Berlin et al. ESMO 2006 Safety and Efficacy of Panitumumab Monotherapy in the Treatment of Metastatic Colorectal Cancer (mCRC) – Summary of Results Across

Berlin et al. ESMO 2006

Safety and Efficacy of Panitumumab Safety and Efficacy of Panitumumab Monotherapy in the Treatment of Metastatic Monotherapy in the Treatment of Metastatic

Colorectal Cancer (mCRC) – Summary of Colorectal Cancer (mCRC) – Summary of Results Across Clinical StudiesResults Across Clinical Studies

Jordan Berlin,Jordan Berlin,11 Eric Van Cutsem Eric Van Cutsem,,22 Marc Peeters, Marc Peeters,33

J. Randolph Hecht, J. Randolph Hecht,44 Michael Wolf, Michael Wolf,5 5 Rafael Amado,Rafael Amado,55 Neal J. MeropolNeal J. Meropol66

Abstract #326OAbstract #326O

11Vanderbilt University Medical Center, Nashville, TN; Vanderbilt University Medical Center, Nashville, TN; 22University Hospital University Hospital Gasthuisberg, Leuven, Belgium; Gasthuisberg, Leuven, Belgium; 33Ghent University Hospital, Ghent, Ghent University Hospital, Ghent, Belgium; Belgium; 44UCLA School of Medicine, Los Angeles, CA; UCLA School of Medicine, Los Angeles, CA; 55Amgen Inc., Amgen Inc., Thousand Oaks, CA; Thousand Oaks, CA; 66Fox Chase Cancer Center, Philadelphia, PAFox Chase Cancer Center, Philadelphia, PA


IntroductionIntroduction

• Panitumumab is a high-affinity (KPanitumumab is a high-affinity (Kd d = 5 = 5 10 10−11−11 M), fully human IgG2 M), fully human IgG2

monoclonal antibody directed against EGFr.monoclonal antibody directed against EGFr.11

• Panitumumab inhibits EGFr-mediated activity, including EGFr Panitumumab inhibits EGFr-mediated activity, including EGFr tyrosine autophosphorylation, tumor cell growth, and tyrosine autophosphorylation, tumor cell growth, and metastases.metastases.1-41-4

• Panitumumab monotherapy shows clinical activity in patients Panitumumab monotherapy shows clinical activity in patients with late‑stage colorectal cancer whose disease progressed after with late‑stage colorectal cancer whose disease progressed after standard irinotecan- and/or oxaliplatin-containing chemotherapy standard irinotecan- and/or oxaliplatin-containing chemotherapy regimens.regimens.55

• This summary of five studies presents efficacy data for This summary of five studies presents efficacy data for panitumumab in a total of 732 patients with mCRC who were panitumumab in a total of 732 patients with mCRC who were refractory to prior therapy. Two studies are complete, three are refractory to prior therapy. Two studies are complete, three are interim.interim.

11Foon et al. Int J Radiat Oncol Biol Phys. 2004;58:984-990.Foon et al. Int J Radiat Oncol Biol Phys. 2004;58:984-990.22Freeman et al. Eur J Cancer Suppl. 2004;2:95-96. Abstract 313.Freeman et al. Eur J Cancer Suppl. 2004;2:95-96. Abstract 313.33Freeman et al. Proc Am Assoc Cancer Res. 2005;46:1062. Abstract 4494. Freeman et al. Proc Am Assoc Cancer Res. 2005;46:1062. Abstract 4494. 44Lynch and Yang. Semin Oncol. 2002;29(suppl 9):47-50.Lynch and Yang. Semin Oncol. 2002;29(suppl 9):47-50.55Peeters et al. Proc Am Assoc Cancer Res. 2006;47: Abstract CP-1.Peeters et al. Proc Am Assoc Cancer Res. 2006;47: Abstract CP-1.


