Data on panitumumab in combination with chemotherapy in the 1 st -line treatment of mCRC Prof Jim Cassidy Glasgow University Scotland
Data on panitumumabin combination with chemotherapy in the 1st-line treatment of mCRC
Prof Jim CassidyGlasgow University
Scotland
IntroductionIntroduction•• PanitumumabPanitumumab is indicated as is indicated as monotherapymonotherapy for the for the
treatment of patients with EGFRtreatment of patients with EGFR--expressing expressing metastaticmetastatic colorectal carcinoma with noncolorectal carcinoma with non--mutated mutated (wild(wild--type) type) KRASKRAS after failure of after failure of fluoropyrimidinefluoropyrimidine--oxaliplatinoxaliplatin and and irinotecanirinotecan--containing chemotherapy containing chemotherapy regimensregimens
•• Initial studies performed in Initial studies performed in chemorefractorychemorefractory patients patients demonstrated activity and efficacy, and the agent was demonstrated activity and efficacy, and the agent was approved for patients who had progressed after approved for patients who had progressed after standard therapystandard therapy
Amgen Europe B.V. Vectibix® Summary of Product Characteristics. 2009. Vectibix® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2009.
1st-line panitumumab in combination with chemotherapy: the phase 2 experience
• Feasibility phase 2 design– Part 1: panitumumab + bolus 5-FU (IFL)– Part 2: panitumumab + infusional 5-FU (FOLFIRI)
• Tolerabilty (grade 3-4 diarrhoea) as primary endpoint
• 11/19 (58%) in part 1 experienced grade 3-4 diarrhoea
• 6/24 (25%) in part 2 experienced grade 3-4 diarrhoea
Berlin J, et al. Clin Colorectal Cancer 2007;6:427-32.
1st-line panitumumab in combination with chemotherapy: phase 2 results
3322.510.924Pmab + FOLFIRI
47175.619Pmab + IFL
RR(%)
OS(months)
PFS(months)
NTherapy
Berlin J, et al. Clin Colorectal Cancer 2007;6:427-32.
Phase 2 trial of Phase 2 trial of panitumumabpanitumumab with FOLFIRI with FOLFIRI as 1as 1stst--line treatment of patients with line treatment of patients with
metastaticmetastatic colorectal cancercolorectal cancer
SCREENING
Previously untreated mCRC
patients
END
OF
TREATMENT
ENROLLMENT
SAFETY
FOLLOW
UP
END
OF
STUDYWithin
28 daysprior today 1
Day 1*
Approx. 56 daysafter end of treatment
Cycles repeatedevery 14 days
*Day 1= day of first treatment administration
Panitumumab(6 mg/kg IV on day 1 of each cycle)
plus FOLFIRI
www.amgentrials.com; protocol ID: 20060314. ClinicalTrials.gov identifier: NCT00508404.Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Phase 2 trial of 1Phase 2 trial of 1stst--line line panitumumabpanitumumab plus FOLFIRI plus FOLFIRI Primary analysis: selected objectives and endpointsPrimary analysis: selected objectives and endpoints
•• ObjectivesObjectives–– To estimate the effect of To estimate the effect of KRAS KRAS mutation status on mutation status on
objective response rate and other measures of efficacy objective response rate and other measures of efficacy for 1for 1stst--line treatment of line treatment of mCRCmCRC patients with patients with panitumumabpanitumumab plus FOLFIRIplus FOLFIRI
–– To describe the safety profile of this combination To describe the safety profile of this combination therapy in the 1therapy in the 1stst--line settingline setting
•• Study endpoints:Study endpoints:–– Primary: Primary:
-- Objective response rateObjective response rate
–– Secondary endpoints include:Secondary endpoints include:-- Disease control rateDisease control rate-- ProgressionProgression--free survivalfree survival-- SafetySafety
