Introduction

Hecht ASCO GI 2008

Interim results from PACCE: irinotecan (Iri)/bevacizumab (bev) ± panitumumab

(pmab) as first-line treatment (tx) for metastatic colorectal cancer (mCRC)

J. Randolph Hecht,1 Edith Mitchell,2 Tarek Chidiac,3 Carroll Scroggin,4 Christopher Hagenstad,5 David Spigel,6 John

Marshall,7 Allen Cohn,8 Sam Suzuki,9 Thomas Griffin9

1UCLA School of Medicine, Los Angeles, CA; 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 3Mid Ohio

Oncology/Hematology, Inc, Columbus, OH; 4NEA clinic, Jonesboro, AR; 5Suburban Hematology-Oncology Associates, Lawrenceville, GA; 6Sarah

Cannon Research Institute, Nashville, TN; 7Georgetown University Hospital, Washington, DC; 8Rocky Mountain Cancer Centers, Denver, CO;

9Amgen Inc., Thousand Oaks, CA

This study was funded by Amgen Inc.

Hecht ASCO GI 20082

Introduction

Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr) and is approved as monotherapy in the US for the treatment of refractory mCRC

Early studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy1,2

PACCE was a US, community-based study designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab as first-line treatment for mCRC

This is an interim analysis for data available as of May 31, 2007 describing the safety and efficacy for the Iri-CT based cohort from PACCE (trial discontinued only panitumumab therapy in March 2007 after a planned interim analysis of ~231 PFS events in the Ox-CT cohort)

1Shaheen et al. Brit J Cancer 2001;85:584-5892Saltz LB et al. ASCO 2005. Abstract #3508 (BOND2)

Hecht ASCO GI 20083

Study SchemaPACCE: Panitumumab Advanced Colorectal Cancer Evaluation

Randomized, Open-Label, Controlled Phase 3b Trial

Stratification Factors: ECOG score, prior adjuvant tx, disease site,Ox doses/Iri regimen, number of metastatic organs

Tumor assessments: Q12W until disease progression or intolerability

Panitumumab 6 mg/kg Q2W

+ Ox-CTBevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Inv choice

Iri-basedCT(eg, FOLFIRI)

N = 200Inv choice

Ox-CT+ Bevacizumab

Panitumumab Panitumumab 6 mg/kg Q2W6 mg/kg Q2W

+ Iri-CT+ Iri-CT+ Bevacizumab+ Bevacizumab

Iri-CTIri-CT+ Bevacizumab+ Bevacizumab

RANDOMIZE

1:1

1:1

SCREENING

Hecht ASCO GI 20084

Investigator Choice – Iri-CT Regimens

Regimen Irinotecan Leucovorin (LV) 5-Fluorouracil (5-FU)

FOLFIRI 180 mg/m2 IV over 90 min on Day1 per cycle

200 mg/m2 IV over 2 hrs on Day1

400 mg/m2 IV bolus over 2-4 min, followed 2400mg/m2 continuous IV over 46 hrs for the first 2 cycles, increased to 3000 mg/m2 if no toxicity >grade 1

Douillard 180 mg/m2 IV over 2 hrs on Day1 per cycle

200 mg/m2 IV over 2 hrs on Day1 and 2

400 mg/m2 IV bolus over 2-4 min, followed by 600 mg/m2 continuous IV over 22 hrs Day 1 and Day 2

Other Iri-CT Q2W

TBD by physician TBD by physician

TBD by physician

Hecht ASCO GI 20085

Key Eligibility CriteriaKey Eligibility Criteria

Age 18 years old

Measurable mCRC per modified RECIST criteria

ECOG status 0 or 1

Adequate hematologic, renal, and hepatic function

No prior chemotherapy or biologic therapy for mCRC

No adjuvant chemotherapy within 6 months

No major surgery within 28 days of randomization or elective and/or planned major surgical procedures during the trial

No clinically significant cardiovascular disease within 1 year prior to randomization

No EGFr testing required

Hecht ASCO GI 20086

Primary endpoint of the PACCE study:*

– Progression-free survival (PFS) by central review in the Ox-CT cohort

– To detect a 30% improvement in median PFS in the panitumumab plus bev/Ox-CT vs the bev/Ox-CT

– Planned interim analysis at ~231 Ox-CT PFS events

Iri-CT cohort analyses were descriptive only

– Safety

– Efficacy including:

• Overall response rate (central and local review)

• PFS (central and local review), TTF, OS

– Exploratory biomarker analyses (eg, KRAS)

Study Endpoints and Design Characteristics

*Powered for oxaliplatin cohort only; descriptive for irinotecan cohort

Hecht ASCO GI 20087

Treatment: Iri-CT CohortTreatment: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

pmab+ bev/Iri-CT(N=115)

bev/Iri-CT(N=115)

Patients randomized, n (%) 115 (100) 115 (100)

Patients received any first-line treatment, n (%)

112 (97) 112 (97)

Median follow-up, weeks Range

37.6 1.1 - 104.6

40.3 1.1 - 104.3

Chemotherapy regimen received on week 1, n (%)a

FOLFIRI 97 (87) 104 (93)

Douillard 9 ( 8) 3 ( 3)

Other Iri-CT 6 ( 5) 5 ( 4)

aOf those who received any first-line treatment

Hecht ASCO GI 20088

Baseline Demographics and Characteristics: Baseline Demographics and Characteristics: Iri-CT CohortIri-CT Cohort

(Interim Analysis, May 2007 Data Cutoff) (Interim Analysis, May 2007 Data Cutoff)pmab+ bev/Iri-CT

(N=115)bev/Iri-CT(N=115)

Male, % 49 62

Race, % White Black Hispanic

Other

751654

7414120

Median age (range), years 60.0 (35 – 84) 59.0 (23 – 80)

Age 65, % 38 28

Baseline ECOG, % 0 1

5941

6436

Prior Adjuvant Therapy, %

33 31

Metastatic organs, % 1 >1

4060

4654

Hecht ASCO GI 20089

Summary of Adverse Events: Iri-CT CohortSummary of Adverse Events: Iri-CT Cohort (Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)


bev/Iri-CT(N=113)

Any event, % 99 100

Grade 3 56 43

Grade 4 23 15

Grade 5* 5 1

Pmab-related grade 5 2 n/a

Any serious (SAE), % 54 33

Ended all first-line treatment due to AE, %

17 5

Ended panitumumab treatment due to AE, %

23 n/a

Panitumumab treatment-related SAE, %

16 n/a

Safety set included all patients who were dosed. Graded per NCI CTCAE v3.0*As reported by investigator – does not include disease progression (ie, neoplasms); n/a= not applicable

Hecht ASCO GI 200810

Grade 3 or 4 Adverse Events of Interest: Iri-CT CohortGrade 3 or 4 Adverse Events of Interest: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

pmab+bev/Iri-CT(N=111)

bev/Iri-CT(N=113)

Grade 3n (%)

Grade 4n (%)

Grade 3n (%)

Grade 4n (%)

Skin toxicitya 41 ( 37) 0 (0) 0 (0) 0 (0)

Diarrhea 30 (27) 1 (1) 10 (9) 0 (0)

Neutropenia 16 (14) 3 (3) 19 (17) 5 (4)

Dehydration 15 (14) 0 (0) 7 (6) 0 (0)

Infectionsb 13 (12) 2 (2) 10 (9) 0 (0)

Nausea 11 (10) 2 (2) 7 (6) 0 (0)

Hypokalemia 10 (9) 2 (2) 5 (4) 0 (0)

Vomiting 9 (8) 2 (2) 8 (7) 0 (0)

Paronychia 4 (4) 0 (0) 0 (0) 0 (0)

Hypomagnesemia 3 (3) 2 (2) 0 (0) 1 (1)

Hypertension 2 (2) 0 (0) 3 (3) 0 (0)

Deep venous thrombosis 14 (13) 0 (0) 7 (6) 0 (0)

Pulmonary embolismc 0 (0) 12 (11) 0 (0) 6 (5)

bGrade 5 infections occurred in 2 (2%) pmab + bev/Iri-CT ptscGrade 5 pulmonary embolism occurred in 1 (1%) pmab + bev/Iri-CT pts Grade 5 gastrointestinal perforations occurred in 2 (2%) pmab + bev/Iri-CT pts

MedDRA v 9.0 preferred terms; graded per NCI CTCAE v 3.0aSkin toxicity included multiple terms from the skin and subcutaneous and infections system organ class (SOC)


Overall Response RateOverall Response Rate: Iri-CT Cohort: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) (Interim Analysis, May 2007 Data Cutoff)

