Predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of 5 clinical trials Jordan Berlin, 1 Eric Van Cutsem, 2 Marc Peeters, 3 J. Randolph Hecht, 4 Rolando Ruiz, 5 Mike Wolf, 5 Rafael G. Amado, 5 Neal J. Meropol 6 1 Vanderbilt University Medical Center, Nashville, TN; 2 University Hospital Gasthuisberg, Leuven, Belgium; 3 Ghent University Hospital, Ghent, Belgium; 4 UCLA School of Medicine, Los Angeles, CA; 5 Amgen Inc., Thousand Oaks, CA; 6 Fox Chase Cancer Center, Philadelphia, PA

Introduction Panitumumab is a high-affinity (K d = 5  10 −11 M), fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr). 1 Panitumumab is a high-affinity (K d = 5  10 −11 M), fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr). 1 Panitumumab is approved for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression during or following fluoropyrimidine-, irinotecan-, and oxaliplatin-containing chemotherapy regimens. 2 Panitumumab is approved for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression during or following fluoropyrimidine-, irinotecan-, and oxaliplatin-containing chemotherapy regimens. 2 A recent analysis of safety data from 789 patients enrolled in 10 clinical studies indicated that panitumumab is well tolerated in patients with mCRC. 3 A recent analysis of safety data from 789 patients enrolled in 10 clinical studies indicated that panitumumab is well tolerated in patients with mCRC. 3 The most common adverse events associated with panitumumab monotherapy were skin-related toxicities. 3 The most common adverse events associated with panitumumab monotherapy were skin-related toxicities. 3 Here we present the results of an exploratory analysis examining the association between skin-related toxicities and panitumumab efficacy as well as the predictive value of skin toxicity severity for response to panitumumab in pooled data for 727 patients from 5 clinical studies of panitumumab monotherapy. Here we present the results of an exploratory analysis examining the association between skin-related toxicities and panitumumab efficacy as well as the predictive value of skin toxicity severity for response to panitumumab in pooled data for 727 patients from 5 clinical studies of panitumumab monotherapy.

Objectives An exploratory analysis on pooled data from 5 clinical studies of panitumumab monotherapy to: An exploratory analysis on pooled data from 5 clinical studies of panitumumab monotherapy to: – assess the association between severity of skin toxicity throughout treatment and panitumumab efficacy – evaluate predictive value of skin toxicity severity in the first 4 weeks for response to panitumumab Key endpoints of panitumumab monotherapy studies: Key endpoints of panitumumab monotherapy studies: – Objective response rate – Progression-free survival – Duration of response – Time to response – Safety (including skin toxicities, infusion reactions, and anti-panitumumab antibody formation)

Van Cutsem & Peeters, et al Berlin, et al Hecht, et al. 2007a 6 Hecht, et al. 2007b 7 Phase 3 Panitumumab Crossover Phase3 3 (ES a ) 222 Patients enrolled, n Patients included in current analysis, n Dose schedule 6 mg/kg Q2W 2.5 mg/kg QW Response assessment RECIST Central review RECIST Local review WHO Central review RECIST Central review Assessment schedule Wks 8-48 and Q3M thereafter until PD Q8W and at investigator discretion Wks 8-48 and Q3M thereafter until PD Q9W and at investigator discretion Tumor cells stained for membrane EGFr b, % ≥ 1% ≥ 10% < 1% or 1-9% High c or low d Design and Methods PD: progression of disease; RECIST: Response Evaluation Criteria in Solid Tumors; WHO: World Health Organization. Van Cutsem & Peeters and Hecht (2007a and b) studies are complete; Berlin study is interim. a ES: extension study. Patients who developed progressive disease while receiving best supportive care in the phase 3 study were allowed to cross over to this extension study to receive panitumumab until disease progression or drug intolerability. b By immunohistochemistry at central laboratory using DakoCytomation EGFr pharmDx TM staining kit (DakoCytomation, Carpinteria, CA). c High: ≥ 10% of tumor cells with 2+ and 3+ staining intensity score. d Low: ≥ 10% of tumor cells with 1+, 2+, and 3+ staining intensity score, but < 10% with 2+ and 3+ staining intensity score.