ObjectivesObjectives

• Assessment of the efficacy of panitumumab in patients with Assessment of the efficacy of panitumumab in patients with disease progression during or after prior fluoropyrimidine, disease progression during or after prior fluoropyrimidine, irinotecan, and/or oxaliplatin treatment for mCRCirinotecan, and/or oxaliplatin treatment for mCRC

• Key objectives of the studies included:Key objectives of the studies included:

–Objective tumor responseObjective tumor response

–Progression-free survivalProgression-free survival

–Duration of responseDuration of response

• Secondary objectives of the studies included:Secondary objectives of the studies included:

–Time to responseTime to response

–Survival timeSurvival time

–Safety (eg, adverse events, skin toxicities, human anti-human Safety (eg, adverse events, skin toxicities, human anti-human antibody responses)antibody responses)


Peeters, et al. 2006Peeters, et al. 2006aa

Berlin, et al. Berlin, et al. 20062006bb

Hecht, et al. Hecht, et al. 20062006cc Malik, et al. 2005Malik, et al. 2005dd

PanitumumabPanitumumab(N=229)(N=229)

CrossoverCrossover(N=177)(N=177) (N=93)(N=93) (N=88)(N=88) (N=150)(N=150)

Phase Phase 33 3 (ES)3 (ES) 22 22 22

Dose Dose scheduleschedule

6 mg/kg Q2W6 mg/kg Q2W 6 mg/kg Q2W6 mg/kg Q2W 6 mg/kg Q2W6 mg/kg Q2W 6 mg/kg Q2W6 mg/kg Q2W 2.5 mg/kg QW2.5 mg/kg QW

Response Response assessmentassessment

RECISTRECISTCentral reviewCentral review

RECISTRECISTLocal reviewLocal review

WHOWHOCentral reviewCentral review

WHOWHOCentral reviewCentral review

RECISTRECISTCentral reviewCentral review

Assessment Assessment scheduleschedule

Wks 8-48 and Wks 8-48 and Q3M thereafter Q3M thereafter until PDuntil PD

Q8W and at Q8W and at investigator investigator discretiondiscretion



Q9W and at Q9W and at investigator investigator discretiondiscretion

EGFr EGFr staining by staining by IHC, central IHC, central reviewreview

≥ ≥ 1% of 1% of evaluatedevaluatedtumor cellstumor cells

≥ ≥ 1% of 1% of evaluatedevaluatedtumor cellstumor cells

≥ ≥ 10% of 10% of evaluated evaluated tumor cellstumor cells

<1% (negative) <1% (negative) or 1 to < 10% or 1 to < 10% of evaluated of evaluated tumor cellstumor cells

High EGFr: 2+ or High EGFr: 2+ or 3+ in ≥ 10% of 3+ in ≥ 10% of tumor cellstumor cells

Low EGFr: sum of Low EGFr: sum of 1+, 2+, and 3+ in ≥ 1+, 2+, and 3+ in ≥ 10%, but 2+ and 10%, but 2+ and 3+ in < 10% of 3+ in < 10% of evaluated tumor evaluated tumor cellscells

Design and MethodsDesign and Methods

aPeeters et al. Proc Am Assoc Cancer Res. 2006;47: Abstract CP-1bBerlin et al. J Clin Oncol. (Meeting Abstracts). 2006;24:3548cHecht et al. J Clin Oncol. (Meeting Abstracts). 2006;24:3547dMalik et al. J Clin Oncol. (Meeting Abstracts). 2005;23:3520


Key Eligibility CriteriaKey Eligibility Criteria

• Age Age 18 years 18 years

• ECOG score of 0 – 2 (4 studies)ECOG score of 0 – 2 (4 studies)0 – 1 (1 study)0 – 1 (1 study)

• Pathologic diagnosis of CRCPathologic diagnosis of CRC

• Radiographic documentation of disease progression during or Radiographic documentation of disease progression during or within 6 months of most recent chemotherapy of within 6 months of most recent chemotherapy of fluoropyrimidine andfluoropyrimidine and

– Irinotecan Irinotecan 65 mg/m 65 mg/m22/week for 8 weeks and /week for 8 weeks and