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Phase 2 trial of 1Phase 2 trial of 1stst--line line panitumumabpanitumumab plus plus FOLFIRI FOLFIRI KRASKRAS mutation statusmutation status
•• At the time of primary analysis (June 2009) At the time of primary analysis (June 2009) KRASKRAS evaluableevaluablesamples were available for 145 of a total of 154 patients samples were available for 145 of a total of 154 patients (94%)(94%)–– 86 patients (59%) with 86 patients (59%) with KRASKRAS WT tumoursWT tumours–– 59 patients (41%) with 59 patients (41%) with KRASKRAS MT tumoursMT tumours
•• DNA was isolated from paraffinDNA was isolated from paraffin--embedded tissue or embedded tissue or unstained tumour slides from primary or unstained tumour slides from primary or metastaticmetastatictumour*tumour*
•• Central Central KRASKRAS testing was performed at testing was performed at HistoGeneXHistoGeneX, , Belgium, with a researchBelgium, with a research--useuse--only only DxSDxS Test Kit that used Test Kit that used alleleallele--specific, realspecific, real--time polymerase chain reaction (PCR)time polymerase chain reaction (PCR)–– The kit can detect approximately 1% of mutant DNA in a The kit can detect approximately 1% of mutant DNA in a
background of wildbackground of wild--type genomic DNAtype genomic DNA
*Greil R, et al. J Clin Oncol 2009;27(15S):4085; Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Phase 2 trial of 1Phase 2 trial of 1stst--line line panitumumabpanitumumab plus FOLFIRIplus FOLFIRIBest objective responseBest objective response
37.9(25.5 - 51.6)
56.5(45.3 - 67.2)
49.3(41.1 - 57.6)
CR + PR,%(95% CI)
18.54(0.84, 34.63)
N/ADifference, % (95% CI)
2.12(1.02, 4.45)
N/AUnadjusted common treatment odds ratio
(95% CI)
Panitumumab + FOLFIRIOverall*(N=152)
KRAS WT (N=85)
KRAS MT(N=58)
Objective response, % Complete response (CR) 2 2 2Partial response (PR) 47 54 36Stable disease (SD) 41 34 52Disease progression 7 7 7Unevaluable 1 0 2Not done 2 2 2
*Two patients did not have measurable disease per RECIST guidelines at baseline and were therefore not included in the analysis of response rate. N/A = not applicable; Disease control rate = CR + PR + SD
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Phase 2 trial of 1Phase 2 trial of 1stst--line line panitumumabpanitumumab plus FOLFIRI plus FOLFIRI Resection rateResection rate
0
10
20
Res
ectio
n ra
te (%
)
KRAS WT(N=85)
KRAS MT(N=58)
15
7
•• Resection rates were 15% (95%CI: 8.3% to 24.5%) and 7% (95% CI: Resection rates were 15% (95%CI: 8.3% to 24.5%) and 7% (95% CI: 1.9% to1.9% to16.5%) in the 16.5%) in the KRASKRAS WT and MT groups, respectivelyWT and MT groups, respectively
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
ProgressionProgression--free survivalfree survivalKRASKRAS tumour response analysis settumour response analysis set
Prop
ortio
n Ev
ent-F
ree
(%)
10
86 85 78 76 71 65 54 51 32 25 22 16 11 8 5 1 059 58 53 53 46 40 30 25 16 14 8 7 3 2 0 0 0
2030405060708090
100
Months0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
0
Patientsat risk:
WTMT
HR=0.46 (95% CI: 0.31 - 0.70)
7.2 (5.6 - 7.8) 48 (81)KRAS MT (N=59)
8.9 (7.6 - 14.3) 44 (51)KRAS WT (N=86)
Median (95% CI) months
EventsN (%)
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Grade 3/4 adverse events of interestGrade 3/4 adverse events of interestKRASKRAS safety analysis setsafety analysis set
2 (3)6 (7)Paronychia
6 (10)7 (8)Fatal adverse events2
13 (22)20 (23)Diarrhoea
