Presentation on theme: "Eric Van Cutsem, MD, PhD University Hospitals Gasthuisberg/Leuven,"— Presentation transcript:
1Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC) Eric Van Cutsem, MD, PhDUniversity Hospitals Gasthuisberg/Leuven,Leuven, BelgiumOn behalf of:Alberto Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouché, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Heinz-Josef Lenz, Richard Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Axel Grothey
2Metastatic CRC: a major problem Globally, 1.2 million new CRC cases and over 600,000 deaths each year1,2≈ 50% of patients develop metastases3,4Current standard medical treatments include:3,4Chemotherapy (fluoropyrimidines, oxaliplatin, irinotecan)Monoclonal antibodies (bevacizumab, cetuximab or panitumumab)No standard salvage therapy available, although many patients retain good performance status3,4High unmet clinical need for treatment options for mCRCGLOBOCAN. Cancer fact sheets: colorectal cancerAmerican Cancer Society. Cancer Facts and Figures 2012.NCCN Guidelines. Colon cancer. vVan Cutsem E et al. ESMO Guidelines 2010.
3Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways1-3 BiochemicalactivityRegorafenib IC50mean ± SD nmol/l (n)VEGFR113± 0.4(2)Murine VEGFR24.2± 1.6(10)Murine VEGFR346± 10(4)TIE2311± 46PDGFR-β22± 3FGFR1202± 18(6)KIT7± 2RET1.5± 0.7RAF-12.5± 0.6B-RAF28B-RAFV600E19± 6RegorafenibInhibition of proliferationInhibition of tumor microenvironment signalingInhibition ofneoangiogenesisKIT PDGFR RETVEGFR1-3TIE2PDGFR-βFGFRWilhelm SM et al. Int J Cancer 2011.Mross K et al. Clin Cancer Research 2012.Strumberg D et al. Expert Opin Invest Drugs 2012.
4Clinical rationale for regorafenib in mCRC: phase I experience1,2 38 patients with CRC:Dose-escalation phase: n=15Regorafenib doses ranging from 60 to 220 mg/day (3 weeks on, 1 week off)Expansion phase: n=23At recommended dose of 160 mg/day (3 weeks on, 1 week off)All treatment-related adverse events grade ≤3 apart from one grade 4 thrombocytopeniaMost common adverse events: skin toxicity (hand–foot skin reaction, rash), diarrhea, fatigue and voice change27 patients evaluable for response:Disease control rate (DCR): 74%Partial response (PR): 4% (n=1); stable disease (SD): 70% (n=19)Progression-free survival (PFS): median 107 days (95% CI, )Decrease in tumor perfusion by dynamic contrast-enhanced magnetic resonance imagingStrumberg D et al. Br J Cancer 2012.Mross K et al. Clin Cancer Research 2012.
5Evaluation with CT scan of abdomen and chest every 8 weeks CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy2:1Evaluation with CT scan of abdomen and chest every 8 weeksMulticenter, randomized, double-blind, placebo-controlled, phase IIIStratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical regionGlobal trial: 16 countries, 114 centersRecruitment: May 2010 to March 2011
6CORRECT endpoints Primary endpoint: overall survival (OS) 90% power to detect 33.3% increase (hazard ratio [HR]=0.75), 1-sided overall α=0.025Planned sample size: 690Interim analyses:≈ 30% of events (for futility only)≈ 70% of events (for futility and efficacy)Secondary endpoints: PFS, overall response rate (ORR), DCRTertiary endpoints: duration of response/SD, quality of life (QoL), PK, biomarkers
7Patient eligibility: key inclusion criteria Histological or cytological documentation of adenocarcinoma of the colon or rectumDisease progression during/within 3 months after last administration of or intolerance to approved standard therapies, which had to include:Fluoropyrimidine, oxaliplatin, irinotecanBevacizumabCetuximab or panitumumab (if KRAS wild-type)Measurable or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1Age ≥18 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, life expectancy ≥3 monthsAdequate bone marrow, liver and renal functionSigned informed consent
8Patient eligibility: key exclusion criteria Previous or concurrent cancer (different site or histology) within 5 years before randomizationMajor surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of studyCardiovascular dysfunction including:Myocardial infarction within 6 monthsUncontrolled hypertensionUnstable or new-onset anginaArterial or venous thrombotic or embolic events within 6 months
9Patient demographics Regorafenib N=505 Placebo N=255 Age, median years (range)61 (22-82)61 (25-85)Sex, %Male61.660.0Female38.440.0Race, %White77.678.8Black1.23.1Asian15.013.7ECOG, %52.557.3147.542.7Region, %North America, Western Europe, Israel, Australia83.283.1AsiaEastern Europe3.2
