Introduction

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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;

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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

LONGTERM

FOLLOWUP

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

Australia vs rest of the world

Q2W – Every 2 weeks

SCREENING

PRIME StudyCountries

Canada

BelgiumCzech RepublicFranceHungaryItalyLatviaPolandSpainSwitzerlandUnited Kingdom

SouthAfrica

Costa RicaMexico

ArgentinaBrazilChile

Australia

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Study Objective and Endpoints

• 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 CharacteristicsWT 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

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WT KRAS - Final Analysis

Eventsn/N (%)

Median (95% CI)months

Panitumumab + FOLFOX4

270 / 325 (83)

10.0 (9.3 – 11.4)

FOLFOX4 280 / 331 (85)

8.6 (7.5 – 9.5)

HR = 0.80 (95% CI: 0.67 – 0.95) Log-rank p-value = 0.01

Eventsn/N (%)

Median (95% CI) months

Worst ST grade 2-4 in panitumumab arm

208 / 250 (83)

11.3 (9.9 - 13.2)

Worst ST grade 0-1 in panitumumab arm

55 / 64 (86)

6.1 (5.3 - 9.2)

FOLFOX4 alone 278 / 320 (87)

8.7 (7.5 - 9.6)

Grade 2-4 panitumumab vs FOLFOX4 HR = 0.71 (95% CI: 0.59 – 0.85) Log-rank p-value = 0.0002

PFSWT KRAS and PFS ≥ 28 Days

Worst Grade ST Severity

Months

Prop

ortio

n Ev

ent-F

ree

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 38 40 42 44

Prop

ortio

n Ev

ent-F

ree

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44

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Eventsn/N (%)

Median (95% CI)months

Panitumumab+FOLFOX4

214 / 325 (66)

23.9 (20.3 - 27.7)

FOLFOX4 231 / 331 (70)

19.7 (17.6 - 22.7)

HR = 0.88 (95% CI: 0.73 – 1.06) Log-rank p-value = 0.17

WT KRAS - Final Analysis

OS

Eventsn/N (%)

Median (95% CI) months

Worst ST grade 2-4 in panitumumab arm

157 / 250 (63)

27.7 (23.8 - 30.8)

Worst ST grade 0-1 in panitumumab arm

50 / 64 (78)

11.5 (9.1 - 20.2)

FOLFOX4 alone 229 / 320 (72)

19.7 (17.6 - 22.7)

Grade 2-4 panitumumab vs FOLFOX4 HR = 0.75 (95% CI: 0.61 – 0.92) Log-rank p-value = 0.006

WT KRAS and PFS ≥ 28 DaysWorst Grade ST Severity

Months

Surv

ival P

roba

bility

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 38 40 42 44 46

Surv

ivalP

roba

bility

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

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Objective Response by Worst Grade ST Severity (Central Review)

WT KRASPanitumumab

+ FOLFOX4Grade 2–4 ST

(n = 246)a

Panitumumab + FOLFOX4

Grade 0–1 ST(n = 61)a

FOLFOX4(n = 313)a

ORR – n (%) [95% CI] 156 (63)[57 – 69]

25 (41)[29 – 54]

154 (49) [44 – 55]

Complete response – n (%) 1 (<1) 0 (0) 2 (<1)

Partial response – n (%) 155 (63) 25 (41) 152 (49)

Stable disease – n (%) 68 (28) 23 (38) 117 (37)

Progressive disease – n (%) 14 (6) 6 (10) 35 (11)

Unevaluable or not done – n (%) 8 (3) 7 (11) 7 (2)

aIncluded only patients with baseline measurable disease per central review

All responses were required to be confirmed at least 28 days after the response criteria were first met

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PRO ResultsSummary of EQ-5D Health State Index Score Through Treatment Discontinuation

Least Squares Adjusted Mean Difference ([panitumumab + FOLFOX4]

– FOLFOX4) (95% CI)

Least Squares Adjusted Mean Difference (Grade 0 or 1 – grade ≥ 2 ST)

(95% CI)EQ-5D Health State Index Score -0.0021 (-0.0319 – 0.0276) -0.0134 (-0.0708 – 0.0441)

EQ-5D Overall Health Rating -1.0690 (-3.6277 – 1.4896) 0.8971 (-4.0224 – 5.8167)

The minimal clinically important difference is 0.08 for the EQ-5D Health State Index Score and 7 for the EQ-5D Overall Health Rating4

'Panitumumab + FOLFOX''FOLFOX alone'

Week

Mea

n EQ

5D-In

dex

scor

e

-0.05 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 1.05

40 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 148 152 156 160 164 168 172 176 180

Overall Health Rating Change From Baseline Through Disease Progression and Impact of ST on PRO(Central Assessment - WT KRAS PRO Analysis Set)

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Grade 3/4 Adverse Events of Interest by Worst Grade ST Severity

WT KRAS mCRC

Adverse event by MedDRA Term – n (%)

Panitumumab + FOLFOX4

Grade 2–4 ST(n = 250)

Panitumumab + FOLFOX4

Grade 0–1 ST(n = 64)

FOLFOX4(n = 320)

Patients with any event 223 (89) 45 (70) 225 (70)

Neutropenias 116 (46) 21 (33) 133 (42)

Diarrhea 46 (18) 12 (19) 28 (9)

Neurologic toxicities 48 (19) 5 (8) 51 (16)

Stomatitis/oral mucositis 27 (11) 1 (2) 2 (<1)

Hypokalemia 25 (10) 6 (9) 15 (5)

Fatigue 23 (9) 7 (11) 10 (3)

Hypomagnesemia 18 (7) 4 (6) 1 (<1)

Paronychia 10 (4) 1 (2) 0 (0)

Pulmonary embolism 8 (3) 1 (2) 5 (2)

Febrile neutropenia 5 (2) 3 (5) 7 (2)

Infusion-related reaction (panitumumab) 2 (<1) 0 (0) –

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.