Panitumumab + FOLFIRI (N=145) Adverse event by MedDRA1, N(%) KRAS WT (N=86) KRAS MT (N=59)Patients with any event 63 (73) 42 (71)Skin toxicity 25 (29) 19 (32)
Neutropenia 14 (16) 12 (20)Pulmonary embolism 6 (7) 6 (10)
Dehydration 4 (5) 2 (3)Stomatits 4 (5) 2 (3)Hypomagnesaemia 4 (5) 1 (2)Febrile neutropenia 1 (1) 0 (0)Infusion-related reaction (panitumumab) 0 (0) 0 (0)
1MedDRA = Medical Dictionary for Regulatory Activities; 2Includes cases in which primary cause of death was reported to be disease progression; 3 were reported to be related to panitumumab: haematemesis (WT), rectal haemorrhage (WT) and vena cava thrombosis (MT)
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Phase 2 trial of 1Phase 2 trial of 1stst--line line panitumumabpanitumumab plus FOLFIRI plus FOLFIRI ConclusionsConclusions
•• PanitumumabPanitumumab combined with FOLFIRI appears to be a wellcombined with FOLFIRI appears to be a well--tolerated regimen in the 1sttolerated regimen in the 1st--line settingline setting
•• The results of these exploratory analyses comparing The results of these exploratory analyses comparing patients with patients with KRASKRAS WT and MT tumours suggest that WT and MT tumours suggest that KRASKRASstatus is predictive of outcome in this settingstatus is predictive of outcome in this setting
–– PFS appears to be longer in patients with PFS appears to be longer in patients with KRASKRAS WT WT tumours (HR=0.46; 95% CI: 0.31tumours (HR=0.46; 95% CI: 0.31--0.70) 0.70)
–– KRASKRAS WT tumours were more likely to respond to WT tumours were more likely to respond to treatment with treatment with panitumumabpanitumumab plus FOLFIRI (OR 2.12; plus FOLFIRI (OR 2.12; 95% CI: 1.0295% CI: 1.02––4.45)4.45)
–– Resection rate was higher in the Resection rate was higher in the KRASKRAS WT population WT population (15%) than in the (15%) than in the KRASKRAS MT population (7%)MT population (7%)
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
Randomised phase 3 study of panitumumabwith FOLFOX4 vs FOLFOX4 alone as 1st-line
treatment in patients with mCRC: the PRIME trial
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
J.Y. Douillard,J.Y. Douillard,11 S. Siena,S. Siena,22 J. Cassidy,J. Cassidy,33
J. Tabernero,J. Tabernero,44 R. Burkes,R. Burkes,55 M.E. Barugel,M.E. Barugel,66 Y.Y. Humblet,Humblet,77
D. Cunningham,D. Cunningham,8 8 M. Wolf,M. Wolf,99 J. GansertJ. Gansert99
11Centre RenCentre Renéé GauducheauGauducheau, Nantes, France; , Nantes, France; 22Ospedale Ospedale NiguardaNiguarda CaCa’’ GrandaGranda, Milan, Italy; , Milan, Italy; 33The The BeatsonBeatson West Of Scotland Cancer Centre, Glasgow, United Kingdom; West Of Scotland Cancer Centre, Glasgow, United Kingdom; 44Vall Vall d'Hebrond'Hebron
University Hospital, Barcelona, Spain; University Hospital, Barcelona, Spain; 55Mount Sinai Hospital, Toronto, Canada; Mount Sinai Hospital, Toronto, Canada; 66Hospital de Hospital de GastroenterologGastroenterologííaa, Buenos Aires, Argentina; , Buenos Aires, Argentina; 77Centre Centre dudu Cancer de Cancer de l'Universitl'Universitéé CatholiqueCatholique de de
LouvainLouvain, Brussels, Belgium; , Brussels, Belgium; 88The Royal The Royal MarsdenMarsden NHS Foundation Trust, London, United NHS Foundation Trust, London, United Kingdom; Kingdom; 99Amgen Inc., Thousand Oaks, CaliforniaAmgen Inc., Thousand Oaks, California
The PRIME trial
• PRIME is an open-label, randomised, global, phase 3 trial prospectively investigating panitumumab with FOLFOX4 vs. FOLFOX4 alone as 1st-line treatment for mCRC among patients with WT KRAS tumours