– Oxaliplatin Oxaliplatin 30 mg/m 30 mg/m22/week for 6 weeks (4 studies)/week for 6 weeks (4 studies)

• Prior fluoropyrimidine and irinotecan Prior fluoropyrimidine and irinotecan oror oxaliplatin, oxaliplatin, or both, any or both, any exposure; no requirement for documentation of disease exposure; no requirement for documentation of disease progression progression (1 study: Malik, et al. 2005)(1 study: Malik, et al. 2005)

• Evaluation of tumor cell EGFr membrane staining (by IHC at Evaluation of tumor cell EGFr membrane staining (by IHC at central laboratory)central laboratory)


Patient DispositionPatient Disposition

All PatientsAll Patients

Patients enrolled, n (%)Patients enrolled, n (%) 739 (100)739 (100)

Patients who received study drug,Patients who received study drug,aa n (%) n (%) 732 (99)732 (99)

Efficacy set, n (%)Efficacy set, n (%) 617 (84)617 (84)

Median (min, max) follow-up,Median (min, max) follow-up,bb weeks weeks

All-enrolled analysis setAll-enrolled analysis set

Efficacy analysis setEfficacy analysis set

56 (3, 151)56 (3, 151)64 (16, 151)64 (16, 151)

aSafety setbFollow-up time is calculated from the enrollment date to the date of the data cut-off

ResultsResults


DemographicsDemographics

aECOG status 3 was reported in 1 panitumumab patient in the phase 3 study

Peeters, et al. 2006Peeters, et al. 2006Berlin, et Berlin, et al. 2006al. 2006

Hecht, et Hecht, et al. 2006al. 2006

Malik, et Malik, et al. 2005al. 2005



Sex - n (%)Sex - n (%)

MenMen 146 (63)146 (63) 111 (63)111 (63) 51 (55)51 (55) 51 (58)51 (58) 83 (56)83 (56)

Median (min, max) Median (min, max) age - yearsage - years

62 (55, 68)62 (55, 68) 62 (32, 83)62 (32, 83) 59 (31, 82)59 (31, 82) 62 (26, 85)62 (26, 85) 60 (21, 88)60 (21, 88)

Race - n(%)Race - n(%)

WhiteWhite 229 (99)229 (99) 175 (99)175 (99) 74 (80)74 (80) 71 (81)71 (81) 120 (81)120 (81)

BlackBlack 1 (0)1 (0) 0 (0)0 (0) 8 (9)8 (9) 12 (14)12 (14) 14 (9)14 (9)

HispanicHispanic 1 (0)1 (0) 0 (0)0 (0) 7 (8)7 (8) 3 (3)3 (3) 5 (3)5 (3)

OtherOther 0 (0)0 (0) 1 (1)1 (1) 4 (4)4 (4) 2 (2)2 (2) 9 (6)9 (6)

ECOG status - n (%)ECOG status - n (%)aa

00 107 (46)107 (46) 53 (30)53 (30) 31 (33)31 (33) 41 (47)41 (47) 37 (25)37 (25)

11 94 (41)94 (41) 85 (48)85 (48) 55 (59)55 (59) 42 (48)42 (48) 111 (75)111 (75)

22 29 (13)29 (13) 38 (22)38 (22) 7 (8)7 (8) 5 (6)5 (6) 0 (0)0 (0)


Disease CharacteristicsDisease Characteristics






Primary diagnosis,Primary diagnosis,n (%)n (%)

Colon cancerColon cancer 153 (66)153 (66) 113 (64)113 (64) 70 (75)70 (75) 61 (69)61 (69) 106 (72)106 (72)

Rectal cancerRectal cancer 78 (34)78 (34) 63 (36)63 (36) 23 (25)23 (25) 27 (31)27 (31) 42 (28)42 (28)

Number of prior lines of Number of prior lines of chemotherapy, n (%)chemotherapy, n (%)

231 (100)231 (100) 176 (100)176 (100) 93 (100)93 (100) 88 (100)88 (100) 6565aa (100) (100)

11 1 (0)1 (0) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0)

22 146 (63)146 (63) 114 (66)114 (66) 2 (2)2 (2) 13 (15)13 (15) 24 (37)24 (37)

≥ ≥ 33 84 (36)84 (36) 62 (35)62 (35) 91 (98)91 (98) 75 (85)75 (85) 41 (63)41 (63)aPrior chemotherapy is based on a subset of patients who had received fluoropyrimidine, oxaliplatin and irinotecan.


