predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic...

Predictive value of skin-toxicity severity for response Predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic colorectal to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of 5 clinical trialscancer (mCRC): a pooled analysis of 5 clinical trials

Jordan Berlin,Jordan Berlin,11 Eric Van CutsemEric Van Cutsem,,22 Marc Peeters, Marc Peeters,33 J. Randolph Hecht, J. Randolph Hecht,44 Rolando Ruiz,Rolando Ruiz,55 Mike Wolf, Mike Wolf,55 Rafael G. Amado, Rafael G. Amado,55 Neal J. Meropol Neal J. Meropol66

11Vanderbilt University Medical Center, Nashville, TN; Vanderbilt University Medical Center, Nashville, TN; 22University Hospital Gasthuisberg, University Hospital Gasthuisberg, Leuven, Belgium; Leuven, Belgium; 33Ghent University Hospital, Ghent, Belgium; Ghent University Hospital, Ghent, Belgium; 44UCLA School of Medicine, UCLA School of Medicine,

Los Angeles, CA; Los Angeles, CA; 55Amgen Inc., Thousand Oaks, CA; Amgen Inc., Thousand Oaks, CA; 66Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PAPhiladelphia, PA

IntroductionIntroduction

• Panitumumab is a high-affinity (KPanitumumab is a high-affinity (Kd d = 5 = 5 10 10−11−11 M), fully human M), fully human monoclonal antibody directed monoclonal antibody directed against the epidermal growth factor receptor (EGFr).against the epidermal growth factor receptor (EGFr).11

• Panitumumab is approved for the treatment of patients with metastatic colorectal cancer Panitumumab is approved for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression during or following fluoropyrimidine-, irinotecan-, and (mCRC) with disease progression during or following fluoropyrimidine-, irinotecan-, and oxaliplatin-containing chemotherapy regimens.oxaliplatin-containing chemotherapy regimens.22

• A recent analysis of safety data from 789 patients enrolled in 10 clinical studies indicated A recent analysis of safety data from 789 patients enrolled in 10 clinical studies indicated that panitumumab is well tolerated in patients with mCRC.that panitumumab is well tolerated in patients with mCRC.33

• The most common adverse events associated with panitumumab monotherapy were skin-The most common adverse events associated with panitumumab monotherapy were skin-related toxicities.related toxicities.33

• Here we present the results of an exploratory analysis examining the association between 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 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 toxicity severity for response to panitumumab in pooled data for 727 patients from 5 clinical studies of panitumumab monotherapy.clinical studies of panitumumab monotherapy.

ObjectivesObjectives

• An exploratory analysis on pooled data from 5 clinical studies of panitumumab monotherapy An exploratory analysis on pooled data from 5 clinical studies of panitumumab monotherapy to: to:

–assess the association between severity of skin toxicity throughout assess the association between severity of skin toxicity throughout treatment and treatment and panitumumab efficacypanitumumab efficacy

–evaluate predictive value of skin toxicity severity in the first 4 weeks for evaluate predictive value of skin toxicity severity in the first 4 weeks for response to panitumumabresponse to panitumumab

• Key endpoints of panitumumab monotherapy studies:Key endpoints of panitumumab monotherapy studies:

–Objective response rateObjective response rate

–Progression-free survivalProgression-free survival

–Duration of responseDuration of response

–Time to responseTime to response

–Safety (including skin toxicities, infusion reactions, and anti-panitumumab Safety (including skin toxicities, infusion reactions, and anti-panitumumab antibody formation)antibody formation)

Van Cutsem & Van Cutsem & Peeters, et al. 2007Peeters, et al. 200744

Berlin, et al. Berlin, et al. 2006200655

Hecht, et al. Hecht, et al. 2007a2007a66

Hecht, et al. Hecht, et al. 2007b2007b77

Phase 3Phase 3PanitumumabPanitumumab CrossoverCrossover

Phase Phase 33 3 (ES3 (ESaa)) 22 22 22

Patients enrolled, nPatients enrolled, n 231231 177177 9393 160160 150150

Patients included in Patients included in current analysis, ncurrent analysis, n 218218 166166 5252 145145 146146

Dose scheduleDose schedule 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 assessmentResponse assessment RECISTRECISTCentral reviewCentral review