• Originally designed to compare the treatment effect in the all randomised population, the trial was amended to focus on hypothesis testing in the WT KRAS subset
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Study schema and stratification
Tx Arm 1:
Panitumumab 6.0 mg/kg Q2W + FOLFOX4 Q2W
ENROLLMENT
END
OF
TREATMENT
LONG
TERM
FOLLOW
UP
Disease assessment every 8 weeks
Tx Arm 2:
FOLFOX4 Q2W
Enrollment Target:1150 patients
Randomization stratification:• ECOG score: 0-1 vs. 2• Geographic Region: Western
Europe, Canada, and Australia vs. Rest of the World
SCREENING
PRIME Study Countries
Canada
United KingdomBelgiumFranceSpainSwitzerlandItalyPolandCzech RepublicHungaryLatvia
SouthAfrica
MexicoCostaRica
BrazilChileArgentina
Australia
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
PRIME study timeline
First Patient Enrolled
23 Aug 2006
2008
Last Patient Enrolled
1 Feb 2008
Final Primary SAP Amendment 10 Dec 2008
2007 20092006
SAP = Statistical analysis planSAP = Statistical analysis plan
Study Unblinding
and Primary Analysis
31 July 2009
KRAS SEQUENCE ANALYSIS
(Selected Samples from CRC Phase 2 Studies)
20020408 KRAS
ANALYSIS
KRAS Testing
CompletedMar 2009
Protocol Amendment 10 Oct 2007
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Study objective and endpoints• Primary objective:
– To assess the effect of panitumumab on progression-free survival (PFS) by KRAS status*
• Primary endpoint:– PFS (by blinded central radiology review)
• Other key endpoints: – Overall survival (OS) – Objective response rate (ORR)– Time-to-response (TTR)– Duration of response (DOR)– Safety
*KRAS status was determined by blinded, independent central testing
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Key eligibility criteria• Metastatic adenocarcinoma of the colon or rectum • No prior treatment for mCRC
– Adjuvant 5-FU-based therapy was allowed if disease progression occurred >6 months after completion
– Prior oxaliplatin was not allowed• No prior EGFR inhibitor therapy• Measurable disease• Paraffin-embedded tumour tissue available for central biomarker
testing– EGFR expression and KRAS status were not required at entry
• ECOG performance status 0-2• Adequate haematologic, renal and hepatic function• Signed informed consent
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Statistical considerations• Sample size calculation for PFS
380 events in WT KRAS stratum90% power for the WT patients (Hazard Ratio [HR] = 0.71)1150 patients planned
• Interim analyses for OS using Haybittle-Peto boundaries, α = 0.001
• This trial was overseen by an independent DMC
PFS, WT KRASα=0.05
OS, WT KRASα=0.05
PFS, MT KRASα=0.05
STOP
OS, MT KRASα=0.05
STOP
p>0.05
p>0.05
p≤0.05
p≤0.05
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
PATIENTS RANDOMIZED (N =1183)
PANITUMUMAB 6.0 mg/kg+ FOLFOX4
(N=593)
Treatment assignment by Treatment assignment by KRASKRAS statusstatusSCREENED FOR ELIGIBILITY (N=1378)
EXCLUDED (DID NOT MEET INCLUSION CRITERIA (N=195)
FOLFOX4(N=590)
TUMOR SAMPLE AVAILABLE AND KRAS TESTING
COMPLETED (N=546)
TUMOR SAMPLE AVAILABLE AND KRAS TESTING
COMPLETED (N = 550)
KRAS WTPANITUMUMAB
+ FOLFOX4(N=325)
KRAS MTPANITUMUMAB
+ FOLFOX4(N=221)
KRAS WTFOLFOX4(N=331)
KRAS MTFOLFOX4(N=219)
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Results: KRAS ascertainment
778Patients with KRAS unevaluable, %
FOLFOX4
404040MT KRAS – %
606060WT KRAS – %
939392Patients included in KRAS analysis – %
1183590593Patients randomized, N
TotalPanitumumab
+ FOLFOX4
KRAS tumour status was determined using the DxS kit (Manchester, UK) that tests the 7 most common KRAS mutations in codons 12 and 13.