10Baseline disease characteristics Regorafenib N=505Placebo N=255Primary site of disease, %Colon64.067.5Rectum29.927.1Colon and rectum5.95.5KRAS mutation, %*No40.636.9Yes54.161.6Unknown5.31.6Histology, %Adenocarcinoma98.097.3Other (adenosquamous or unspecified carcinoma)2.02.8Number of prior lines of therapy for metastatic disease, %1-226.724.7324.828.2≥448.547.1Prior bevacizumab, %100*KRAS status based on historical patient record
11Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis)
13Overall response and disease control rates (secondary endpoints) Regorafenib significantly improves DCR compared to placeboBest response, %Regorafenib N=505Placebo N=255Complete responsePR1.00.4SD42.814.5Progressive disease49.580.0DCR*41.014.9*DCR = PR + SD (≥6 weeks after randomization); p<
14Subgroup analysis of overall survival Regorafenib benefit vs placebo is achieved across subgroupsNHR (95% CI)All patientsSexMaleFemaleAge<65 years≥65 yearsRegionNA, WE, IS, AUAsiaEEBaseline ECOG1Primary site of diseaseColonRectumColon and rectumNA (North America), WE (Western Europe), IS (Israel), AU (Australia), EE (Eastern Europe)Favors regorafenibFavors placebo
15Subgroup analysis of overall survival Regorafenib benefit vs placebo is achieved across subgroupsNHR (95% CI)All patientsTime from first diagnosis of metastatic disease to randomization<18 months≥18 monthsPrior anticancer treatmentF, Ox, Iri, BevF, Ox, Iri, Bev, anti-EGFRPrior treatment lines for metastatic disease≤3>3KRAS mutation status (historical)NY0.816 (0.532, 1.251)0.760 (0.609, 0.948)3750.825 (0.625, 1.089)3850.710 (0.538, 0.938)3010.709 (0521, 0.967)4590.804 (0.624, 1.038)0.653 (0.476, 0.895)0.867 (0.670, 1.123)F (fluoropyrimidine), Ox (oxaliplatin), Iri (irinotecan), Bev (bevacizumab)Favors regorafenibFavors placebo
16Subgroup analysis of PFS Regorafenib benefit vs placebo is achieved across subgroupsSubgroupNHazard ratio (regorafenib/placebo)Estimate95% CIAll patients7600.494Age< 65 years≥ 65 years4752850.4180.651RegionNA, WE, IS, AUAsiaEastern Europe632104240.5000.4330.576Primary site of diseaseColonRectumColon and rectum495220440.5500.4540.348Prior line of Tx≤ 3>33014590.5230.478KRAS mutationY2994300.4750.525NA (North America), WE (Western Europe), IS (Israel), AU (Australia)
17KRAS subgroup analysis RegorafenibN=505PlaceboN=255HR (95% CI)KRAS mutation, %No40.636.9NAYes54.161.6Median OS, monthsKRAS wild-type7.35.00.653 ( )KRAS mutant220.127.116.117 ( )Median PFS, months2.01.80.475 ( )18.104.22.1685 ( )Regorafenib shows OS and PFS benefit in both KRAS-wild-type and KRAS- mutant subgroupsKRAS mutational status was not prognostic nor predictive in the study population
18Drug-related treatment-emergent adverse events occurring in ≥10% of patients RegorafenibN=500PlaceboN=253All gradesGrade 3Grade 4Grade 5*Hand-foot skin reaction46.622.214.171.124Fatigue126.96.36.199.7Hypertension188.8.131.52.8Diarrhea33.87.00.28.3Rash / desquamation26.05.84.0Anorexia184.108.40.206.8Mucositis, oral27.23.03.6Thrombocytopenia220.127.116.11Fever10.4Nausea14.411.1Bleeding11.4Voice changes29.45.5Weight loss13.82.4* Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm
19Health-related QoL analyses: time-adjusted area under the curve No significant difference in health-related QoL with regorafenib vs placeboTreatment groupLeast-squares mean(95% CI)EORTC QLQ-C30Placebo58.13(55.72, 60.53)Regorafenib56.93(54.79, 59.08)EQ-5D index0.67(0.64, 0.70)EQ-5D VAS61.84(59.59, 64.09)60.62(58.62, 62.63)VAS, visual analog scale
20Summary of CORRECT results The study met its primary endpoint at the preplanned interim analysisRegorafenib vs placebo:OS: 6.4 vs 5.0 months, HR=0.77, p=0.0052Crossed prespecified boundary (1-sided p< )PFS: 1.9 vs 1.7 months, HR=0.49, p<DCR (PR + SD): 41.0% vs 14.9%, p<Subgroup analyses:Regorafenib showed OS and PFS benefit across prespecified subgroupsEfficacy of regorafenib was independent of KRAS mutation statusNo new or unexpected safety findings:Most frequent grade 3 events related to regorafenib were hand–foot skin reaction, fatigue, diarrhea, hypertension and rash
21ConclusionsRegorafenib is the first oral multikinase inhibitor with proven activity in mCRCRegorafenib increases OS and PFS in patients with mCRC who have failed current standard therapiesBenefit is shown across prespecified subgroups (including KRAS)Side effects are manageable in this patient populationRegorafenib is a new potential standard of care for patients with chemorefractory mCRC
22Thanks to the investigating centers and study participants Lead investigators: AUSTRALIA: Philip Beale, Kathryn Field, Peter Gibbs, Nick Pavlakis, Timothy Price; BELGIUM: Eric Van Cutsem, Hans Prenen, 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, Wataru Okamoto, Yasutsuna Sasaki, Hiroya Takiuchi, Kazuma Kobayashi, Hiroyuki Uetake, Takashi Ura, Yasuhide Yamada, Kensei Yamaguchi, Kentaro 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