ASPECCT A randomized, multicenter, open-label, phase 3 study of panitumumab vs cetuximab for previously treated wild-type (WT) KRAS metastatic colorectal cancer (mCRC) Timothy Price, 1 Marc Peeters, 2 Tae Won Kim, 3 Jin Li, 4 Stefano Cascinu, 5 Paul Ruff, 6 Atilli Satya Suresh, 7 Kathy Zhang, 8 Swaminathan Murugappan, 8 Roger Sidhu 8 1 The Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia; 2 Antwerp University Hospital and University of Antwerp, Edegem, Belgium; 3 Asan Medical Center, University of Ulsan, Seoul, Korea; 4 Fudan University Cancer Hospital, Shanghai, P.R. China; 5 Universita Politecnica delle Marche, Ancona, Italy; 6 University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa; 7 Apollo Hospital, Hyderabad, India; 8 Amgen Inc., Thousand Oaks, CA, USA
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ASPECCT A randomized, multicenter, open-label, phase 3 study of panitumumab vs cetuximab for previously treated wild-type (WT) KRAS metastatic colorectal.
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ASPECCTA randomized, multicenter,
open-label, phase 3 study of panitumumab vs cetuximab for previously treated wild-type (WT) KRAS metastatic
colorectal cancer (mCRC)
Timothy Price,1 Marc Peeters,2 Tae Won Kim,3 Jin Li,4 Stefano Cascinu,5 Paul Ruff,6 Atilli Satya Suresh,7 Kathy Zhang,8
Swaminathan Murugappan,8 Roger Sidhu8
1The Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia; 2Antwerp University Hospital and University of Antwerp, Edegem, Belgium; 3Asan Medical Center, University of Ulsan, Seoul, Korea; 4Fudan University
Cancer Hospital, Shanghai, P.R. China; 5Universita Politecnica delle Marche, Ancona, Italy; 6University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa; 7Apollo Hospital, Hyderabad, India;
8Amgen Inc., Thousand Oaks, CA, USA
Disclosures For Prof T. Price
Advisory Board: Amgen Inc. (uncompensated)
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Therapeutic indication (EU)
Vectibix® Summary of Product Characteristics.
Panitumumab is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC):
In first-line in combination with FOLFOX or FOLFIRIIn second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan)As monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens
The combination of panitumumab with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown
The recommended dose of panitumumab is 6 mg/kg of bodyweight given once every two weeks
Introduction
Anti-EGFR agents (panitumumab and cetuximab) are approved as monotherapy in the treatment of patients with chemorefractory WT KRAS mCRC
Cetuximab has demonstrated OS benefit prospectively in chemorefractory (3rd line) mCRC (CO.17 study; Jonker et al, 2007 NEJM)
Panitumumab has not prospectively demonstrated a statistically significant survival benefit in monotherapy setting in mCRC patients, potentially due to frequent use of anti-EGFR crossover treatment
ASPECCT is the first head-to-head, randomized phase 3 study evaluating the efficacy and safety of panitumumab vs cetuximab for the treatment of chemorefractory WT KRAS mCRC
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ASPECCT Study Schema
Stratification Factors:• North America and Western Europe and Australia vs rest of world (ROW) • ECOG PS (0 or 1 vs 2)
Crossover between arms during study treatment was not allowed
RANDOMISE
1:1
Panitumumab 6.0 mg/kg Q2W
Cetuximab 400 mg/m2 loading dose,
250 mg/m2 QW
PD
PD
SURVIVAL
Patients with previously
treated, WT KRAS mCRC
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Study Endpoints
Primary endpoint: Overall Survival (OS)
Key secondary endpoints:
Progression-Free Survival (PFS)
Objective response rate (ORR)
Safety
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Key Eligibility Criteria
Age ³ 18 years oldHistologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum Metastatic diseaseWT KRAS tumor status, assessed centrallyMeasurable or non-measurable disease per RECIST version 1.1 Disease progression or intolerability on irinotecan-, oxaliplatin- and fluorouracil-based therapy for mCRCAdequate hematologic, renal, hepatic, metabolic functionNo prior anti-EGFR therapyNo symptomatic brain metastasesSigned informed consent
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Statistical Considerations
Non-inferiority design: Compare the effect of panitumumab vs cetuximab on OS
Treatment effect of cetuximab compared to BSC was derived from the CO.17 trial (9.5 vs 4.8 months, HR=0.55) (CO.17 study; Karapetis et al 2008, NEJM)
Retention rate – what fraction of the treatment effect of cetuximab over BSC is preserved by panitumumab (point estimate and confidence interval)
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Statistical Considerations (cont.)
To satisfy the non-inferiority test at a 1-sided 2.5% significance level, panitumumab will demonstrate preservation of at least 50% of the cetuximab OS effect relative to Best Supportive Care (BSC).