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Demographics and disease characteristics
73716969Liver + other sites16141718Liver only
52475457Median follow-up time, weeks
ECOG performance status, %89899391Race – White, %
Sites of metastatic disease, %
MT KRASWT KRAS
56545660Western EU, Canada, AustraliaRegion, %
Primary Diagnosis, %
4a4562a969694940-1
1634
66
62 (27, 85)67
Panitumumab + FOLFOX4
(N=325)
1735
65
61 (24, 82)62
FOLFOX4(N=331)
1632
68
63 (33, 83)66
Panitumumab+ FOLFOX4
(N=221)
73Colon cancer
27Rectal cancer12Prior adjuvant, %
61 (27, 82)Age – years, median (min, max)58Sex – Men, %
FOLFOX4(N=219)
a Includes 1 patient with ECOG 4NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Months
Prop
ortio
n Ev
ent-F
ree
0
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Patients at risk:Panitumumab+FOLFOX4FOLFOX4 alone
325 313 294 284 254 243 204 187 156331 321 296 281 242 231 185 172 127
145113
11182
9465
7341
5736
3929
2822
2216
1412
1010
42
11
01
01
00
8.0 (7.5 - 9.3)215 (65)FOLFOX4
9.6 (9.2 - 11.1)199 (61)Panitumumab + FOLFOX4
Median(95% CI) months
EventsN (%)
HR=0.80 (95% CI: 0.66 - 0.97)p=0.02
WT WT KRASKRAS: progression: progression--free survival free survival
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
0.10 1.00 10.00
Factors N HR 95% CIFavours: pmab no pmab
All randomized 656 0.80 0.66-0.97Primary: colon 430 0.79 0.62-1.00Primary: rectal 226 0.83 0.59-1.16Liver mets: yes 566 0.78 0.64-0.96Liver mets: no 90 0.91 0.54-1.54Liver mets only: yes 116 0.82 0.50-1.34Liver mets only: no 540 0.81 0.65-1.00Met sites: <3 363 0.85 0.65-1.11Met sites: ≥3 290 0.76 0.57-1.02ECOG: 0 369 0.68 0.52-0.90ECOG: 1 248 0.92 0.68-1.24ECOG: 2 38 1.99 0.96-4.15Age ≥65 261 1.02 0.75-1.38Age <65 395 0.70 0.54-0.89Men 421 0.71 0.55-0.90Women 235 1.00 0.73-1.39
Hazard ratio (pmab / no pmab)
WT KRAS: subgroup analyses for PFS
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
KRASKRAS WT: trend for longer overall survivalWT: trend for longer overall survival(Secondary endpoint)(Secondary endpoint)
Months
Surv
ival
Pro
babi
lity
0
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Patients at risk:Panitumumab+FOLFOX4FOLFOX4 alone
325 315 310 288 266 242 227 217 207 189 164 135 104 74 55 29 9 2 0331 320 301 281 265 242 223 207 188 170 145 116 77 56 36 21 9 3 0
19.7 (17.6 - 22.6) 190 (57)FOLFOX4
23.9 (20.3 - 28.3) 165 (51)Panitumumab + FOLFOX4
Median (95% CI) months
EventsN (%)
HR=0.83 (95% CI: 0.67 - 1.02) p=0.07
Siena S, et al. ASCO-GI 2010, #283, oral presentation.
KRASKRAS WT: subgroup analyses for OSWT: subgroup analyses for OS
0.10 1.00 10.00
Factors N HR 95% CIFavours: pmab no pmab
All randomized 656 0.83 0.67-1.02Primary: colon 430 0.82 0.64-1.05Primary: rectal 226 0.77 0.53-1.12Liver mets: yes 566 0.77 0.61-0.96Liver mets: no 90 1.12 0.65-1.91Liver mets only: yes 116 0.93 0.51-1.69Liver mets only: no 540 0.79 0.63-0.99Met sites: <3 363 0.88 0.65-1.17Met sites: ≥3 290 0.71 0.53-0.96ECOG: 0 369 0.72 0.53-0.98ECOG: 1 248 0.89 0.65-1.22ECOG: ≥2 38 1.46 0.73-2.92Age ≥65 261 0.81 0.59-1.11Age <65 395 0.80 0.61-1.06Men 421 0.77 0.59-1.00Women 235 0.88 0.62-1.24
Hazard ratio (pmab / no pmab)
Siena S, et al. ASCO-GI 2010, #283, oral presentation.