RECISTRECISTLocal reviewLocal review

WHOWHOCentral reviewCentral review

WHOWHOCentral reviewCentral review

RECISTRECISTCentral reviewCentral review

Assessment scheduleAssessment schedule Wks 8-48 and Wks 8-48 and Q3M thereafter Q3M thereafter

until PDuntil PD

Q8W and at Q8W and at investigator investigator discretiondiscretion

Wks 8-48 and Wks 8-48 and Q3M thereafter Q3M thereafter

until PDuntil PD

Wks 8-48 and Wks 8-48 and Q3M thereafter Q3M thereafter

until PDuntil PD

Q9W and at Q9W and at investigator investigator discretiondiscretion

Tumor cells stained for Tumor cells stained for membrane EGFrmembrane EGFrbb, %, % ≥ ≥ 1%1% ≥ ≥ 1%1% ≥ ≥ 10%10% < 1% or 1-9%< 1% or 1-9% HighHighcc or low or lowdd

Design and MethodsDesign and Methods

PD: progression of disease; RECIST: Response Evaluation Criteria in Solid Tumors; WHO: World Health Organization. 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.Van Cutsem & Peeters and Hecht (2007a and b) studies are complete; Berlin study is interim.aaES: extension study. Patients who developed progressive disease while receiving best supportive care in the phase 3 study were 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.allowed to cross over to this extension study to receive panitumumab until disease progression or drug intolerability.bbBy immunohistochemistry at central laboratory using DakoCytomation EGFr pharmDxBy immunohistochemistry at central laboratory using DakoCytomation EGFr pharmDxTMTM staining kit (DakoCytomation, Carpinteria, CA). staining kit (DakoCytomation, Carpinteria, CA). ccHigh: ≥ 10% of tumor cells with 2+ and 3+ staining intensity score.High: ≥ 10% of tumor cells with 2+ and 3+ staining intensity score.ddLow: ≥ 10% of tumor cells with 1+, 2+, and 3+ staining intensity score, but < 10% with 2+ and 3+ staining intensity score.Low: ≥ 10% of tumor cells with 1+, 2+, and 3+ staining intensity score, but < 10% with 2+ and 3+ staining intensity score.

Key Eligibility CriteriaKey Eligibility Criteria

• Pathologic diagnosis of CRCPathologic diagnosis of CRC

• 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)

• Radiographic documentation of disease progression during or within 6 Radiographic documentation of disease progression during or within 6 months after the most recent chemotherapy of fluoropyrimidine withmonths after the most recent chemotherapy of fluoropyrimidine with

• 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/week for 6 weeks

– For the Hecht 2007b study, For the Hecht 2007b study, documentation of disease progression was documentation of disease progression was not required and patients could have received not required and patients could have received prior fluoropyrimidine and prior fluoropyrimidine and irinotecan irinotecan oror oxaliplatin, oxaliplatin, or both.or both.

• Pre-specified levels of EGFr tumor membrane staining according to each Pre-specified levels of EGFr tumor membrane staining according to each study (by immunohistochemistry at central laboratory).study (by immunohistochemistry at central laboratory).

Statistical AnalysisStatistical Analysis

Analyses by skin toxicity severity:Analyses by skin toxicity severity:– Included patients common to the primary efficacy and safety analysis Included patients common to the primary efficacy and safety analysis

sets for each trial with known worst severity of skin toxicity or with no sets for each trial with known worst severity of skin toxicity or with no skin toxicity reported.skin toxicity reported.

– Included patients with at least 2 infusions of panitumumab to ensure Included patients with at least 2 infusions of panitumumab to ensure adequate exposure and time for skin toxicity onset.adequate exposure and time for skin toxicity onset.

– Descriptive estimates of objective response rate (ORR), disease Descriptive estimates of objective response rate (ORR), disease control rate, and 95% confidence intervals (CI) by worst skin toxicity control rate, and 95% confidence intervals (CI) by worst skin toxicity severity throughout the trial or in the first 4 weeks. severity throughout the trial or in the first 4 weeks.

– Descriptive estimates of median progression-free survival (PFS), Descriptive estimates of median progression-free survival (PFS), overall survival (OS), and 95% CI by worst skin toxicity severity overall survival (OS), and 95% CI by worst skin toxicity severity throughout the trial or in the first 4 weeks. throughout the trial or in the first 4 weeks.

– Descriptive estimates of sensitivity, specificity, positive/negative Descriptive estimates of sensitivity, specificity, positive/negative prediction values, and kappa statistics.prediction values, and kappa statistics.

– Univariate regression analysis of skin toxicity severity (throughout Univariate regression analysis of skin toxicity severity (throughout trial vs. the first 4 weeks) as a predictor for objective response or trial vs. the first 4 weeks) as a predictor for objective response or disease control (logistic model), and PFS or OS (proportional hazards disease control (logistic model), and PFS or OS (proportional hazards model).model).

