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Updated results from the GRID trial – an international phase 3, randomized, double-blind, placebo- controlled trial of regorafenib in patients (pts) with.

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Presentation on theme: "Updated results from the GRID trial – an international phase 3, randomized, double-blind, placebo- controlled trial of regorafenib in patients (pts) with."— Presentation transcript:

1 Updated results from the GRID trial – an international phase 3, randomized, double-blind, placebo- controlled trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (im) and sunitinib (su) Presented at CTOS 2012 by Peter Reichardt on behalf of Team GRID, including: Paolo Casali, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Leahy, Margaret von Mehren, Heikki Joensuu, Robert Maki, Jianming Xu, Toshirou Nishida, Christian Kappeler, Iris Kuss, Dirk Laurent, and George Demetri HELIOS Klinikum, Bad Saarow, Germany; Istituto Nazionale dei Tumori, Milan, Italy; Asan Medical Center, Seoul, South Korea; Centre Léon Bérard, Lyon, France; Maria Skłodowska-Curie Memorial Cancer Center, Warsaw, Poland; Leiden University Medical Center, Leiden, Netherlands; Mannheim University Medical Center, Mannheim, Germany; Christie NHS Foundation Trust, Manchester, UK; Fox Chase Cancer Center, Philadelphia, PA, USA; Helsinki University Central Hospital, Helsinki, Finland; Mount Sinai School of Medicine, New York, NY, USA; Affiliated Hospital of Academy Military Medical Sciences, Beijing, China; Osaka Police Hospital, Osaka, Japan; Bayer HealthCare Pharmaceuticals, Berlin, Germany; Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

2 Regorafenib (BAY ) is a structurally distinct oral agent with a unique profile of inhibiting multiple kinases relevant to GIST Regorafenib IC 50 (nmol/l) KIT 7 VEGFR-1 13 Murine VEGFR-2 4 PDGFR-β 22 RET 1.5 B-RAF28 FGFR1202 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:

3 OFFTREATMENTOFFTREATMENT OFFTREATMENTOFFTREATMENT Disease progression per independent blinded central review Disease progression per independent blinded central review GIST – Regorafenib In Progressive Disease (GRID): study design Multicenter, randomized, double-blind (DB), placebo-controlled phase 3 study –Primary endpoint: progression-free survival (PFS) –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”) 2 : 1 Regorafenib + best supportive care (BSC) 160 mg once daily 3 weeks on, 1 week off (n=133) Regorafenib + best supportive care (BSC) 160 mg once daily 3 weeks on, 1 week off (n=133) Placebo + BSC 3 weeks on, 1 week off (n=66) RANDOMIZATIONRANDOMIZATION Unblinding Crossover offered for placebo arm or continued regorafenib for treatment arm Unblinding Crossover offered for placebo arm or continued regorafenib for treatment arm Regorafenib (unblinded) until next progression Metastatic/ unresectable GIST patients progressing despite at least prior imatinib and sunitinib (n=236 screened; n=199 randomized) Metastatic/ unresectable GIST patients progressing despite at least prior imatinib and sunitinib (n=236 screened; n=199 randomized)

4 Adverse events occurring in ≥20% of patients during double-blind treatment NCI-CTCAE v4.0 term Regorafenib (N=132), %Placebo (N=66), % All GradesG3G4G5All GradesG3G4G5 Hypertension HFSR Fatigue Diarrhea Oral mucositis Anorexia Constipation Abdominal pain Alopecia Hoarseness Fever Nausea NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events HFSR: hand–foot skin reaction On-study adverse events resulting in permanent discontinuation of study treatment, n (%) RegorafenibPlacebo 8 (6.1)5 (7.6)

5 PFS per blinded central review (primary endpoint) Regorafenib significantly improved PFS vs placebo (p<0.0001) Days from randomization PFS probability Placebo Regorafenib Regorafenib, N= months (4.1–5.8) 81 (60.9%) Placebo, N= months (0.9–1.1) 63 (95.5%) Median PFS (95% CI) Number of events Hazard ratio (95% CI):0.27 (0.19–0.39) 1-sided p-value:<0.0001

6 PFS per investigator assessment Regorafenib significantly improved PFS vs placebo (p< ) * A: value cannot be estimated because of censored data Days from randomization PFS probability Placebo Regorafenib Regorafenib, N= months (6.5–A*) 48 (36.1%) Placebo, N= months (1.0–1.9) 51 (77.3%) Median PFS (95% CI) Number of events Hazard ratio (95% CI):0.22 (0.14–0.35) 1-sided p-value:<

7 High rate of disease control despite low overall response rate with regorafenib Objective response rate6 (4.5)1 (1.5) Complete response0 (0.0) Partial response6 (4.5)1 (1.5) Stable disease (at any time)95 (71.4)22 (33.3) Progressive disease28 (21.1)42 (63.6) Responses based on modified RECIST v1.1 Regorafenib (N=133), n (%) Placebo (N=66), n (%) Disease control rate Complete response + partial response + durable stable disease (≥12 weeks) 70 (52.6)6 (9.1)