WT KRAS: objective response
Central Review
117Progressive disease
3630Stable disease
4755Partial response
0.30Complete response
48(42 – 53)
55(50 – 61)
Objective response rate, % (95% CI)*
FOLFOX4(N=323)
Panitumumab+ FOLFOX4
(N=317)
All responses were confirmed no earlier than 28 days after All responses were confirmed no earlier than 28 days after the response criteria were first metthe response criteria were first met
*P = 0.068 *P = 0.068 (descriptive)(descriptive)
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Months
Prop
ortio
n Ev
ent-
Free
00%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Months
Prop
ortio
n Ev
ent-F
ree
00%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
KRAS WT KRAS MT
8.0 (7.5 8.0 (7.5 -- 9.3)9.3)215 (65)215 (65)FOLFOX4FOLFOX4
9.6 (9.2 9.6 (9.2 -- 11.1)11.1)199 (61)199 (61)Panitumumab + Panitumumab + FOLFOX4FOLFOX4
Median Median (95% CI) months(95% CI) months
EventsEventsN (%) N (%)
8.8 (7.7 8.8 (7.7 -- 9.4)9.4)157 (72)157 (72)FOLFOX4FOLFOX4
7.3 (6.3 7.3 (6.3 -- 8.0)8.0)167 (76)167 (76)Panitumumab + Panitumumab + FOLFOX4FOLFOX4
Median Median (95% CI) months(95% CI) months
EventsEventsN (%) N (%)
HR=1.29 (95% CI: 1.04 HR=1.29 (95% CI: 1.04 -- 1.62)1.62)pp=0.02=0.02
HR=0.80 (95% CI: 0.66 - 0.97)p=0.02
KRAS WT: significant improvement of PFS KRAS MT: significant detrimental effect on PFS
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Trends for OS benefit in Trends for OS benefit in KRASKRAS WT patients WT patients and detrimental effect in and detrimental effect in KRASKRAS MT patientsMT patients
HR=0.83 (95% CI: 0.67 HR=0.83 (95% CI: 0.67 -- 1.02) 1.02) pp=0.07=0.07
19.7 (17.6 19.7 (17.6 -- 22.6)22.6)190 (57)190 (57)FOLFOX4FOLFOX4
23.9 (20.3 23.9 (20.3 -- 28.3)28.3)165 (51)165 (51)Panitumumab+ Panitumumab+ FOLFOX4FOLFOX4
Median Median (95% CI) months(95% CI) months
EventsEventsN (%)N (%)
HR=1.24 (95% CI: 0.98 HR=1.24 (95% CI: 0.98 -- 1.57)1.57)pp=0.07=0.07
19.3 (16.5 19.3 (16.5 -- 21.8)21.8)142 (65)142 (65)FOLFOX4FOLFOX4
15.5 (13.1 15.5 (13.1 -- 17.6)17.6)152 (69)152 (69)Panitumumab+ Panitumumab+ FOLFOX4FOLFOX4
Median Median (95% CI) months(95% CI) months
EventsEventsN (%)N (%)
MonthsMonths
Surv
ival
Pro
babi
lity
Surv
ival
Pro
babi
lity
00
10%10%
20%20%
30%30%
40%40%
50%50%
60%60%
70%70%
80%80%
90%90%
100%100%
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828 3030 3232 3434 3636
MonthsMonths
Surv
ival
Pro
babi
lity
Surv
ival
Pro
babi
lity
00
10%10%
20%20%
30%30%
40%40%
50%50%
60%60%
70%70%
80%80%
90%90%
100%100%
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828 3030 3232 3434 3636
KRAS WT KRAS MT
Median actual follow-up time (data cut-off 28 August 2009): 20 months pmab + FOLFOX4 and 17 months FOLFOX4 (KRAS wt), 14 months pmab + FOLFOX4 and 16 months FOLFOX4 (KRAS MT)A pre-specified descriptive final analysis of OS is planned after a 2.5 year minimum follow-up period
Siena S, et al. ASCO-GI 2010, #283, oral presentation.
