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Sponsored by ArQule, Inc.

Preliminary Results from a Phase 2 Study of ARQ 197 in Patients with Microphthalmia Transcription Factor Family (MiT) Associated Tumors.

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Sponsored by ArQule, Inc.

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  1. Preliminary Results from aPhase 2 Study of ARQ 197in Patients withMicrophthalmia Transcription Factor Family (MiT) Associated Tumors Andrew Wagner1*, George Demetri1, Edwin Choy2, Alberto Pappo3, Steven DuBois4, James Geller5, Lee Rosen6, Neil Senzer7, Karen Albritton1, Feng Chai8, Dora Ferrari8, John Goldberg9* 1Dana Farber Cancer Institute, Boston, MA; 2Massachusetts General Hospital, Boston, MA; 3Texas Children's Cancer Center, Houston TX; 4University of California San Francisco Medical Center, San Francisco, CA; 5Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 6Premiere Oncology, Santa Monica, CA; 7Mary Crowley Medical Research Center, Dallas, TX; 8ArQule, Inc., Woburn, MA ; 9University of Miami Miller School of Medicine, Miami, FL * These authors contributed equally to the study Sponsored by ArQule, Inc.

  2. Background – MiT Associated Tumors • Include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS) and Xp11.2-translocatedrenal cell carcinoma (tRCC) • Associated with dysregulation of a related group of transcription factors including MITF, TFE3 and TFEB • Generally resistant to all conventional systemic therapies

  3. Members of the MiT family of transcription factors are oncogenes Mechanism is dysregulated expression through amplification or translocation • MITF targeted by EWS-ATF1 in CCS • MITF amplified in melanoma • TFE3 translocated: ASPS, tRCC • TFEB translocated: tRCC MITF~TFE3~TFEB I. Davis/D. Fisher J. Fletcher M. Ladanyi L. Garraway/W. Sellers

  4. Transcription Factors are Notoriously Poor Drug Targets “Drugable” downstream gene products? MET is a transcriptional target of MiT family proteins

  5. J Biol Chem 2006 Cancer Res 2007

  6. MET and HGF are Highly Expressed in Primary Clear Cell Sarcoma Tumors Data from Segal et al J. ClinOncol 2003 Slide courtesy IJ Davis

  7. Clear Cell Sarcoma Cells Express Active HGF mRNA (PCR) HGF ELISA Starved 501mel Ian Davis/David Fisher

  8. ARQ 197 • Selective, non-ATP • competitive inhibitor of MET MET Ki for MET ~ 350 nM IC50s: CAMKIId ~ 10 mM Flt4 ~ 16 mM PAK3 ~ 6.6 mM Pim-1 33% inhibition @ 10 mM Ki orIC50 • ARQ 197 demonstrates a • favorable safety profile and • preliminary anti-cancer • activity in Phase 1 studies

  9. ARQ197 Inhibits Phospho-c-MET in CCS292 Cell Line CCS292 rhHGF (100 ng/ml): - + + + ARQ 197 (mM): 0 0 1 3 Phospho c-MET c-MET GI50 ~ 200 nM CCS292 cells were seeded in 96-well plates at 5,000 cells/well overnight in medium with 10% FBS. The next day, cells were treated with increasing concentrations of compound for 72 hours at 37° C. After addition of MTS reagents, the results were quantitated by spectrophotometry at l = 490 nm and the GI50 was determined. b-actin CCS292 cells courtesy of Jonathan Fletcher

  10. Study Design • Multi-center, single arm, two-stage Phase 2 trial of ARQ 197 in patients with MiT Associated Tumors • Objectives • Determine the ORR in patients treated with ARQ 197 • Evaluate PFS in patients treated with ARQ 197 • Evaluate 6-month and 1-year OS rates in patients treated with ARQ 197 • Further characterize the safety of ARQ 197 in adolescent and young adult patients with MiT tumors

  11. Inclusion Criteria • Tumor types: CCS, ASPS and tRCC • Patient age: ≥ 13 years • Patients with treated CNS metastases eligible if stable for ≥ 3 months and no neurologic symptoms • No limitation on number of prior therapies • Sufficient organ function

  12. Methods • Oral administration twice daily • Continuous dosing over 28-day cycles • Dosing initially 120 mg BID, then amended to 360 mg BID • 18 patients on 120 mg BID • 8 patients escalated from 120 to 360 mg BID • 15 patients on 360 mg BID • Tumor assessment by RECIST at 8-week intervals

  13. Enrollment Status Cumulative Enrollment Month and Year

  14. Demographics *12 patients aged 11.3-18 years

  15. Number and Sites of Lesions at Baseline • Median number of lesions at baseline: 5 • Location of lesions:

  16. Drug Safety (1)

  17. Drug Safety (2)

  18. Efficacy (1) # Disease control rate = (PR+SD) / Number of evaluable patients X 100 * In 3 of 9 RCC patients, Xp11.2 translocations (TFE3 gene fusions) were not confirmed 36 patients evaluable for efficacy analysis

  19. CT Scans of Patient 10 with CCS Baseline - April 7, 2008 Cycle 6 - October 6, 2008 (45.3% reduction) 29.4 mm 8.8 mm 18.3 mm 17.3 mm

  20. Kaplan-Meier TTP Curve ASPS (Day)

  21. Kaplan-Meier TTP Curve CCS (Day)

  22. Efficacy (2) Time to Progression (TTP)

  23. Median Time on Treatment ARQ 197 vs. Prior Systematic Therapy * Prior anticancer treatment history was not available for all patients.

  24. Conclusions • ARQ 197 has demonstrated a favorable safety profile in both adult and pediatric patients • Preliminary evidence of anti-cancer activity observed • Enrollment at 360 mg BID is ongoing

  25. Thank You! • Patients who participated in this study, their families, and referring physicians • Co-investigators and clinical research teams at participating sites

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