8 Continuing regorafenib after progression: PFS in initial blinded phase vs post-progression Rx (investigator assessments) Median PFS 7.4 months 4.5 months 5.0 months Continuing regorafenib after PD N=41 Regorafenib initial blinded Rx N=133 Regorafenib after PD on blinded placebo N=56 Days (from randomization for initial blinded Rx or from first progression for unblinded Rx) PFS probability 0 Progression on initial placebo, then crossed over to regorafenib (unblinded Rx) Regorafenib (initial blinded Rx) 350 Regorafenib (post-progression, unblinded Rx)

9 Prespecified subgroup analysis: PFS per central review Hazard ratio (95% Cl) Favors regorafenibFavors placebo Third Fourth or more Asia Rest of world North America Not North America Male Female <65 years ≥ 65 years <25 kg/m 2 25 to <30 kg/m 2 ≥30 kg/m <6 months ≥6 to <18 months ≥18 months All patients Anticancer line Region Sex Age BMI ECOG score Duration of imatinib treatment N Hazard ratio % Cl (0.19, 0.39) (0.14, 0.37) (0.18, 0.54) (0.15, 0.62) (0.16, 0.37) (0.19, 0.92) (0.15, 0.34) (0.20, 0.48) (0.09, 0.34) (0.19, 0.46) (0.08, 0.30) (0.18, 0.46) (0.12, 0.48) (0.06, 0.61) (0.14, 0.37) (0.18, 0.51) (0.17, 1.73) (0.07, 0.55) (0.15, 0.36)

10 Regorafenib GRID study: OS (following 85% crossover of patients on placebo arm) Days from randomization OS probability 0 Placebo Regorafenib, N=33 Placebo, N=66 Median OS Not reached Not reached Number of events 29 (21.8%) 17 (25.6%) Hazard ratio (95% CI): 0.77 (0.42–1.41) 1-sided p-value: 0.199

11 Subgroup PFS analysis of age in regorafenib group Age <65 years 65–74 years ≥75 years Median PFS (months) PFS probability (%) Months from randomization <65 years (n=90) 65–74 years (n=31) ≥75 years (n=12) Patients at risk <65 years –74 years ≥75 years

12 Subgroup PFS analysis of requirement for dose interruption in regorafenib group Dose interruption No dose interruption Median PFS (months) Months from randomization Dose interruption (n=84) No dose interruption (n=48) Patients at risk Dose interruption No dose interruption PFS probability (%)

13 Subgroup PFS analysis of requirement for dose reduction in regorafenib group Dose reduction No dose reduction Median PFS (months) Months from randomization Dose reduction (N=46) No dose reduction (N=86) Patients at risk Dose reduction No dose reduction PFS probability (%)

14 Summary Regorafenib significantly increased PFS compared with placebo in patients with metastatic or unresectable GIST –PFS: median 4.8 vs 0.9 months, hazard ratio 0.27, p< Regorafenib showed PFS benefit in most patient subgroups Post progression, regorafenib treatment showed sustained benefit –Continuing regorafenib post progression: median PFS 4.5 months –Placebo crossed over to regorafenib: median PFS 5.0 months OS rates were not statistically different, as expected, with crossover post progression to regorafenib in the majority of placebo-treated patients Benefit of regorafenib observed independent of: –Age of participants –Requirement for dose reduction or interruption

15 Thanks to patients, families, and colleagues at all of the investigating centers Lead investigators: AUSTRIAHellmut Samonigg, Thomas Brodowicz, Wolfgang Eisterer BELGIUMPatrick Schöffski CANADAMartin Blackstein, Karen Mulder, Jawaid Younus CHINAJin Li, Shukui Qin, De Sen Wan, Jianming Xu FINLANDHeikki Joensuu FRANCEJean-Yves Blay, Binh Bui Nguyen, Antoine Adenis, Axel Le Cesne GERMANYPeter Reichardt, Jens Chemnitz, Sebastian Bauer, Peter Hohenberger, Viktor Grünwald, Frank Mayer, Jochen Schütte ISRAELOfer Merimsky ITALYElena Fumagalli, Guido Biasco, Massimo Aglietta, Giuseppe Badalamenti JAPANToshihiko Doi, Tatsuo Kanda, Toshirou Nishida, Yasuhide Yamada, Yoshito Komatsu, Akira Sawaki NETHERLANDSHans Gelderblom, Winette Van der Graaf POLANDPiotr Rutkowski SINGAPORERichard Quek SOUTH KOREAYoon-Koo Kang, Hyuk Chan Kwon, Seock-Ah Im, Joon Oh Park, Sun Young Kim SPAINClaudia M Valverde Morales, Xavier Garcia Del Muro UKIan Judson, Michael Leahy, Anne Thomas USAGeorge 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


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