1 - Panitumumab 1st-Line Therapy - April 2010

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


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


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 (%)


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)


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%)


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


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


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


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


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


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


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)


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.


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


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


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)


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)


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


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


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


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


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


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)


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


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 - %


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.

1 - Panitumumab 1st-Line Therapy - April 2010

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