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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 Biochemical activity Percent control IC50 (nmol/l) KIT 7 VEGFR-1 13 Murine VEGFR-2 4 PDGFR-β 22 RET 1.5 B-RAF 28 FGFR1 202 0% 0.1% 0.1-1% 1-5% 5-10% 10-35% Wilhelm SM et al. Int J Cancer 2011; 129:

3 GIST – Regorafenib In Progressive Disease (GRID): study design
2 : 1 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) RANDOM I ZAT I ON Metastatic/ unresectable GIST patients progressing despite at least prior imatinib and sunitinib (n=236 screened; n=199 randomized) Disease progression per independent blinded central review OF F TREATMENT Unblinding Crossover offered for placebo arm or continued regorafenib for treatment arm Regorafenib (unblinded) until next progression 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”) Best supportive care includes any method to preserve the comfort and dignity of the patient, excluding disease-specific antineoplastic therapy, such as any kinase inhibitor, chemotherapy, radiotherapy, or surgical intervention.

4 Adverse events occurring in ≥20% of patients during double-blind treatment
NCI-CTCAE v4.0 term Regorafenib (N=132), % Placebo (N=66), % All Grades G3 G4 G5 Hypertension 59.1 27.3 0.8 4.5 HFSR 56.8 20.5 13.6 Fatigue 50.0 3.0 37.9 1.5 Diarrhea 46.2 7.6 9.1 Oral mucositis 40.9 Anorexia 30.3 21.2 Constipation 28.0 22.7 Abdominal pain 26.5 15.2 Alopecia 24.2 Hoarseness 6.1 Fever 22.0 10.6 Nausea 12.1 On-study adverse events resulting in permanent discontinuation of study treatment, n (%) Regorafenib Placebo 8 (6.1) 5 (7.6) NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events HFSR: hand–foot skin reaction

5 PFS per blinded central review (primary endpoint)
Regorafenib, N=133 Placebo, N=66 Median PFS 4.8 months 0.9 months 1.00 (95% CI) (4.1–5.8) (0.9–1.1) Number of events 81 (60.9%) 63 (95.5%) 0.75 Hazard ratio (95% CI): 0.27 (0.19–0.39) 1-sided p-value: <0.0001 PFS probability 0.50 Placebo Regorafenib 0.25 Days from randomization Regorafenib significantly improved PFS vs placebo (p<0.0001)

6 PFS per investigator assessment
Regorafenib, N=133 Placebo, N=66 Median PFS 7.4 months 1.7 months (95% CI) (6.5–A*) (1.0–1.9) 1.00 Number of events 48 (36.1%) 51 (77.3%) Hazard ratio (95% CI): 0.22 (0.14–0.35) 1-sided p-value: < 0.75 PFS probability 0.50 0.25 Placebo Regorafenib 50 100 150 200 250 300 350 Days from randomization Regorafenib significantly improved PFS vs placebo (p< ) *A: value cannot be estimated because of censored data

7 High rate of disease control despite low overall response rate with regorafenib
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) Objective response rate 6 (4.5) 1 (1.5) Complete response 0 (0.0) Partial response Stable disease (at any time) 95 (71.4) 22 (33.3) Progressive disease 28 (21.1) 42 (63.6) Responses based on modified RECIST v1.1

8 Continuing regorafenib after progression: PFS in initial blinded phase vs post-progression Rx (investigator assessments) Continuing regorafenib after PD N=41 Regorafenib after PD on blinded placebo N=56 Regorafenib initial blinded Rx N=133 1.00 Median PFS months months months 0.75 PFS probability 0.50 Regorafenib (initial blinded Rx) 0.25 Regorafenib (post-progression, unblinded Rx) Progression on initial placebo, then crossed over to regorafenib (unblinded Rx) 50 100 150 200 250 300 350 Days (from randomization for initial blinded Rx or from first progression for unblinded Rx)

9 Prespecified subgroup analysis: PFS per central review
Hazard ratio 0.27 0.23 0.31 0.30 0.24 0.42 0.22 0.18 0.15 0.29 0.19 0.50 N 199 113 86 47 152 36 163 127 72 136 63 112 56 22 110 89 33 144 95% 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) (0.18, 0.51) (0.17, 1.73) (0.07, 0.55) (0.15, 0.36) All patients Anticancer line Region Sex Age BMI ECOG score Duration of imatinib treatment Third Fourth or more Asia Rest of world North America Not North America Male Female <65 years ≥ 65 years <25 kg/m2 25 to <30 kg/m2 ≥30 kg/m2 1 <6 months ≥6 to <18 months ≥18 months Favors regorafenib Favors placebo 0.5 1.0 1.5 2.0 Hazard ratio (95% Cl)

10 GRID study: OS (following 85% crossover of patients on placebo arm)
1.00 Placebo Regorafenib 0.75 Regorafenib, N=33 Placebo, N=66 Median OS Not reached Not reached Number of events (21.8%) (25.6%) Hazard ratio (95% CI): 0.77 (0.42–1.41) 1-sided p-value: 0.199 OS probability 0.50 0.25 50 100 150 200 250 300 350 400 Days from randomization

11 Subgroup PFS analysis of age in regorafenib group
100 <65 years (n=90) 65–74 years (n=31) ≥75 years (n=12) 75 PFS probability (%) 50 25 Age <65 years –74 years ≥75 years Median PFS (months) Months from randomization Patients at risk <65 years 54 50 19 5 65–74 years 20 15 4 2 ≥75 years 8 7 4 2

12 Subgroup PFS analysis of requirement for dose interruption in regorafenib group
100 75 Dose interruption (n=84) No dose interruption (n=48) PFS probability (%) 50 25 Dose interruption No dose interruption Median PFS (months) Months from randomization Patients at risk Dose interruption 57 49 19 6 No dose interruption 25 23 8 3

13 Subgroup PFS analysis of requirement for dose reduction in regorafenib group
100 Dose reduction (N=46) 75 No dose reduction (N=86) PFS probability (%) 50 25 Dose reduction No dose reduction Median PFS (months) Months from randomization Patients at risk Dose reduction 3 5 2 1 No dose reduction 4 7 6

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<0.0001 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: AUSTRIA Hellmut Samonigg, Thomas Brodowicz, Wolfgang Eisterer BELGIUM Patrick Schöffski CANADA Martin Blackstein, Karen Mulder, Jawaid Younus CHINA Jin Li, Shukui Qin, De Sen Wan, Jianming Xu FINLAND Heikki Joensuu 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, Jochen Schütte ISRAEL Ofer Merimsky ITALY Elena Fumagalli, Guido Biasco, Massimo Aglietta, Giuseppe Badalamenti JAPAN Toshihiko Doi, Tatsuo Kanda, Toshirou Nishida, Yasuhide Yamada, Yoshito Komatsu, Akira Sawaki NETHERLANDS Hans Gelderblom, Winette Van der Graaf POLAND Piotr Rutkowski 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


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