Patient DispositionPatient DispositionPatientsPatients

Patients enrolled – n Patients enrolled – n 851851

Safety set – n (%)Safety set – n (%) 847 (>99)847 (>99)

Efficacy set – n (%)Efficacy set – n (%) 762 (90)762 (90)

Patients in both safety and efficacy sets – n (%) Patients in both safety and efficacy sets – n (%) 758 (89)758 (89)

Patients included in this analysisPatients included in this analysisa,ba,b – n (%) – n (%) 727 (96)727 (96)

Patients excludedPatients excludeda,b a,b – n (%)– n (%) 31 (4)31 (4)

Received < 2 infusionsReceived < 2 infusionsbb – n (%)– n (%) 30 (4)30 (4)

Severity of skin toxicity unknownSeverity of skin toxicity unknownbb – n (%)– n (%) 1 (<1)1 (<1)

Median (min, max) follow-upMedian (min, max) follow-upcc - weeks - weeks 27 (2, 111)27 (2, 111)

aPatients 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.

bPercentages based on patients in both the safety and efficacy sets.cFollow-up time was calculated from the day of enrollment to the date of last contact.

ResultsResults

DemographicsDemographics

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

PanitumumabPanitumumab(N = 727)(N = 727)

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

MenMen 446 (61)446 (61)

AgeAge

Median (min, max) yearsMedian (min, max) years 61 (20, 88)61 (20, 88)

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

WhiteWhite 649 (89)649 (89)

Black / African AmericanBlack / African American 45 (6)45 (6)

Asian / JapaneseAsian / Japanese 15 (2)15 (2)

Hispanic / LatinoHispanic / Latino 15 (2)15 (2)

OtherOther 3 (<1)3 (<1)

ECOG statusECOG statusaa - n (%) - n (%)

00 297 (41)297 (41)

11 369 (51)369 (51)

22 60 (8)60 (8)

Disease CharacteristicsDisease Characteristics

PanitumumabPanitumumab (N = 727) (N = 727)

Primary diagnosis - n (%)Primary diagnosis - n (%)

Colon cancerColon cancer 491 (68)491 (68)

Rectal cancerRectal cancer 235 (32)235 (32)

UnknownUnknown 1 (<1)1 (<1)

Prior chemotherapy - n (%)Prior chemotherapy - n (%)

At least 2 linesAt least 2 lines 619 (85)619 (85)

At least 3 linesAt least 3 lines 206 (28)206 (28)

Not collected / unknownNot collected / unknownaa 80 (11)80 (11)

Tumor cells with membrane EGFr Tumor cells with membrane EGFr staining – Mean % (SD)staining – Mean % (SD)bb 33 (34)33 (34)

aHecht 2007b study had incomplete data.bValue unknown for 6 patients.

Incidence and Severity of Skin-Related ToxicitiesIncidence and Severity of Skin-Related Toxicities

Panitumumab Panitumumab (N = 727)(N = 727)

All skin-related toxicity - n (%)All skin-related toxicity - n (%) 695 (96)695 (96)

Grade 1Grade 1 207 (28)207 (28)

Grade 2Grade 2 380 (52)380 (52)

Grade 3Grade 3 105 (14)105 (14)

Grade 4Grade 4 3 (<1)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 PatientsSkin-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 gradeAny grade Grade 3/4Grade 3/4

All events, n (%) All events, n (%) 695 (96)695 (96) 108 (15)108 (15)

ErythemaErythema 415 (57)415 (57) 31 (4)31 (4)

Pruritus Pruritus 413 (57)413 (57) 15 (2)15 (2)

Dermatitis acneiform Dermatitis acneiform 385 (53)385 (53) 38 (5)38 (5)

RashRash 274 (38)274 (38) 20 (3)20 (3)

Skin exfoliationSkin exfoliation 134 (18)134 (18) 7 (1)7 (1)

Skin fissuresSkin fissures 124 (17)124 (17) 4 (1)4 (1)

Dry skinDry skin 112 (15)112 (15) 1 (0)1 (0)

AcneAcne 54 (7)54 (7) 5 (1)5 (1)

Pustular rashPustular rash 43 (6)43 (6) 5 (1)5 (1)

Exfoliative rashExfoliative rash 36 (5)36 (5) 3 (0)3 (0)

Probability of Time to Skin Toxicity Onset for Patients With a Probability of Time to Skin Toxicity Onset for Patients With a Skin ToxicitySkin Toxicityaa