Best Objective ResponseBest Objective Response

aModified RECIST criteria; blinded central reviewbModified RECIST criteria; local reviewcModified WHO criteria; blinded central reviewAll responses were confirmed > 4 weeks after response criteria were first metDisease control rate is the sum of the objective response and stable disease rates


Hecht, et al. Hecht, et al. 20062006




Analysis SetAnalysis Set All EnrolledAll Enrolled

Modified Modified Intent-to-Intent-to-

treattreat

AdjudAdjudPrior Prior

FailureFailure

AdjudAdjudPrior Prior

FailureFailureAll All

EnrolledEnrolled

Overall objective Overall objective response (CR or response (CR or PR), n (%)PR), n (%)

19 (8)19 (8)aa 20 (11)20 (11)bb 3 (8)3 (8)cc 3 (13)3 (13)cc 13 (9)13 (9)aa

Stable Disease, n (%)Stable Disease, n (%) 64 (28)64 (28) 58 (33)58 (33) 8 (21)8 (21) 7 (30)7 (30) 43 (29)43 (29)

Disease ControlDisease Control 83 (36)83 (36) 78 (44)78 (44) 11 (28)11 (28) 10 (43)10 (43) 55 (37)55 (37)

PD, n (%)PD, n (%) 113 (49)113 (49) 65 (37)65 (37) 20 (51)20 (51) 10 (43)10 (43) 59 (40)59 (40)


Time and Duration of ResponseTime and Duration of Response

aObjective responses were assessed by blinded central review except for Peeters, et al (2006) crossover study, where the responses were assessed by local review.bNot estimable

Peeters, et al. 2006Peeters, et al. 2006Berlin, et al. Berlin, et al.

20062006Hecht, et al. Hecht, et al.

20062006Malik, et al. Malik, et al.

20052005



Median (range) Median (range) time to time to response - response - weeksweeksaa 7.9 (7, 15)7.9 (7, 15) 7.7 (7, 25)7.7 (7, 25) 11.0 (8, 11)11.0 (8, 11) 11.0 (7, 12)11.0 (7, 12) 8.1 (7, 25)8.1 (7, 25)

Median (range) Median (range) duration of duration of response – response – weeksweeks95% CI95% CI

17.0 (8, 25)17.0 (8, 25)

16.4, 25.316.4, 25.3

16.4 (8, 35)16.4 (8, 35)

16.0, 23.916.0, 23.9

13.2 (12,14)13.2 (12,14)

12.4, 14.012.4, 14.0

16.1 (16, 16)16.1 (16, 16)

NE, NENE, NEbb

18.1 (8, 36)18.1 (8, 36)

17.9, 23.317.9, 23.3


Progression-Free SurvivalProgression-Free Survival

Median (95% CI) in WeeksPeeters, et al. (2006): 8.0 (7.9, 8.4)

Berlin, et al (2006): 7.9 (7.4, 11.4)Hecht, et al (2006): 8.1 (7.1, 22.9)Malik, et al (2005) : 13.6 (8.3, 16.1)

Peeters, et al (2006) (ES): 8.1 (8.0, 12.4)

0%

10%

20%

30%

40%

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60%

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Weeks0 4 8 12 16 20 24 28 32 36 40 44

Peeters, et al (2006)

Berlin, et al (2006)Hecht, et al (2006)

Malik, et al (2005)

Peeters, et al (2006) (ES)231

5932

148

174209

5332

139

149118

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94

8376

1815

70

5649

128

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Patients at risk:


Progression-Free Survival by Objective Progression-Free Survival by Objective Response in the Phase 3 Trial Response in the Phase 3 Trial