Key Eligibility Criteria Pathologic diagnosis of CRC Pathologic diagnosis of CRC Age  18 years Age  18 years ECOG score of 0 – 2 (4 studies) 0 – 1 (1 study) ECOG score of 0 – 2 (4 studies) 0 – 1 (1 study) Radiographic documentation of disease progression during or within 6 months after the most recent chemotherapy of fluoropyrimidine with Radiographic documentation of disease progression during or within 6 months after the most recent chemotherapy of fluoropyrimidine with Irinotecan  65 mg/m 2 /week for 8 weeks and Irinotecan  65 mg/m 2 /week for 8 weeks and Oxaliplatin  30 mg/m 2 /week for 6 weeks Oxaliplatin  30 mg/m 2 /week for 6 weeks – For the Hecht 2007b study, documentation of disease progression was not required and patients could have received prior fluoropyrimidine and irinotecan or oxaliplatin, or both. Pre-specified levels of EGFr tumor membrane staining according to each study (by immunohistochemistry at central laboratory). Pre-specified levels of EGFr tumor membrane staining according to each study (by immunohistochemistry at central laboratory).

Statistical Analysis Analyses by skin toxicity severity: – Included patients common to the primary efficacy and safety analysis sets for each trial with known worst severity of skin toxicity or with no skin toxicity reported. – Included patients with at least 2 infusions of panitumumab to ensure adequate exposure and time for skin toxicity onset. – Descriptive estimates of objective response rate (ORR), disease control rate, and 95% confidence intervals (CI) by worst skin toxicity severity throughout the trial or in the first 4 weeks. – Descriptive estimates of median progression-free survival (PFS), overall survival (OS), and 95% CI by worst skin toxicity severity throughout the trial or in the first 4 weeks. – Descriptive estimates of sensitivity, specificity, positive/negative prediction values, and kappa statistics. – Univariate regression analysis of skin toxicity severity (throughout trial vs. the first 4 weeks) as a predictor for objective response or disease control (logistic model), and PFS or OS (proportional hazards model).

Patient Disposition Patients Patients enrolled – n 851 Safety set – n (%) 847 (>99) Efficacy set – n (%) 762 (90) Patients in both safety and efficacy sets – n (%) 758 (89) Patients included in this analysis a,b – n (%) 727 (96) Patients excluded a,b – n (%) 31 (4) Received < 2 infusions b – n (%) Received < 2 infusions b – n (%) 30 (4) Severity of skin toxicity unknown b – n (%) Severity of skin toxicity unknown b – n (%) 1 (<1) Median (min, max) follow-up c - weeks 27 (2, 111) a Patients in both the safety and efficacy sets who received at least 2 infusions (exposure over 2 weeks for QW dosing or over 4 weeks for Q2W dosing) and had known grade of skin toxicity. b Percentages based on patients in both the safety and efficacy sets. c Follow-up time was calculated from the day of enrollment to the date of last contact. Results

Demographics a ECOG status 3 was reported in 1 patient in the phase 3 study. Panitumumab (N = 727) Sex - n (%) Men 446 (61) Age Median (min, max) years 61 (20, 88) Race - n (%) White 649 (89) Black / African American 45 (6) Asian / Japanese 15 (2) Hispanic / Latino 15 (2) Other 3 (<1) ECOG status a - n (%) (41) (51) 2 60 (8)

Disease Characteristics Panitumumab (N = 727) Primary diagnosis - n (%) Colon cancer Colon cancer 491 (68) Rectal cancer Rectal cancer 235 (32) Unknown Unknown 1 (<1) Prior chemotherapy - n (%) At least 2 lines 619 (85) At least 3 lines 206 (28) Not collected / unknown a 80 (11) Tumor cells with membrane EGFr staining – Mean % (SD) b 33 (34) a Hecht 2007b study had incomplete data. b Value unknown for 6 patients.

Incidence and Severity of Skin-Related Toxicities Panitumumab (N = 727) All skin-related toxicity - n (%) 695 (96) Grade (28) Grade (52) Grade (14) Grade 4 3 (<1) Graded using the NCI CTCAE v 2.0, except for selected dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications.

