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

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!

1. GLOBOCAN Cancer fact sheets: colorectal cancer. 2008.2. NCCN Guidelines. Colon cancer. v.2.2012.

Multiple signaling pathways activated in CRC

• 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

1. Macarulla T et al. Clin Colorectal Cancer 20062. Siena S et al. J Natl Cancer Inst 20093. Kopetz S et al. J Clin Oncol 2010

Figure adapted from Siena S et al 20092

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

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)

CORRECT study design

• 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

RANDOM I ZAT I ON

Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off

Placebo + BSC 3 weeks on, 1 week off

2 : 1

Primary Endpoint: OS

90% power to detect 33.3%

increase (HR=0.75), with 1-sided overall

a=0.025

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

Patient demographicsRegorafenib

N=505PlaceboN=255

Age, median years (range) 61 (22–82) 61 (25–85)

Sex, % Male 61.6 60.0

Female 38.4 40.0

Race, % White 77.6 78.8

Black 1.2 3.1

Asian 15.0 13.7

Other/not reported 6.1 4.3

ECOG, % 0 52.5 57.3

1 47.5 42.7

Region, % Asia (Japan, China) 13.7 13.7

North America, Western Europe, Israel, Australia 83.2 83.1

South America, Turkey, Eastern Europe 3.2 3.1

Baseline disease characteristicsRegorafenib

N=505PlaceboN=255

Primary site of disease, % Colon 64.0 67.5

Rectum 29.9 27.1

Colon and rectum 5.9 5.5

KRAS mutation, %* No 40.6 36.9

Yes 54.1 61.6Unknown 5.3 1.6

Histology, % Adenocarcinoma 98.0 97.3

Other 2.0 2.8

Prior systemic anti-cancer therapies (palliative), % 2 16.0 15.3

3 24.0 23.5

≥ 4 59.8 60.8Prior bevacizumab, % 100 100

*KRAS status based on historical patient record

Overall survival (primary endpoint)

Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450

Days from randomization

Sur

viva

l dis

tribu

tion

func

tion

Placebo N=255Regorafenib N=505

Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052

Regorafenib Placebo

1.00

0.50

0.25

0

0.75

200100500 150 300250 350

Days from randomization

Sur

viva

l dis

tribu

tion

func

tion

Placebo N=255Regorafenib N=505

Regorafenib Placebo

Median 1.9 mos 1.7 mos95% CI 1.9–2.1 1.7–1.7

Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001

Progression-free survival (secondary endpoint)

Overall response and disease control rates(secondary endpoints)

Best response, % RegorafenibN=505

PlaceboN=255

Complete response 0 0

Partial response 1.0 0.4

Stable disease 43.8 14.9

Progressive disease 49.5 80.0

Disease control rate, %* 44.8 15.3

*DCR = PR + SD; p<0.000001

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

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

Adverse event, % RegorafenibN=500

PlaceboN=253

All grades

Grade 3

Grade 4

Grade 5

All grades

Grade 3

Grade 4

Grade 5

Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0Hypertension 27.8 7.2 0 0 5.9 0.8 0 0Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0Anorexia 30.4 3.2 0 0 15.4 2.8 0 0Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0Fever 10.4 0.8 0 0 2.8 0 0 0Nausea 14.4 0.4 0 0 11.1 0 0 0Bleeding 11.4 0.4 0 0.4 2.8 0 0 0Voice changes 29.4 0.2 0 0 5.5 0 0 0Weight loss 13.8 0 0 0 2.4 0 0 0

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

Adverse event, % RegorafenibN=500

PlaceboN=253

All grades

Grade 3

Grade 4

Grade 5

All grades

Grade 3

Grade 4

Grade 5

Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0Hypertension 27.8 7.2 0 0 5.9 0.8 0 0Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0Anorexia 30.4 3.2 0 0 15.4 2.8 0 0Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0Fever 10.4 0.8 0 0 2.8 0 0 0Nausea 14.4 0.4 0 0 11.1 0 0 0Bleeding 11.4 0.4 0 0.4 2.8 0 0 0Voice changes 29.4 0.2 0 0 5.5 0 0 0Weight loss 13.8 0 0 0 2.4 0 0 0Adverse events leading to permanent Tx discontinuation 8.2% 1.2%

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

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

Thanks to the investigating centersand study participants

Lead investigators: AUSTRALIA: Philip Beale, Kathryn Field, Peter Gibbs, Nick Pavlakis, Timothy Price; BELGIUM: Eric van Cutsem, Jochen Decaestecker, Alain Hendlisz, Yves Humblet, Marc Peeters,Jean-Luc Van Laethem; CANADA: Mary Mackenzie, Wilson Miller, Mark Rother, Rafal Wierzbicki,

Asif Shaik, Scott Berry; CHINA: Jianming Xu; CZECH REPUBLIC: Vladimira Stahalova, Ilona Kocakova, Bohuslav Melichar, Eugen Kubala; 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, Meinolf Karthaus, Claus-Henning Koehne, Nicolas Ziegenhagen, Hendrik Kroening, Wolfgang Schepp, Tanja Trarbach, Michael Clemens,

Gunnar Folprecht, Ulrich Hacker, Ralf-Dieter Hofheinz, Arndt Vogel; HUNGARY: Janos Szanto,Laszlo Thurzo; ISRAEL: Adi Shani, Eina Shaham-Shmueli, Alex Beny, Ayala Hubert, Sofia Man,

Baruch Brenner; ITALY: Alberto Sobrero, Giacomo Carteni, Gabriele Luppi, Alfredo Falcone,Salvatore Siena, Alberto Zaniboni, Carlo Barone, Fortunato Ciardiello, Corrado Boni; JAPAN: Hideo Baba,

Eishi Baba, Tadamichi Denda, Hirofumi Fujii, Junji Furuse, Etsuko Warita, Yoshito Komatsu,Nobuyuki Mizunuma, Tomohiro Nishina, Yasutsuna Sasaki, Hiroya Takiuchi, Kazuma Kobayashi,

Hiroyuki Uetake, Takashi Ura, Yasuhide Yamada, Kensei Yamaguchi, Kentarou Yamazaki, Takayuki Yoshino, Hideyuki Mishima; NETHERLANDS: A. J. Gelderblom, D. H. Verheul; SPAIN: Josep Tabernero,Rocio Garcia-Carbonero, Carles Pericay Pijaume, Cristina Gravalos, Manuel Benavides, Javier Sastre,

Jaime Feliu, Mercedes Martinez Villaca; SWITZERLAND: Arnaud Roth; TURKEY: Mustafa Benekli,Faruk Aykan; USA: Axel Grothey, Billy Clowney, Martin Hyzinski, Ali Khojasteh, Marc Saltzman,

Heinz-Josef Lenz, Udit Verma, John Kugler, Jyotsna Fuloria, 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