GICS 2012 Final skin toxicity and patient‑reported outcomes results from PRIME: A randomized phase 3 study of panitumumab + FOLFOX4 for 1 st ‑line metastatic colorectal cancer Jean‑Yves Douillard, 1 Salvatore Siena, 2 Josep Tabernero, 3 Ronald Burkes, 4 Mario E. Barugel, 5 Yves Humblet, 6 David Cunningham, 7 Feng Xu, 8 Zhongyun Zhao, 8 Roger Sidhu 8 1 Centre René Gauducheau, Nantes, France; 2 Ospedale Niguarda Ca’ Granda, Milan, Italy; 3 Vall d'Hebrón University Hospital, Barcelona, Spain; 4 Mount Sinai Hospital, Toronto, Canada; 5 Hospital de Gastroenterología, Buenos Aires, Argentina; 6 Centre du Cancer de l'Université Catholique de Louvain, Brussels, Belgium; 7 The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8 Amgen Inc., Thousand Oaks, California;
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GICS 2012 Final skin toxicity and patient ‑ reported outcomes results from PRIME: A randomized phase 3 study of panitumumab + FOLFOX4 for 1 st ‑ line metastatic.
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GICS 2012
Final skin toxicity and patient‑reported outcomes results from PRIME: A randomized phase 3 study of panitumumab + FOLFOX4
for 1st‑line metastatic colorectal cancer
Jean‑Yves Douillard,1 Salvatore Siena,2 Josep Tabernero,3 Ronald Burkes,4 Mario E. Barugel,5 Yves Humblet,6 David Cunningham,7 Feng Xu,8
Zhongyun Zhao,8 Roger Sidhu8
1Centre René Gauducheau, Nantes, France; 2Ospedale Niguarda Ca’ Granda, Milan, Italy; 3Vall d'Hebrón University Hospital, Barcelona, Spain; 4Mount Sinai
Hospital, Toronto, Canada; 5Hospital de Gastroenterología, Buenos Aires, Argentina; 6Centre du Cancer de l'Université Catholique de Louvain, Brussels,
Belgium; 7The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Amgen Inc., Thousand Oaks, California;
GICS 2012
Introduction• Panitumumab is a fully human monoclonal antibody targeting the epidermal
growth factor receptor (EGFR)• PRIME (20050203) was an open-label, randomized, global, phase 3 trial
prospectively investigating panitumumab + FOLFOX4 vs FOLFOX4 alone as 1st-line treatment for metastatic colorectal cancer (mCRC) among patients with wild-type (WT) KRAS tumors
• The results from the primary analysis of this study showed that panitumumab + FOLFOX4 was generally tolerable and significantly improved progression-free survival (PFS) in patients with WT KRAS mCRC vs FOLFOX4 alone1
• Efficacy and patient-reported outcomes (PRO) by skin toxicity (ST) severity from the final descriptive analysis of PRIME are presented
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Study Schema and Stratification
Treatment Arm 1:
Panitumumab 6.0-mg/kg Q2W + FOLFOX4 Q2W
ENROLLMENT
END
OF
TREATMENT
LONG
TERM
FOLLOW
UP
PRO assessments every 4 weeks
Disease assessment every 8 weeks
Treatment Arm 2:
FOLFOX4 Q2W
Enrollment target:1150 patients
Randomization stratification:• Eastern Cooperative Oncology Group (ECOG)
performance status: 0–1 vs 2• Geographic region: Western Europe, Canada, and
• Primary Objective:– To assess the effect of panitumumab on PFS by KRAS
mutation status*
• Primary Endpoint:– PFS (by blinded central radiology review)
• Other Key Endpoints: – Overall survival (OS) – Objective response rate (ORR)– Time to progression– Duration of response– PRO– Safety
*KRAS status was determined by blinded, independent central testing
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Key Eligibility Criteria
• Metastatic adenocarcinoma of the colon or rectum • No prior treatment for mCRC
– Adjuvant 5-fluorouracil-based therapy was allowed if disease recurrence occurred > 6 months after completion
– Prior oxaliplatin was not allowed• No prior EGFR inhibitor therapy• Measurable disease• Paraffin-embedded tumor tissue available for central biomarker
testing– EGFR expression and KRAS status were not required at entry
• ECOG performance status 0–2• Adequate hematologic, renal, and hepatic function• Signed informed consent
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Statistical Considerations for the ST and PRO Analyses
• The ST and PRO analyses were based on data from the final analysis that occurred 30 months after the last patient was enrolled
• PRO were assessed using the EuroQol EQ‑5D Health State Index Score and the EQ‑5D Overall Health Rating
• PRO data were analyzed using a mixed‑effect model repeated measure (MMRM) model to analyze longitudinal PRO data with missing values2,3
• All statistical tests were performed at a 2‑sided significance level of 5% without adjusting for multiple comparisons and are regarded as descriptive
• The primary goal of this analysis was to evaluate the correlation between worst grade ST and efficacy and PRO endpoints
• The ST analysis includes the primary endpoint of PFS, and secondary endpoints of OS, objective response, and safety
• Landmark analysis was performed in the efficacy by ST analyses to reduce bias• A landmark of day 28 was selected because > 50% of patients had their
maximum grade ST by day 28• Patients who were alive without disease progression at day 28 were included in
the ST analyses
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Demographics and Disease Characteristics
WT KRAS mCRC
Panitumumab + FOLFOX4
Grade 2–4 ST(n = 250)
Panitumumab + FOLFOX4
Grade 0–1 ST(n = 64)
FOLFOX4(n = 320)
Sex, men – n (%) 164 (66) 43 (67) 199 (62)
Age – years, median (min, max) 61.0 (27, 81) 63.5 (30, 80) 61.5 (24, 82)
Race, white – n (%) 227 (91) 59 (92) 299 (93)
ECOG performance status – n (%)
0–1 240 (96) 58 (91) 301 (94)
2 10 (4) 6 (9) 18 (6)*
Primary tumor type – n (%)
Colon cancer 162 (65) 43 (67) 207 (65)
Rectal cancer 88 (35) 21 (33) 113 (35)
Sites of metastatic disease:
Liver only 48 (19) 11 (17) 56 (18)
Liver + other 174 (70) 40 (63) 219 (68)
Other only 28 (11) 12 (19) 45 (14)
Missing or unknown 0 (0) 1 (2) 0 (0)
*One patient had missing/unknown ECOG performance status score
MedDRA: Medical Dictionary for Regulatory Activities
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Conclusions
• In the final analysis of PRIME, results from the primary analysis were confirmed:
– Statistically significant improvement in PFS in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4 vs FOLFOX4 alone
– Trend toward improved OS in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4 vs FOLFOX4 alone
– Higher objective response in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4
• Patients with WT KRAS mCRC receiving 1st-line treatment with panitumumab who develop ST grade 2-4 had longer PFS and OS vs patients receiving chemotherapy alone
• No significant difference in PRO was observed using the EQ-5D instrument in patients with WT KRAS mCRC who received panitumumab+FOLFOX4 that developed high grade 2-4 ST vs low grade 0-1 ST
• The adverse event profile was as expected for patients receiving anti-EGFR antibodies
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References1. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.
2. Siddiqui O, et al. J Biopharm Stat. 2009;19:227-246.
3. Lane P. Pharm Stat. 2008;7:93-106.
4. Pickard AS, et al. Health Qual Life Outcomes. 2007;5:70.