1. Sorafenib is active in patients with imatinib and sunitinib-resistant gastrointestinal stromal tumors (GIST): A phase II trial of the University of Chicago Phase II Consortium L Wiebe, K Kasza, RG Maki, DR D’Adamo, WA Chow, JL Wade, E Agamah, WM Stadler, EE Vokes, HL Kindler

2. Disclosures Authors with no disclosures : L Wiebe, K Kasza, WA Chow, JL Wade HL Kindler Bayer: Honorarium EE Vokes Bayer: Compensated consultant/advisor WM Stadler Bayer: Compensated consultant/advisor, Research funding Onyx: Compensated consultant/advisor DR D’Adamo Bayer: Compensated consultant/advisor, Research funding RG Maki Bayer: Research funding

3. Treatment of Advanced GIST 1 st line: Imatinib Response rate: 80% Median PFS: 19 months 2 nd line: Sunitinib Response rate: 7% Median PFS: 6.2 months After failure on imatinib and sunitinib: Therapeutic options are limited

4. Sorafenib in GIST Sorafenib inhibits KIT, VEGFR and PDGFR-β In preclinical models: Sorafenib inhibits KIT activity and cell growth of multiple IM-resistant KIT mutants 1 In a randomized, phase II discontinuation trial: 2 patients with imatinib-resistant GIST developed partial responses lasting 11 months 2 1 Guo, Clin Ca Res 2007 2 Ratain, Proc ASCO 2004

5. Endpoints Primary: Objective response rate Secondary: Toxicity Progression-free survival Overall survival Laboratory: Correlate KIT or PDGFR-α mutations with outcome

6. Trial Design and Statistical Analysis NCI-sponsored, multi-center phase II trial IM-resistant GIST: Closed to further accrual IM/SU-resistant GIST: –After FDA approval of sunitinib for 2 nd -line treatment –Cohort currently enrolling Simon minimax 2-stage design requires: 18 IM/SU-RES pts in 1 st stage If ≥ 1 response, proceeds to 2 nd stage for an additional 14 IM/SU-RES pts ≥ 4 responses in 32 IM/SU-RES pts required to show drug activity

7. Eligibility Criteria - 1 KIT-expressing GIST –histologically-confirmed and unresectable Documented disease progression –per RECIST, on or after imatinib In 8/06, study amended to require: –progression on or after IM and SU No chemotherapy, embolization, or other investigational agents after sunitinib > 14 days since prior sunitinib

8. Eligibility Criteria - 2 ECOG Performance Status: 0-2 Measurable disease per RECIST Adequate hematologic, hepatic, renal function Anticoagulation permitted with: –A stable INR –No clear bleeding risks No bowel obstruction or perforation Specimen availability for correlative studies: –Tumor block or 10 unstained slides Written informed consent

9. Treatment Sorafenib 400 mg po BID One cycle = 28 days CT scans every 2 cycles Only 2 dose reductions permitted: Level -1 = 200 mg BID Level -2 = 200 mg QD Patient medication diaries collected

10. Patient Characteristics CharacteristicIM-RES N=6 IM/SU-RES N=23 OVERALL N=29 Median Age (yrs) Range 57 54-82 56 42-85 57 42-85 ECOG PS 0 1 2 4 (67%) 2 (33%) 0 (0%) 8 (35%) 13 (56%) 2 (9%) 12 (41%) 15 (52%) 2 (7%) Primary Site: Small intestine Stomach Unknown Colon 2 (33%) 1 (17%) 3 (50%) 0 (0%) 5 (22%) 9 (39%) 7 (30%) 2 (9%) 7 (24%) 10 (34%) 2 (7%) Metastatic sites: Liver Peritoneum 3 (50%) 5 (83%) 20 (87%) 15 (65%) 23 (79%) 20 (69%)

11. Drug Delivery Total # cycles154 Median4 Range1 - 15 % patients requiring dose reduction 59%

12. Toxicities (N=29) ToxicityGrade 3 % pts Grade 4 % pts Hypertension 24%-- Hand-foot 24%-- Rash 17%-- Diarrhea 10%-- Fatigue 7%-- Hemorrhage 7%-- Thrombosis--3% Perforation 3%-- Anemia 3%--

13. IM-RES (N=6) IM/SU- RES (N=23) OVERALL (N=29) Complete Response 0 (0%) Partial Response 1 (17%) 3 (13%)4 (14%) Stable Disease 3 (50%)15 (65%)18 (62%) Disease control: CR+PR+SD 4 (67%) 18 (78%) 22 (76%) Response

14. Best Response -100 -80 -60 -40 -20 0 20 40 60 80 100 PD PR % Change In Tumor Size + indicates new lesions 4 Partial Response 18 Stable Disease 7 Progressive Disease

15. Progression-Free Survival 0.00 0.25 0.50 0.75 1.00 Survival Probability 051015 Time (months) IM-RESIM/SU-RES IM-RES: 3.4 months IM/SU-RES: 5.7 months

16. Overall Survival 0.00 0.25 0.50 0.75 1.00 Survival Probability 05101520 Time (months) IM-RESIM/SU-RES IM-RES 13.6 months IM/SU-RES 8.5 months

17. Mutational Analysis: Methods 22 samples analyzed to date 5 IM-RES 17 IM/SU-RES All 22 samples obtained at diagnosis, prior to IM 6 additional samples obtained prior to sorafenib –Analysis pending Paraffin-embedded tissue PCR used to sequence DNA hotspots All 22 samples sequenced for KIT exons 9 and 11

18. Mutational Analysis: Results KIT Receptor Exon 11 mutations: 14 patients (63%) –Deletions (7), point mutations (5), insertions (1), and internal tandem duplication (1) Exon 9 mutations: 2 patients (9%) –Both samples had 3 amino acid internal tandem duplications –Both patients had SD for  6 months PDGFRA Exon 18: 1 patient: D842V substitution

19. Preliminary Mutational Data and Outcome ResponseExon 11 Exon 9 Neither exon 9 or 11* PDGFR-  ND** PR211 SD SD  6 mo 9292 2222 2121 14242 PD 313 *Pending analysis of exon 13, 17 and PDGFR-  mutations **ND = Not done

20. Conclusions Sorafenib has activity in imatinib/sunitinib-resistant GIST –Disease control rate 76% Sorafenib is reasonably well-tolerated –HTN and HFS most common grade 3 toxicities –Dose reductions required in 59% of patients Mutational analysis is ongoing Enrollment continues

21. Acknowledgments The patients who participated in this study University of Chicago: Hedy Lee Kindler, Kristen Kasza, Blase Polite, James Jin, Walter Stadler, Halla Nimeiri, Dan Catenacci, Everett Vokes Memorial Sloan Kettering Cancer Center: Cristina Antonescu, Robert Maki, David D’Adamo University of California at Davis: David Gandara City of Hope National Medical Center: Warren Chow Decatur Memorial Hospital: Phillip Dy Central Illinois Hematology/Oncology: Edem Agamah National Cancer Institute: John Wright Supported by NCI N01-CM-17102