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Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255. PowerPoint Presentation
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Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255.

Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255.

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Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255.

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  1. GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki,P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida,D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA;HELIOS Klinikum,BadSaarow, Germany; Asan Medical Center, Seoul, South Korea; Centre Léon Bérard, Lyon, France; Helsinki University Central Hospital, Helsinki, Finland;Mount Sinai School of Medicine,New York, NY, USA; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; Mannheim University Medical Center, Mannheim, Germany; Leiden University Medical Center, Leiden, Netherlands;Christie NHS Foundation Trust, Manchester, UK; Fox Chase Cancer Center, Philadelphia,PA, USA; UniversitaireZiekenhuisGasthuisberg, Leuven, Belgium; Mount Sinai Hospital, Toronto, Canada; InstitutGustaveRoussy, Villejuif, France; University of Palermo, Italy; Affiliated Hospital of Academy Military Medical Sciences, Beijing, China; Department of Surgery, Osaka Police Hospital, Osaka, Japan;Bayer HealthCare Pharmaceuticals, Berlin, Germany; IstitutoNazionaledeiTumori, Milan, Italy Randomized Phase III Trial of Regorafenibin Patients (pts) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST)Progressing Despite Prior Treatment with at least Imatinib (IM) and Sunitinib (SU): The GRID Trial

  2. Background: Advances and Limitations in Current Therapeutic Options for Patients with Metastatic GIST • GIST is the most common subtype of sarcoma and the most common mesenchymal malignancy of the GI tract • Tyrosine kinase inhibitors (TKIs) are the mainstay of therapy for patients with metastatic GIST, targeting the root cause of the disease: uncontrolled signaling from KIT or PDGFRA kinases • Imatinib and sunitinib are currently the only two drugs approved for the treatment of advanced GIST • Although imatinib and sunitinib have revolutionized the management of GIST, drug resistance remains a challenge • TKI-refractory GIST is a life-threatening unmet medical need

  3. Regorafenib (BAY 73-4506) is a Structurally Distinct Oral Inhibitor of Multiple Kinases Relevant to GIST and Other Cancers Regorafenib Biochemical activity Percent control 0% 0.1% 0.1-1% 1-5% 5-10% 10-35% Wilhelm SM et al. Int J Cancer 2011; 129: 245-255.

  4. Clinical Experience of Regorafenib in Patients With Solid Tumors and Advanced GIST: Rationale for Phase III Trial • Phase I dose escalation study in unselected solid tumor patients 1 • Established recommended phase II dose and schedule as160 mg orally once daily for 3 weeks on and 1 week off (4-week cycle) • Acceptable safety profile and preliminary evidence of efficacy • Phase II study in patients with metastatic GISTafter failure of at least imatinib and sunitinib2 • Disease control in 79% of patients • Median progression-free survival: 10 months • Median overall survival: not reached after 8.3 monthsof follow up Mross K et al. Clin Cancer Res 2012; 18: 2658-2667. George S et al. J ClinOncol2012; May 21 (epub ahead of print).

  5. GIST – RegorafenibIn Progressive Disease (GRID): Study Design Regorafenib + best supportive care (BSC) 160 mg once daily 3 weeks on, 1 week off (n=133) • Multicenter, randomized, double-blind,placebo-controlled phase III study • Global trial: 17 countries across Europe,North America, and Asia-Pacific • Stratification: treatment line (2 vs >2 prior lines),geographical location (Asia vs “Rest of World”) RANDOM I ZAT I ON Metastatic/ unresectable GIST pts progressing despite at least prior imatiniband sunitinib (n=236 screened; n=199 randomized) Disease progression per independent blinded central review 2 : 1 OF F TREATMENT Placebo + BSC 3 weeks on, 1 week off (n=66) Unblinding Crossover offered for placebo arm or continued regorafenib for treatment arm Regorafenib(unblinded)until next progression

  6. GRID Study: Endpoints • Primary Endpoint: Progression-Free Survival (PFS) • 90% power to detect 100% increase in PFS,hazard ratio [HR]=0.5, with 1-sided overall α=0.01 • Secondary Endpoints: • Overall survival • Time to progression • Overall response rate • Disease control rate • Duration of response • Exploratory Endpoints: • Correlative science to assess impact of GIST genotype with outcomes • Assay circulating DNA to screen more comprehensivelyfor GIST kinase mutations (“liquid biopsy”) • Health-related quality of life