MT KRAS: objective response
Central Review
1113Progressive disease
4338Stable disease
4040Partial response
00Complete response
40(34 - 47)
40(33 - 46)
Objective tumor response, %(95% CI)*
FOLFOX4(N=211)
Panitumumab + FOLFOX4
(N=215)
All responses were confirmed no earlier than 28 All responses were confirmed no earlier than 28 days after the response criteria were first metdays after the response criteria were first met
*P = 0.98 (descriptive) *P = 0.98 (descriptive)
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
121212125-FU (continuous infusion)
-57-62Panitumumab - mg/kgMedian cumulative total dose
818181785-FU (continuous infusion)818081775-FU (bolus)80807977Oxaliplatin-83-81Panitumumab
Relative dose intensity - %
5-FU (continuous infusion) – mg/m2
5-FU (bolus) – mg/m2
Oxaliplatin – mg/m2
5-FU (bolus)OxaliplatinPanitumumab
Median number of cycles received
Wild-type KRAS Mutant KRASPanitumumab +
FOLFOX4(N=322)
FOLFOX4(N=327)
Panitumumab + FOLFOX4(N=217)
FOLFOX4(N=218)
11 - 10 -11 11 11 1112 12 12 12
859 865 824 8568627 8618 8294 871113483 13229 12878 13109
Treatment exposureTreatment exposure
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Grade 3/4 adverse events of interest
aMedDRA = Medical Dictionary for Regulatory Activities, bThere were 2 grade 5 pulmonary embolism in the panitumumab arm (1 each in the WT and MT KRAS group) cThere was 1 grade 5 febrile neutropenia in the panitumumab arm (MT KRAS group)
17161616Neurologic toxicity
3865Fatal adverse events
0203Paronychia
3322Febrile neutropeniac
4323Pulmonary embolismb
-<1-<1Infusion-related reaction (panitumumab)
<13
10471
73
FOLFOX4(N=218)
MT KRASWT KRAS
66
203730
80
Pmab + FOLFOX4(N=217)
06Hypomagnesemia19Stomatitis
918Diarrhea
6984Patients with any event
4142Neutropenia236Skin toxicity
FOLFOX4(N=327)
Pmab + FOLFOX4(N=322)
Adverse Event by MedDRAa - %
NCT00364013; Amgen 20050203.Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
PRIME conclusions• In patients with WT KRAS tumours, panitumumab significantly improved
PFS when added to FOLFOX4– median 9.6 vs 8.0 mo– HR=0.80, p=0.02
• RR was improved in patients with WT KRAS tumours (55% vs 48%)
• Interim OS was improved in patients with WT KRAS tumours– median 23.9 vs 19.7 mo– HR=0.83, p=0.07– Additional follow-up is required
• In patients with MT KRAS tumours, outcomes were inferior for panitumumab + FOLFOX4 vs FOLFOX4 alone
– Mechanism unknown
• Panitumumab was well-tolerated when administered with FOLFOX4– The AE profile was as expected for an anti-EGFR antibody – Grade 3/4 panitumumab-related infusion reactions were rare (N=2/539)
Siena S, et al. ASCO-GI 2010, #283, oral presentation; Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation.
Overall conclusionsOverall conclusions•• In 1In 1stst--line treatment of mCRC, line treatment of mCRC, KRASKRAS status was status was
predictive of efficacy of panitumumab in combination predictive of efficacy of panitumumab in combination withwith–– FOLFOX4 (PRIME) orFOLFOX4 (PRIME) or–– FOLFIRI (phase 2 studies)FOLFIRI (phase 2 studies)
•• In patients with In patients with KRASKRAS WT tumours, the PRIME study WT tumours, the PRIME study showed a significant PFS advantage and nonshowed a significant PFS advantage and non--significant benefits in OS and ORR for the addition of significant benefits in OS and ORR for the addition of panitumumab to chemotherapypanitumumab to chemotherapy
•• Panitumumab in combination with chemotherapy Panitumumab in combination with chemotherapy (FOLFOX4 or FOLFIRI) had a favourable safety profile, (FOLFOX4 or FOLFIRI) had a favourable safety profile, in line with other studies of antiin line with other studies of anti--EGFR mAbs in similar EGFR mAbs in similar settingssettings
Siena S, et al. ASCO-GI 2010, #283, oral presentation; Douillard JY, et al. Eur J Cancer 2009; 7(3S):6.10LBA, oral presentation; Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.