Central part of tumor Apoptosis Antiangiogenic Small new BVs Peripheral tumor Inhibition of proliferation Tubulin antagonists AVE862A Combretastatin A4 ZD6126 Flavone acetic acids ASA44 (DMXAA) Kelland. Curr Cancer Ther Rev. 25;1:1-9. 5

6 ASA44: VDA Molecular target - unclear Early phase : apoptosis of endothelial cells Late phase: may stimulate IκB kinase, thereby releasing active NF-κB influence the organization of the cytoskeleton causing loss of contact between adjacent cells, and increasing vascular permeability ASA44 with Paclitaxel/Carboplatin Advanced NSCLC Phase II Extension ASA44 1,8 mg/m 2 + P/C Response N = 29 PR 11 (37.9%) SD 14 (48.3%) Median TTP Median survival 5.5 mo 14.9 mo Baguley. Lancet Oncol. 23;4: McKeage et al. IASLC 27. Ongoing studies with ASA 44 ATTRACT I : First line Carboplatin/taxol ± ASA44 ATTRACT 2 Second line Docetaxel ± ASA44 6

7 Targeting IGFR IGF-1R in lung cancer InsR-B Ins Courtesy: K. Reckamp InsR-A IGF-II IGF-1R MoAbs IMC-A12 AMG 479 CP-751,871 R157 TKI s OSI 96 IGF-I XL228 IGF-2R M6P/IGF-2R Survival Proliferation Metastasis EGF HGF EGFR IGF1/ IGF2 and IGF-1R are overexpressed in NSCLC and correlate with decreased apoptosis (Pavelic 25 ). More than 5% of squamous cell cancers of the lung have LOH or mutation of M6P/IGF-2R (Kong 2). Loss of heterozygosity (LOH) of M6P/IGF-2R is associated with increased amount of IGF-2 protein and a higher proliferation index (Ki67). IGF level associated with worse prognosis in stage I NSCLC (Merrick ASCO 27, Abst#755) MoAbs Targeting IGF-1R Agent Type of Antibody Studies IMC- A12 Fully human bivalent MoAb Phase II planned NSCLC CP-751,871 Fully human MoAb Phase III planned NSCLC Phase II sarcoma AMG 479 Fully human MoAb Phase I Phase II sarcoma MK 646 Fully human MoAb Phase II planned NSCLC R157 Fully human Phase II sarcoma Inhibit binding of ligand to receptor, inhibit receptor activation, receptor internalization Phase II of CP-751,871(Figitumumab) with paclitaxel, carboplatin in first-line advanced NSCLC 2:1 randomization Step 3: single-arm, post-study extension in squamous n=97 n=53 PCI: paclitaxel 2 mg/m 2, carboplatin (AUC=6), Step 1: CP-751,871 1 mg/kg Step 2: CP-751,871 2 mg/kg PC: paclitaxel 2 mg/m 2, carboplatin (AUC=6) PCI: paclitaxel 2 mg/m 2, carboplatin (AUC=6) CP-751,871 2 mg/kg CP-751,871 Single agent PCI Optional upon progression CP-751,871 Single agent 3 patients (14 evaluable) Karp, JCO 29, 27:2516 7

8 Phase II of Figitumumab with paclitaxel, carboplatin in first-line advanced NSCLC Response rates PCF (2mg/m2 dose) Adenoca 57% 25% Squamous 78% 46% NOS 5% 52% PC Karp, ASCO 28, Abstr # 815 Progression rate (%) Phase II of Figitumumab with paclitaxel, carboplatin in first-line advanced NSCLC Progression Free Survival (PFS) All Histologies Dose (PC + F mg/kg) 1 2 Median PFS (months) Hazard Ratio Squamous Cell Dose (PC + F mg/kg) 2 Sample size (n) 13 9 Median PFS (months) PC 2 PCF 1 mg/kg PCF 2 mg/kg Time (months) Study Design CALGB 383 NSCLC II/IIIA Phase II PET/MRI Med-scopy/ EBUS Tumor/blood Biomarker analysis R A N D O M IZ E Cisplatin docetaxel q 21 days x 3 cycles Cisplatin docetaxel q 21 days x 3 cycles MK646 1mg/kg/wk MK646: 1mg/Kg once weekly beginning with first dose of chemotherapy and continuing until one week prior to surgery. PI: Dubey 8

9 Toxicities of targeted Unique : quite different from cytotoxics Anti-angiogenic : hypertension, hemorrhage, poor wound healing, proteinuria IGFR inhibitors: hyperglycemia inhibitors: skin rash, transaminitis, interstitial lung disease Multi- TKI: QT prolongation, sdubey@medicine.ucsf.edu 9