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Axel Grothey , MD

Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Axel Grothey , MD.

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Axel Grothey , MD

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  1. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT)of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies Axel Grothey, MD Co-investigators: Alberto Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou,Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon,Andrea Wagner, Eric Van Cutsem CORRECT: Patients with metastatic colorectal cancer treated with  regorafenib or placebo after failure of standard therapy

  2. Standard management of mCRC • Globally, 1,234,000 new CRC cases and 608,000 deaths each year1 • Vast majority of patients with mCRC are in a palliative situation2 • Standard medical treatment options:2 • 5-Fluorouracil + folinic acid/leucovorin or capecitabine • Oxaliplatin • Irinotecan • Bevacizumab • Cetuximab or panitumumab for KRAS wild-type CRC • No standard salvage therapy, although many patients long retain good performance status • High unmet clinical need for active salvage therapy! GLOBOCAN Cancer fact sheets: colorectal cancer. 2008. NCCN Guidelines. Colon cancer. v.2.2012.

  3. Multiple signaling pathways activated in CRC Figure adapted from Siena S et al 20092 • Multiple pathways implicated in CRC,including:1–3 • EGF / EGFR • VEGF / VEGFR • PDGF / PDGFR • FGF / FGFR • Downstream pathways: • RAS–RAF–MEK–ERK • PI3K–PTEN–AKT–mTOR • Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI3 • Provides rationale for using a multitargeted agent following progression Macarulla T et al. Clin Colorectal Cancer 2006 Siena S et al. J Natl Cancer Inst 2009 Kopetz S et al. J Clin Oncol 2010

  4. Mode of action of regorafenib (BAY 73-4506) • Regorafenib inhibits multiple cell-signaling kinases: • Angiogenic • VEGFR1–3, TIE2 • Stromal • PDGFR-β, FGFR • Oncogenic • KIT, PDGFR, RET • T1/2 in man: approx. 26-28 hrs • Two major metabolites (M2, M5) are pharmacologically active Wilhelm SM et al. Int J Cancer 2011

  5. Clinical rationale for regorafenib in CRC: Phase I experience • 38 patients with mCRC at dose levels of 60–220 mg/day (3 weeks on, 1 week off) • 26 patients received regorafenib at 160 mg daily, the dose recommended for further studies • 27 patients evaluable for response: • Disease control rate (DCR): 74% • Partial response n=1 (4%) • Stable disease ≥7 weeks n=19 (70%) • PFS: median 101 days (range 1–279 days) • At steady state, regorafenib and its active metabolites had similar systemic exposure • Pharmacodynamic assessment indicated decreased tumor perfusion in most patients Strumberg D et al. ASCO 2009, abstr. 3560 (poster update)

  6. CORRECT study design Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025 RANDOM I ZAT I ON • Multicenter, randomized, double-blind, placebo-controlled, phase III • 2:1 randomization • Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region • Global trial: 16 countries, 114 active centers • 1,052 patients screened, 760 patients randomized within 10 months • Secondary endpoints: PFS, ORR, DCR • Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers mCRC after standard therapy 2 : 1 Placebo + BSC 3 weeks on, 1 week off

  7. Patient eligibility • Histological or cytological documentation of adenocarcinoma of the colon or rectum • Disease progression during, or within 3 months after last administration of approved standard therapies • Standard therapies had to include fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab (if KRAS wild-type) • Age ≥18 years, ECOG performance status 0–1, life expectancy ≥3 months

  8. Patient demographics

  9. Baseline disease characteristics *KRAS status based on historical patient record

  10. Overall survival (primary endpoint) • RegorafenibPlacebo 1.00 Median 6.4 mos 5.0 mos 95% CI 5.9–7.3 4.4–5.8 0.75 Hazard ratio: 0.77(95% CI: 0.64–0.94) 1-sided p-value: 0.0052 Survival distribution function 0.50 0.25 Placebo N=255 Regorafenib N=505 0 0 50 100 150 200 250 300 350 400 450 Days from randomization Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)

  11. Progression-free survival (secondary endpoint) 1.00 • RegorafenibPlacebo Median 1.9 mos 1.7 mos 95% CI 1.9–2.1 1.7–1.7 0.75 Hazard ratio: 0.49(95% CI: 0.42–0.58) 1-sided p-value: <0.000001 Survival distribution function 0.50 Placebo N=255 0.25 Regorafenib N=505 0 0 50 100 150 200 250 300 350 Days from randomization

