Randomized Phase III 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): The GRID Trial 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,Bad Saarow, 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;
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Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255.
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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
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,Bad Saarow, 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; Universitaire Ziekenhuis Gasthuisberg, Leuven, Belgium; Mount Sinai Hospital, Toronto, Canada; Institut Gustave Roussy, 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; Istituto Nazionale dei Tumori, Milan, Italy
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
Regorafenib (BAY 73-4506) is a Structurally Distinct Oral Inhibitor of Multiple Kinases
Relevant to GIST and Other Cancers
Wilhelm SM et al. Int J Cancer 2011; 129: 245-255.
Regorafenib
IC50 (nmol/l)KIT 7
VEGFR-1 13Murine VEGFR-2 4
PDGFR-β 22RET 1.5
B-RAF 28FGFR1 202
Biochemical activityPercent control
0%0.1%
0.1-1%1-5%
5-10%10-35%
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 sunitinib 2
– Disease control in 79% of patients– Median progression-free survival: 10 months– Median overall survival: not reached after 8.3 months of follow up
1. Mross K et al. Clin Cancer Res 2012; 18: 2658-2667.2. George S et al. J Clin Oncol 2012; May 21 (epub ahead of print).
OF F
TREATMENT
Disease progression
per independent blinded central review
GIST – Regorafenib In Progressive Disease (GRID): Study Design
• 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”)
Wild type KIT and PDGFRA 2 (5.6%) 6 (10.0%) 8 (8.3%)
Unspecified or other exon mutant 11 (30.5%) 11 (18.3%) 22 (22.9%)
Baseline GIST Genotype per Site Reports:Exploratory Analysis of Outcomes
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
Thanks to the patients, families, and colleagues at all of the investigating centers
Lead investigators at centers which accrued patients to this trial:AUSTRIA: Hellmut Samonigg, Thomas Brodowicz, Wolfgang EistererBELGIUM: Patrick SchöffskiCANADA: Martin Blackstein, Karen Mulder, Jawaid YounusCHINA: Jin Li, Shukui Qin, De Sen Wan, Jianming XuFINLAND: Heikki JoensuuFRANCE: Jean-Yves Blay, Binh Bui Nguyen, Antoine Adenis, Axel Le CesneGERMANY: Peter Reichardt, Jens Chemnitz, Sebastian Bauer, Peter Hohenberger, Viktor Grünwald,
Frank Mayer, Jochen SchütteISRAEL: Ofer MerimskyITALY: Paolo Casali, Guido Biasco, Massimo Aglietta, Giuseppe BadalamentiJAPAN: Toshihiko Doi, Tatsuo Kanda, Toshirou Nishida, Yasuhide Yamada, Yoshito Komatsu,
Akira SawakiNETHERLANDS: A J Gelderblom, Winette Van der GraafPOLAND: Piotr RutkowskiSINGAPORE: Richard QuekSOUTH KOREA: Yoon-Koo Kang, Hyuk Chan Kwon, Seock-Ah Im, Joon Oh Park, Sun Young KimSPAIN: Claudia M Valverde Morales, Xavier Garcia Del MuroUK: Ian Judson, Michael Leahy, Anne ThomasUSA: 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