A synthesis approach with an asymptotic standard normal test statistic will be used to test the OS inferiority null hypothesis
Non-inferiority is claimed if Zpc score is less than ‘-1.96’
Constancy – qualitative assessment that study population and assumptions are aligned in this study vs CO.17
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Demographics and Disease Characteristics
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Panitumumab(N = 499)
Cetuximab(N = 500)
Men 315 (63.1) 318 (63.6)
Race, white – n (%) 266 (53.3) 258 (51.6)
Age – years, median (range) 61.0 (19-86) 60.5 (20-89)
ECOG PS – n (%)
0 154 (30.9) 163 (32.6)
1 303 (60.7) 297 (59.4)
2 42 (8.4) 40 (8.0)
Region – n (%)
North America, Western EU, AUS 154 (30.9) 156 (31.2)
ROW 345 (69.1) 344 (68.8)
Primary diagnosis, colon cancer – n (%) 292 (58.5) 326 (65.2)
Prior chemotherapy – n (%) 499 (100) 499 (99.8)
Prior bevacizumab – n (%) 126 (25.3) 132 (26.4)
Sites of metastatic disease – n (%)Liver onlyLiver plus other sites
52 (10.4)447 (89.6)
50 (10)450 (90)
Median follow-up time – months (range) 9.5 (0.3, 35.6) 9.3 (0.1, 34.5)
Stable disease or Non CR/Non PD 226 (46.5) 236 (48.7)
Patients with objective response* – n (%) 107 (22.0) 96 (19.8)
Rate (95% CI) - %22.02
(18.41, 25.97)19.79
(16.34, 23.62)
Odds Ratio (95% CI) 1.15 (0.83, 1.58)
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*Objective response is defined as a best tumor response of complete or partial response. Baseline measurable patients only.
Summary of Adverse Events
Panitumumab(N=496)
Cetuximab(N=503)
Patients with any adverse events - n (%) 485 (97.8) 494 (98.2)
Worst grade 3 180 (36.3) 159 (31.6)
Worst grade 4 37 (7.5) 27 (5.4)
Worst grade 5 29 (5.8) 50 (9.9)
Any serious 151 (30.4) 169 (33.6)
Permanent discontinuation of study drug
69 (13.9) 61 (12.1)
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Includes only patients who received protocol treatment
Incidence of Grade 3 or Higher Adverse Events Of Interest
Adverse Event – n (%) PanitumumabN=496
CetuximabN =503
Fatal AE’sColon cancerOthers
29 (5.8)20 (4.0)9 (1.8)
50 (9.9)34 (6.8)16 (3.2)
Treatment-related fatal AE’s 0 (0) 1 (0.2)
Skin and Subcutaneous tissue AE’sAny gradeGrade 3Grade 4Serious
430 (86.7)60 (12.1)
2 (0.4)1 (0.2)
440 (87.5)48 (9.5)
0 (0)0 (0)
HypomagnesemiaAny gradeGrade 3Grade 4
143 (28.8)27 (5.4)9 (1.8)
95 (18.9)10 (2.0)3 (0.6)
Infusion reactionsAny gradeGrade 3Grade 4
14 (2.8)1 (0.2)0 (0)
63 (12.5)5 (1.0)4 (0.8)
DiarrheaAny gradeGrade 3Grade 4
91 (18.3)7 (1.4)3 (0.6)
89 (17.7)9 (1.8)0 (0.0)
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Conclusions
ASPECCT met its primary endpoint of non-inferiority for OS
Panitumumab retained 106% (95% CI 82-129) of the OS benefit of cetuximab over best supportive care in patients with WT KRAS mCRC
Observed safety profiles between the two treatment arms were consistent with previously reported studies for both agents
No new toxicities or safety signals were identified for panitumumab
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AcknowledgementsWe wish to thank the patients, their families and friends, and the study staffs
We wish to thank Amgen Inc.
The ASPECCT Investigators
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• N. M. A. Abdullah �• R. Adams• M. Aghmesheh• J. B. Ahn• B. Aleknaviciene• D. Amadori• S. Attili• Y. Ba• Y. Bai• J. Bennouna• V. M. K. Bhavaraju• S. Bondarde• C. Borg• D. Borg• P. Cao• G. Carlsson• A. Cheng• S. Chiara• G. Chong• J. Chovanec• L. Ciuffreda• G. Cohen
• B. Colwell• P. Cooray• G. Cruciani• D. Cunningham• S. Dakhil• G. de Lima Lopes Jr• A. Deptala• C. Deshmukh• N. Dobrovolskaya• F. Drudi• M. Ducreux• A. Dudov• S. Essapen• P. L. Etienne• M. Faedi• S. Falk• E. Fernebro• M. Foszczynska-Kloda• V. Gangadharan• M. R. A. Gentili• P. Gibbs• V. Gorbunova
• M. Goyal• E. Grincuka• S. Grumett• S. Gupte• J. Haux• H. Heleniak• G. F. Ho• E. Idelevich• C. Jacobs• R. Janciauskiene• D. Jovanovic• E. Kalbacher• T. W. Kim• Y. H. Kim• S. Y. Kim• T. Y. Kim• K. Krizan• M. Kubecova• K. D. Lee• H. Letocha• J. Li• R. K. LI
• H. Liang• R. S.C. Lim• F. Lofts• C. Lozada Zingoni• B. Ma• J. Malan• S. Man• G. Manikhas• L. Manzyuk• G. Marx• B. Melichar• P. Montenegro Beltran• A. Mukhopadhyay• R. Nagarkar• W. Ng• T. Niederman• S. Nirni• J. Novotny• Z. Nowecki• P. Nygren• R. Orlova• H. Pan
• J. O. Park• R. Passalacqua• N. Pavlakis• M. Peeters• J. Pikiel• S. Plate• T. Price• S. Protsenko• G. Purkalne• S. Qin• P. Ruff• I. Ryniewicz-Zander• D. Sacdalan• J. F. Salas Sanchez• T. Salek• A. Scarfe• L. Shen• M. Smakal• S. Sonawane• K. Srinivasan• M. Stresko• W. C. Su
• C. J. Tai• S. Tamberi• N. Tebbutt• C. Y. Teoh• A. Thomas• S. Tjulandin• M. N. A Uy• D. Vorobiof• J. Wang• L. Wang• C-H Wang• G. Wilson• R. Wilson• E. Wojcik• F.C.S. Wong• L. Wong• K. Wozniak• J. Xu• T. S. Yang• D. Ygael
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