Central Reviewa Local Reviewa


bev/Iri-CT(N=115)


bev/Iri-CT(N=115)

Best ORR 43% 39% 55% 46%

Complete response 0% 0% 10% 6%

Partial response 43% 39% 44% 40%

Stable disease 27% 38% 23% 30%

Progressive diseaseb 13% 3% 5% 10%

Not done/Unevaluablec 17% 19% 17% 15%

aCT scans performed Q12W; responses did not require confirmationbCentral review unable to evaluate clinical disease progression (ie, non-radiographic PD); central review unable to accurately evaluate PD after surgical resections cIncluded missing and unreadable scans


Interim PFS – Iri-CT Cohort Interim PFS – Iri-CT Cohort (May 2007 Data Cutoff) (May 2007 Data Cutoff)

# PFS events (%)

Median (95%CI), mos

62 (54) 11.0 (9.1, 13.6)

53 (46) 10.7 (9.0, 12.5)

Pmab+bev/Iri-CT

Bev/Iri-CT

HR= 1.21 (95% CI: 0.80, 1.82)*

# PFS events (%)

Median (95%CI), mos

54 (47) 10.1 (8.2, 13.7)

43 (37) 11.7 (9.0, 13.2)

Central Reviewa Local Reviewb

aCensoring based on last available scan read centrally Q12W bCensoring based on last day of patient contact or visit Q2W

HR= 0.92 (95% CI: 0. (0.63, 1.34)*

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25

Months

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25

MonthsPmab

Censored1150

7419

2332

76

14

00

No PmabCensored

1150

7629

2334

67

12

00

1150

869

3331

711

21

01

1150

8514

2734

611

03

00

*Descriptive only

• Differences in censoring rules; more early censoring in central review and in bev/Iri-CT cohort• Central review unable to assess clinical disease progression• Central review unable to accurately evaluate PD after surgical resections • Investigator bias

*Descriptive only

Central vs Local Review


PFS - Differences Between Central vs Local PFS - Differences Between Central vs Local ReviewReview

• Differences in censoring rules

• Central censoring: if endpoint not reached, pt was censored back to their last scan date (Q12W)

• Local censoring: if endpoint not reached, pt was censored back to their last investigator contact (Q2W on treatment, Q12W post-treatment follow-up)

• More early censoring in central review and in bev/Iri-CT cohort

• Central review unable to assess clinical disease progression

• Per protocol, central review defined as single radiologist read, no oncologist review

• Central review unable to accurately evaluate PD after surgical resections

• Potential investigator bias for local review


Other Efficacy Endpoints: Iri-CT CohortOther Efficacy Endpoints: Iri-CT Cohort (Interim Analysis, (Interim Analysis, May 2007 Data Cutoff) May 2007 Data Cutoff)


bev/Iri-CT(N=115)

Time to Treatment Failure, Median (95% CI), months 6.6 (5.9 - 8.0) 6.0 (4.8 - 6.9)

Overall Survival,Median (95% CI), months 20.7 (17.8 - NE) 20.5 (19.8 - NE)

Deaths events, n (%)a 26 (23) 18 (16)

Within 60 days of first dose, n (%)

5 ( 4) 2 ( 2)

Within 30 days of last dose of 1st line tx, n (%)

8 ( 7) 3 ( 3)

aDeaths at any time including long-term follow-up (post-study treatment)NE= not evaluable


Reasons for First-Line Treatment Reasons for First-Line Treatment Discontinuation: Iri-CT CohortDiscontinuation: Iri-CT Cohort

(Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

pmab + bev/Iri-CT(N=115)

bev/Iri-CT(N=115)

Patients discontinued first-line tx, n (%) 102 (89) 99 (86)

Progressive events, n (%)a 42 (41) 29 (29)

Disease progression 36 (35) 27 (27)

Deaths 6 (6) 2 (2)

Non-progressive events, n (%)a 60 (59) 70 (71)

Adverse events 17 (17) 6 (6)

Protocol violation 3 (3) 5 (5)

Consent withdrawn/ refused treatment 15 (15) 26 (26)

Otherb 25 (25) 33 (33)aOf those who discontinued first-line treatmentbOther included end of first-line treatment without progression, requirement for alternative therapy, administrative, lost to follow-up, and other


Treatment Exposure: Iri-CT CohortTreatment Exposure: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