Eve

nt-f

ree

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

CR/PRCR/PRSDSDOtherOther

CR/PR 8%CR/PR 8%SD 28%SD 28%

OtherOther64%64%

Other=Pts with progressive disease, unevaluable assessments, or no assessments; Groups not comparable due tolead-time bias and lack of randomization. By central review by modified RECIST; responses were confirmed at least 4 weeks after response criteria were first met


Progression-Free Survival by Objective Progression-Free Survival by Objective Response in the Phase 3 Trial Response in the Phase 3 Trial

Eve

nt-f

ree

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization

0 8 16 24 32 40 48 56

BSC SDBSC SD

BSC OtherBSC Other

Panitumumab CR/PRPanitumumab CR/PR

Panitumumab SDPanitumumab SD

Panitumumab OtherPanitumumab Other

CR/PRCR/PRSDSD

OtherOther

Other=Pts with progressive disease, unevaluable assessments, or no assessments; Groups not comparable due to lead-time bias and lack of randomization. By central review by modified RECIST; responses were confirmed at least 4 weeks after response criteria were first met

28%28%10%10%

64%64%90%90%

8%8%


Adverse Events of InterestAdverse Events of Interest

MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, with the exception of some dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modificationsaSafety analysis setbCaptured as laboratory values above grade 0

AnyAny(N = 732)(N = 732)

Grade 3-4Grade 3-4(N = 732)(N = 732)

Subjects with any adverse eventSubjects with any adverse eventaa – n (%) – n (%)

Fatigue Fatigue

Nausea Nausea

DiarrheaDiarrhea

VomitingVomiting

Abdominal PainAbdominal Pain

Constipation Constipation

DyspneaDyspnea

CoughCough

Edema peripheralEdema peripheral

EdemaEdema

Pleural effusionPleural effusion

Deep vein thrombosisDeep vein thrombosis

Pulmonary embolismPulmonary embolism

HypomagnesemiaHypomagnesemia

239 (33)239 (33)

208 (28)208 (28)

185 (25)185 (25)

152 (21)152 (21)

147 (20)147 (20)

146 (20)146 (20)

106 (14)106 (14)

100 (14)100 (14)

83 (11)83 (11)

30 (4)30 (4)

16 (2)16 (2)

9 (1)9 (1)

7 (1)7 (1)

31 (4)31 (4)

41 (6)41 (6)

14 (2)14 (2)

15 (2)15 (2)

21 (3)21 (3)

37 (5)37 (5)

13 (2)13 (2)

28 (4)28 (4)

4 (1)4 (1)

9 (1)9 (1)

4 (1)4 (1)

7 (1)7 (1)

6 (1)6 (1)

4 (1)4 (1)

9 (1)9 (1)

Hypomagnesemia (Lab)Hypomagnesemia (Lab)bb 226 (31)226 (31) 32 (4)32 (4)


Skin-Related Toxicities Occurring Skin-Related Toxicities Occurring in in 10% of Patients 10% of Patients

MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, with the exception of some dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modificationsaSafety analysis set

AnyAny

(N = 732) (N = 732)

Grade 3-4Grade 3-4

(N = 732)(N = 732)

Subjects with any adverse eventSubjects with any adverse eventaa – n (%) – n (%)

Dermatitis acneiform Dermatitis acneiform

Pruritus Pruritus

Erythema Erythema

Rash Rash

Skin exfoliationSkin exfoliation

ParonychiaParonychia

Skin fissuresSkin fissures

Dry skinDry skin

669 (91)669 (91)

382 (52)382 (52)

379 (52)379 (52)

384 (52)384 (52)

263 (36)263 (36)

145 (20)145 (20)

142 (19)142 (19)

115 (16)115 (16)

99 (14)99 (14)

95 (13)95 (13)

36 (5)36 (5)

13 (2)13 (2)

33 (5)33 (5)

20 (3)20 (3)

10 (1)10 (1)

8 (1)8 (1)

5 (1)5 (1)