  7. GRID Study: Patient Eligibility

  8. GRID Study: Baseline Patient Demographics

  9. GRID Study: Prior GIST Therapies at Entry

  10. GRID Study: Results • Patient accrual initiated January 2011 and completed July 2011 • Data cut-off for final efficacy analysis: January 2012 • Analysis of primary endpoint (PFS) demonstrated a highly statistically significant difference between regorafenib and placebo • Treatment was unblinded after reaching the prespecified number of events and final efficacy analysis • Data reviewed by steering committee and independent data and safety monitoring board

  11. GRID Study: Progression-Free Survival (primary endpoint per blinded central review) Regorafenib significantly improved PFS vs placebo (p<0.0001);primary endpoint met

  12. Prespecified Subgroup Analysis: PFS per central review

  13. GRID Study: Overall Survival (following 85% cross-over of patients on placebo arm) Because of the crossover design, lack of statistical significance between regorafenib and placebo was not unexpected

  14. Progression-Free Survival Following Crossover (per Investigator Assessment) Days from first progression for open label Days from first randomization for double blind Substantial PFS benefit in patients initially randomized to placebo and subsequently crossed over to open-label regorafenib PFS benefit in placebo arm after crossover to regorafenib is comparable to PFS benefit in patients initially randomized to regorafenib

  15. Disease Control and Overall Response Rates Responses based on modified RECIST v1.1 Regorafenib improved rates of disease control vs placebo

  16. Drug-Related Treatment-Emergent Adverse Eventsin ≥10% of Patients During Double-Blind Treatment Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of Study Treatment RegorafenibPlacebo 8 (6.1%) 5 (7.6%)

  17. Baseline GIST Genotype per Site Reports:Exploratory Analysis of Outcomes

  18. Conclusions • Regorafenib significantly increases PFS compared with placeboin patients with metastatic or unresectable GIST progressingdespite prior therapy with at least imatinib and sunitinib • PFS: median 4.8 vs 0.9 months, HR 0.27, p<0.0001 • No new or unexpected safety findings with regorafenib • Most common grade ≥3 adverse events related to regorafenib were hand-foot skin reaction, hypertension, and diarrhea • Regorafenib has the potential to fulfill an unmet need for advanced GIST patients progressing after imatinib and sunitinib • Potential new standard of care for this patient population

  19. Thanks to the patients, families, and colleagues at all of the investigating centers Lead investigators at centers which accrued patients to this trial: AUSTRIA: HellmutSamonigg, Thomas Brodowicz, Wolfgang Eisterer BELGIUM: Patrick Schöffski CANADA: Martin Blackstein, Karen Mulder, JawaidYounus CHINA: Jin Li, Shukui Qin, De Sen Wan, JianmingXu FINLAND: HeikkiJoensuu FRANCE: Jean-Yves Blay, Binh Bui Nguyen, Antoine Adenis, Axel Le Cesne GERMANY: Peter Reichardt, Jens Chemnitz, Sebastian Bauer, Peter Hohenberger, Viktor Grünwald, Frank Mayer, JochenSchütte ISRAEL: OferMerimsky ITALY: Paolo Casali, Guido Biasco, Massimo Aglietta, Giuseppe Badalamenti JAPAN: Toshihiko Doi, Tatsuo Kanda, Toshirou Nishida, Yasuhide Yamada, Yoshito Komatsu,Akira Sawaki NETHERLANDS: A J Gelderblom, Winette Van der Graaf POLAND: PiotrRutkowski SINGAPORE: Richard Quek SOUTH KOREA: Yoon-Koo Kang, Hyuk Chan Kwon, Seock-Ah Im, Joon Oh Park, Sun Young Kim SPAIN: Claudia M Valverde Morales, Xavier Garcia Del Muro UK: Ian Judson, Michael Leahy, Anne Thomas USA: George Demetri, Mary Louise Keohan, Michael Heinrich, Margaret von Mehren, Robin Jones, Bruce Brockstein, Pamela Kaiser, Keith Skubitz, Michael Gordon The GRID trial was sponsored by Bayer HealthCare AG, Leverkusen, Germany