Dose Delays% Pts

Dose Reductions% Pts

Relative Dose Intensity(RDI) %

pmab+ bev/Irin=111

bev/Irin=113

pmab+ bev/Irin=111

bev/Irin=113

pmab+bev/Irin=111

bev/IriN=113

Panitumumab 65 n/a 34 n/a 83 n/a

Bevacizumab 61 45 1 3 88 92

Irinotecan 63 46 21 18 81 88

5-FU 61a 45a 24a 16a 81b 87b

% Pts % Pts

Inf 5-FU/Iri/Bev ≥ 85%

n/a n/a n/a n/a 34 44

aBolus 5-FUbInfusional 5-FU n/a=not applicable


Prevalence of Mutant Prevalence of Mutant KRASKRAS:: Iri-CT CohortIri-CT Cohort(Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

pmab+ bev/Iri-CT

bev/Iri-CT

Patients randomized, n 115 115

KRAS not tested, n (%) 6 (5) 8 (7)

KRAS tests failed, n (%) 3 (3) 9 (8)

Did not receive treatment, n (%) 3 (3) 1 (1)

Patients included in KRAS analysis, n (%)

103 (90) 97 (84)

Patients included in KRAS analysis, n 103 97

Wild-type KRAS, n (%) 57 (55) 58 (60)

Mutant KRAS, n (%) 46 (45) 39 (40)


Overall Response RateOverall Response Rate By By KRASKRAS Status Status (Interim Analysis, May 2007 Data Cutoff)(Interim Analysis, May 2007 Data Cutoff)

Central Review N

pmab+ bev/Iri-CT

(n/N) %bev/Iri-CT (n/N) %

Odds Ratioa (95% CI)

Wild-type KRAS 115 31/57 (54) 27/58 (47) 1.42 (0.63-3.21)

Mutant KRAS 85 14/46 (30) 15/39 (38) 0.59 (0.23-1.55)

KRAS efficacy set 200 45/103 (44) 42/97 (43) 1.00 (0.56-1.80)

Iri-CT ITT set 230 49/115 (43) 45/115 (39) 1.15 (0.67-1.98)

Local Review N

pmab+ bev/Iri-CT

(n/N) %bev/Iri-CT (n/N) %

Odds Ratioa (95% CI)

Wild-type KRAS 115 40/57 (70) 34/58 (59) 1.71 (0.75-3.88)

Mutant KRAS 85 19/46 (41) 17/39 (44) 0.81 (0.32-2.05)

KRAS efficacy set 200 59/103 (57) 51/97 (53) 1.28 (0.71-2.29)

Iri-CT ITT set 230 63/115 (55) 53/115 (46) 1.45 (0.85-2.46)aOdds ratio for pmab:control (greater than 1.0 favors pmab+bev/Iri-CT). Descriptive only


SUMMARYSUMMARY This is a descriptive interim analysis of bev/Iri-CT +/- panitumumab in the

PACCE study

Response rates were higher in the panitumumab + bev/Iri-CT cohort; no significant differences in PFS and OS between cohorts were observed

Most patients withdrew due to non-progressive events (59% on panitumumab + bev/Iri-CT arm, 71% on bev/Iri-CT arm), similar to the Ox-CT cohort, limiting the utility of PFS as a valid endpoint in this study

Increased response rates with panitumumab + bev/Iri-CT were seen only in wild-type KRAS patients; these findings are consistent with previously reported data on KRAS analyses in the monotherapy setting1-3

Further data collection and analyses are ongoing

1Amado RG et al. JCO 2008, Manuscript in press2Khambata-Ford S et al. JCO 2007; 25: 3230-3237 3Lievre A et al. Cancer Res 2006;66: 3992-3995


SUMMARY (SUMMARY (contcont.).)

Phase 3 registrational studies are currently ongoing to investigate panitumumab with chemotherapy alone in first- line and second-line mCRC

– Study 20050181 investigates FOLFIRI +/- panitumumab in second-line mCRC (Peeters et al., Abstract #335, Poster #A56)

– PRIME/Study 20050203 investigates FOLFOX +/- panitumumab in first-line mCRC (Douillard et al., Abstract #443, Poster #A63)

– Independent data monitoring committees for these studies have recommended continuation per protocol


ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Patients who participated in this study and their families

All investigators, co-investigators, and study staffs at 194 sites across the US

The Amgen study team

Introduction

Documents

Transcript of Introduction