1 (0)1 (0)


Infusion reactionsInfusion reactions

• Six of 732 (0.8%) patients had infusion reactions of any grade per Six of 732 (0.8%) patients had infusion reactions of any grade per investigatorinvestigator

• Two (0.3%) patients had a grade 3 infusion reaction per Two (0.3%) patients had a grade 3 infusion reaction per investigatorinvestigator

• One patient discontinued panitumumab per patient decisionOne patient discontinued panitumumab per patient decision


Antibodies to PanitumumabAntibodies to Panitumumab

aaAcid dissociation ELISA assayAcid dissociation ELISA assay



Malik, et Malik, et al. 2005al. 2005 TotalTotal


CrossoverCrossover(N=176)(N=176) (N=91)(N=91) (N=88)(N=88) (N=148)(N=148) (N=732)(N=732)

Samples Samples available for available for testing,testing,aa n n

224224 152152 9090 8888 145145 699699

Baseline Baseline samples, n (%)samples, n (%)

221 (99)221 (99) 150 (99)150 (99) 88 (97)88 (97) 87 (100)87 (100) 142 (98)142 (98) 688 (98)688 (98)

Post-dose Post-dose samples, n (%)samples, n (%)

185 (83)185 (83) 71 (47)71 (47) 66 (73)66 (73) 66 (76)66 (76) 107 (74)107 (74) 495 (71)495 (71)

Baseline Baseline positivepositive

3 (1)3 (1) 2 (1)2 (1) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 5 (<1)5 (<1)

Post-dose Post-dose positivepositive

0 (0)0 (0) 2 (1)2 (1) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 2 (<1)2 (<1)


ConclusionsConclusions

• Across all studies, panitumumab had consistent antitumor activity Across all studies, panitumumab had consistent antitumor activity in patients with mCRC:in patients with mCRC:

– Objective response rates ranged from 8% to 13%Objective response rates ranged from 8% to 13%

– Disease control rates ranged from 28% to 44%Disease control rates ranged from 28% to 44%

– Progression-free survival ranged from 8 to 14 weeksProgression-free survival ranged from 8 to 14 weeks

• Panitumumab was well toleratedPanitumumab was well tolerated

– Of 732 patients, 0.3% had grade 4 skin-related toxicities, and Of 732 patients, 0.3% had grade 4 skin-related toxicities, and 13% had grade 3 skin-related toxicities13% had grade 3 skin-related toxicities

– The majority of patients (78%) had grade 1 or 2 skin-related The majority of patients (78%) had grade 1 or 2 skin-related toxicitiestoxicities

– Grade 3 infusion reaction rate was 0.3% (there were no grade 4 Grade 3 infusion reaction rate was 0.3% (there were no grade 4 infusion reactions); premedication was not requiredinfusion reactions); premedication was not required

– Less than 1% of patients had anti-panitumumab antibodies Less than 1% of patients had anti-panitumumab antibodies


ConclusionsConclusions

• Across all studies, EGFr staining levels were not Across all studies, EGFr staining levels were not associated with panitumumab activityassociated with panitumumab activity

• There was an association of panitumumab activity with There was an association of panitumumab activity with the incidence of skin toxicity (data not shown)the incidence of skin toxicity (data not shown)

• Additional studies in mCRC with other agents are Additional studies in mCRC with other agents are ongoingongoing


AcknowledgementsAcknowledgements

• We wish to thank the patients who participated in these We wish to thank the patients who participated in these studies and their familiesstudies and their families

• We also wish to acknowledge the investigators and We also wish to acknowledge the investigators and research teams who enrolled patientsresearch teams who enrolled patients

• We acknowledge the assistance of Mee Rhan Kim and We acknowledge the assistance of Mee Rhan Kim and Geoffrey Smith for slide productionGeoffrey Smith for slide production

Documents

Berlin et al. ESMO 2006 Safety and Efficacy of Panitumumab Monotherapy in the Treatment of Metastatic Colorectal Cancer (mCRC) – Summary of Results Across