  12. Overall response and disease control rates(secondary endpoints) *DCR = PR + SD; p<0.000001

  13. Efficacy subgroup analyses • Based on preliminary results, no apparent effect of historical KRAS status on efficacy was observed • Biomarker analyses of plasma and tissue samples collected in this study are ongoing • Quality of life analysis ongoing

  14. Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade

  15. Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade

  16. Summary of CORRECT results • The study met its primary endpoint at the preplanned interim analysis • Regorafenib vs placebo: • Overall survival: 6.4 vs 5.0 months, HR=0.77, p=0.0052 • Crossed prespecified boundary (1-sided p<0.009279) • Progression-free survival: 1.9 vs 1.7 months, HR=0.49, p<0.000001 • Disease control rate (PR + SD): 44.8% vs 15.3%, p<0.000001 • No new or unexpected safety findings: • Main treatment-related adverse events observed in the regorafenib arm were fatigue, hand–foot skin reaction, diarrhea, anorexia, voice changes, hypertension, oral mucositis, and rash/desquamation

  17. Conclusions • Regorafenib: • Increases overall survival vs placebo in patients with mCRC progressing after standard therapies • First small-molecule multi-kinase inhibitor with proof of efficacy in CRC • Potential new standard of care in this patient population • CORRECT demonstrates that: • We can accrue to placebo-controlled trials in a patient population with an unmet need • Refractory CRC is a realistic setting for drug development

  18. Thanks to the investigating centersand study participants Lead investigators: AUSTRALIA: Philip Beale, Kathryn Field, Peter Gibbs, Nick Pavlakis, Timothy Price; BELGIUM: Eric van Cutsem, JochenDecaestecker, Alain Hendlisz, Yves Humblet, Marc Peeters,Jean-Luc Van Laethem; CANADA: Mary Mackenzie, Wilson Miller, Mark Rother, RafalWierzbicki,AsifShaik, Scott Berry; CHINA: JianmingXu; CZECH REPUBLIC: VladimiraStahalova, IlonaKocakova, BohuslavMelichar, EugenKubala; FRANCE: Marc Ychou, Olivier Bouche, Thierry Andre, Antoine Adenis, Mohamed Hebbar, Olivier Dupuis, Jean-Francois Seitz, Laurent Mineur, Christian Borel; GERMANY:H.-J. Schmoll, Martin Becker, Claudio Denzlinger, Volker Heinemann, MeinolfKarthaus, Claus-Henning Koehne, Nicolas Ziegenhagen, HendrikKroening, Wolfgang Schepp, TanjaTrarbach, Michael Clemens,Gunnar Folprecht, Ulrich Hacker, Ralf-Dieter Hofheinz, Arndt Vogel; HUNGARY: Janos Szanto,Laszlo Thurzo; ISRAEL: AdiShani, EinaShaham-Shmueli, Alex Beny, Ayala Hubert, Sofia Man,Baruch Brenner; ITALY: Alberto Sobrero, GiacomoCarteni, Gabriele Luppi, Alfredo Falcone,Salvatore Siena, Alberto Zaniboni, Carlo Barone, FortunatoCiardiello, CorradoBoni; JAPAN: Hideo Baba, Eishi Baba, TadamichiDenda, Hirofumi Fujii, JunjiFuruse, Etsuko Warita, Yoshito Komatsu,Nobuyuki Mizunuma, Tomohiro Nishina, Yasutsuna Sasaki, HiroyaTakiuchi, Kazuma Kobayashi,Hiroyuki Uetake, Takashi Ura, Yasuhide Yamada, Kensei Yamaguchi, Kentarou Yamazaki, Takayuki Yoshino, Hideyuki Mishima; NETHERLANDS: A. J. Gelderblom, D. H. Verheul; SPAIN: JosepTabernero,Rocio Garcia-Carbonero, CarlesPericayPijaume, Cristina Gravalos, Manuel Benavides, Javier Sastre, Jaime Feliu, Mercedes Martinez Villaca; SWITZERLAND: Arnaud Roth; TURKEY: Mustafa Benekli,FarukAykan; USA: Axel Grothey, Billy Clowney, Martin Hyzinski, Ali Khojasteh, Marc Saltzman,Heinz-Josef Lenz, UditVerma, John Kugler, JyotsnaFuloria, Kenneth Nahum, George Kim, Rex Mowat, Philip Stella, Martin Wiesenfeld, Brian Dicarlo, George Geils, Youram Nassir The CORRECT trial was sponsored by Bayer HealthCare AG, Leverkusen, Germany

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