Crizotinib is a c-MET inhibitor that has demonstrated potent inhibitory activity against ALK fusion cells. The document discusses clinical trials of crizotinib in patients with ALK-positive non-small cell lung cancer (NSCLC). Results from Phase I and II trials showed an objective response rate of 57% and disease control rate of 87% with crizotinib. Current ongoing trials are evaluating crizotinib versus chemotherapy as first-line or second-line treatment in ALK-positive NSCLC.

1. Crizotinib (PF-02341066 ) c-MET inhibitor in Patient with Alk ( anaplastic lymphoma kinase ) -positive NSCLC MET is commonly overexpressed in lung cancer and its amplification may produce resistance to EGFR-TKI’s therapy EML4 (Echinoderm Microtube associated protein Like4) Alk (Anaplastic lymphoma kinase) fusion frequency=4% adenocarcinoma (at least 7 fusion variants) Crizotinib demonstrated potent growth inhibitory activity against H3122 (ALK fusion) cells Patients with ALK -positive NSCLC Do not Appear to Respond to EGFR TKIs Inamura K et al. J Thorac Oncol 2008;3:13–17 Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897 Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 ; Inversion Translocation OR Break-apart FISH assay for ALK -fusion genes Non-split signal Split signal

2. Available data with crizotinib Objective response rate (ORR): 57% (95% CI: 46, 68%) 57% in patients with PS 2 or 3 Response duration: 1 to 15 months Disease Control Rate (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%) No grade 3 or 4 toxicities reported. 2% of grade 3 constipation and 1% grade 2 nausea, diarrhea and vomiting, respectively. 42% grade 1 visual disturbance (changes in light/dark accommodation, no abnormalities on ophthalmologic exam) ORR according to previous line therapies No. prior regimens* ORR % (n/N) 0 80 (4/5) 1 52 (14/27) 2 67 (10/15) ≥ 3 56 (19/34)

3. Current crizotinib clinical trials Available at: www.clinicaltrials.gov . NCT00890825 . http://www.clinicaltrials.gov/ct2/show/NCT00890825?term=NCT00890825&rank=1 Key entry criteria (N=318) Positive for ALK by central laboratory 1 prior chemotherapy (platinum-based) PHASE III PHASE II Key entry criteria (N=250) Positive for ALK by central laboratory Progressive disease in Arm B of study A8081007 >1 prior chemotherapy Crizotinib 250 mg BID Pemetrexed 500 mg/m 2 or Docetaxel 75 mg/m 2 infused on day 1 of a 21-day cycle R Crizotinib 250 mg BID PHASE III Key entry criteria (N=344) Positive non squamous carcinoma for ALK by central laboratory Chemonaive patients Crizotinib 250 mg BID Pemetrexed 500 mg/m 2 Cisplatin 75 mg/m 2 or Carboplatin AUC5or6 infused on day 1 of a 21-day cycle R R Pemetrexed 500 mg/m 2 Cisplatin 75 mg/m 2 or Carboplatin AUC5or6 infused on day 1 of a 21-day cycle Primary Endpoint: PFS Primary Endpoint: PFS Primary Endpoint: ORR