Skin-Related Toxicities Occurring in at Least 5% of Patients MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, except for selected dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications. Any grade Grade 3/4 All events, n (%) 695 (96) 108 (15) Erythema 415 (57) 31 (4) Pruritus 413 (57) 15 (2) Dermatitis acneiform 385 (53) 38 (5) Rash 274 (38) 20 (3) Skin exfoliation 134 (18) 7 (1) Skin fissures 124 (17) 4 (1) Dry skin 112 (15) 1 (0) Acne 54 (7) 5 (1) Pustular rash 43 (6) 5 (1) Exfoliative rash 36 (5) 3 (0)

Probability of Time to Skin Toxicity Onset for Patients With a Skin Toxicity a Median weeks All grades1.4 Grade Event probability Weeks Subjects at risk: Grade 1-4 Grade

Severity of Skin Toxicity Throughout Treatment is Weakly Associated With Objective Response Grade 0–1 skin toxicity (N = 239) Grade 2–4 skin toxicity (N = 488) P value Responders – n (%) 10 (4.2) 55 (11.3) 55 (11.3) a Non-responders – n (%) 229 (95.8) b 433 (88.7) Specificity c Sensitivity d Kappa e (95% CI) (0.02, 0.08) Excluded patients common to the efficacy and safety analysis sets with < 2 infusions or with unknown grade of skin toxicity. a Predictive value of grade 2-4 for response. b Predictive value of grade 0-1 for non-response. c Percentage of non-responders with grade 0-1 skin toxicity throughout treatment. d Percentage of responders with grade 2-4 skin toxicity throughout treatment. e Statistical measure of agreement between objective response and grade 2-4 skin toxicity, a value of 1.0 indicates positive agreement, and -1.0 negative agreement. Association Between Severity of Skin Toxicity and Panitumumab Efficacy

Severity of Skin Toxicity Throughout Treatment is Associated With Progression-Free Survival Median Months Grade Grade Event-free probability (%) Months Patients at risk: Grade 2-4 Grade Hazard ratio = 0.66 (95% Cl: 0.56, 0.78) P <

Median Months Grade Grade Survival probability (%) Months Patients at risk: Grade 2-4 Grade Hazard ratio = 0.62 (95% Cl: 0.52, 0.74) P < Severity of Skin Toxicity Throughout Treatment is Associated With Overall Survival

Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Objective Response Grade 0–1 skin toxicity (N = 327) Grade 2–4 skin toxicity (N = 400) Odds ratio (Grade 2–4:0–1) (95% Cl) P value Responders – n (%) 24 (7.3) 41 (10.3) 41 (10.3) a 1.4 (0.9, 2.4) Non-responders – n (%) 303 (92.6) b 359 (89.8) Excluded patients common to the efficacy and safety analysis set with < 2 infusions or with unknown grade of skin toxicity. a Predictive value of grade 2-4 for response. b Predictive value of grade 0-1 for non-response. Predictive Value of Skin Toxicity Severity in the First 4 Weeks for Response to Panitumumab

Median Months Grade Grade Event-free probability (%) Months Patients at risk: Grade 2-4 Grade Hazard ratio = 0.85 (95% Cl: 0.73, 0.99) P = Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Progression-Free Survival

Median Months Grade Grade Survival probability (%) Months Patients at risk: Grade 2-4 Grade Hazard ratio = 0.79 (95% Cl: 0.67, 0.93) P = Severity of Skin Toxicity in the First 4 Weeks is a Predictive Factor for Overall Survival

Conclusions In this large combined analysis, severity of skin toxicity throughout treatment was associated with a numerically higher ORR and disease control rate and better PFS and OS. In this large combined analysis, severity of skin toxicity throughout treatment was associated with a numerically higher ORR and disease control rate and better PFS and OS. – The association between efficacy outcomes and severity of skin toxicity reported throughout the treatment may have been confounded by the lead- time bias. Substantial number of patients developed severe skin toxicity after the first 4 weeks of treatment. Substantial number of patients developed severe skin toxicity after the first 4 weeks of treatment. Severity of skin toxicity in the first 4 weeks of treatment was a predictive factor for OS but not for ORR, disease control rate, and PFS. Severity of skin toxicity in the first 4 weeks of treatment was a predictive factor for OS but not for ORR, disease control rate, and PFS. Overall, patients with a higher skin toxicity severity appear to have a better prognosis. Overall, patients with a higher skin toxicity severity appear to have a better prognosis. The findings of this exploratory analysis suggest that lack of grade 2-4 skin toxicity at week 4 should not guide the treatment. The findings of this exploratory analysis suggest that lack of grade 2-4 skin toxicity at week 4 should not guide the treatment. – Careful monitoring and early treatment of skin toxicities should be performed while continuing to treatment with panitumumab.

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