Median weeksAll grades 1.4Grade 2-4 2.6

Even

t 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

Weeks0 4 8 12 16 20 24 28 32 36 40 44 48

Subjects at risk:Grade 1-4Grade 2-4

727 294 70 42 29 18 8 3 2 2 2 2 1 1 0 0 0 0 0 0 0 0 0 0727 479 341 282 236 175 117 88 79 63 56 44 36 29 24 15 15 12 9 5 3 2 1 1

Severity of Skin Toxicity Throughout Treatment is Severity of Skin Toxicity Throughout Treatment is Weakly Associated With Objective ResponseWeakly Associated With Objective Response

Grade 0–1 Grade 0–1 skin toxicityskin toxicity

(N = 239)(N = 239)


(N = 488)(N = 488) PP value value

Responders – n (%)Responders – n (%) 10 (4.2)10 (4.2) 55 (11.3)55 (11.3)a 0.00250.0025

Non-responders – n (%)Non-responders – n (%) 229 (95.8)b 433 (88.7)433 (88.7)

SpecificitySpecificitycc SensitivitySensitivitydd KappaKappae e (95% CI)(95% CI)

0.35 0.85 0.05 (0.02, 0.08)Excluded patients common to the efficacy and safety analysis sets with < 2 infusions or with unknown grade of skin toxicity.aPredictive value of grade 2-4 for response.bPredictive value of grade 0-1 for non-response.cPercentage of non-responders with grade 0-1 skin toxicity throughout treatment .dPercentage of responders with grade 2-4 skin toxicity throughout treatment.eStatistical 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 Association Between Severity of Skin Toxicity and Panitumumab Efficacy Panitumumab Efficacy

Severity of Skin Toxicity Throughout Treatment is Associated Severity of Skin Toxicity Throughout Treatment is Associated With Progression-Free Survival With Progression-Free Survival

Median MonthsGrade 2-4 2.6Grade 0-1 1.8

Even

t-fre

e pr

obab

ility

(%)

0

10

20

30

40

50

60

70

80

90

100

Months0 2 4 6 8 10 12 14 16 18 20 22 24

Patients at risk:Grade 2-4Grade 0-1

488 466 255 212 132 123 73 63 38 28 18 14 8 8 5 3 2 2 1 1 1 1 1 1239 224 87 67 44 34 19 16 10 7 5 3 2 0 0 0 0 0 0 0 0 0 0 0

Hazard ratio = 0.66(95% Cl: 0.56, 0.78) P < 0.0001


Surv

ival p

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


488 456 393 310 233 159 110 73 42 27 19 9 3239 204 138 99 72 48 32 21 17 9 5 1 1

Hazard ratio = 0.62 (95% Cl: 0.52, 0.74)P < 0.0001

Severity of Skin Toxicity Throughout Treatment is Associated Severity of Skin Toxicity Throughout Treatment is Associated With Overall Survival With Overall Survival

Severity of Skin Toxicity in the First 4 Weeks is Not Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Objective Responsea Predictive Factor for Objective Response


(N = 327)(N = 327)


(N = 400)(N = 400)

Odds ratioOdds ratio(Grade 2–4:0–1)(Grade 2–4:0–1)

(95% Cl)(95% Cl) PP value value

Responders – n (%)Responders – n (%) 24 (7.3)24 (7.3) 41 (10.3)41 (10.3)a 1.4 (0.9, 2.4)1.4 (0.9, 2.4) 0.17320.1732

Non-responders – n (%)Non-responders – n (%) 303 (92.6)b 359 (89.8)359 (89.8)

Excluded patients common to the efficacy and safety analysis set with < 2 infusions or with unknown grade of skin toxicity.aPredictive value of grade 2-4 for response.bPredictive value of grade 0-1 for non-response.

Predictive Value of Skin Toxicity Severity in the First 4 Predictive Value of Skin Toxicity Severity in the First 4 Weeks for Response to PanitumumabWeeks for Response to Panitumumab

Median Months

Grade 2-4 2.5Grade 0-1 1.9

Even

t-fre

e pr

obab

ility

(%)

0

10

20

30

40

50

60

70

80

90

100

Months0 2 4 6 8 10 12 14 16 18 20 22 24


400 383 196 162 97 90 57 50 29 21 14 11 6 6 4 3 2 2 1 1 1 1 1 1327 307 146 117 79 67 35 29 19 14 9 6 4 2 1 0 0 0 0 0 0 0 0 0

Hazard ratio = 0.85(95% Cl: 0.73, 0.99) P = 0.0332

Severity of Skin Toxicity in the First 4 Weeks is Not Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Progression-Free Survival a Predictive Factor for Progression-Free Survival


Surv

ival p

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


400 372 323 250 183 124 86 56 31 21 15 8 2327 288 208 159 122 83 56 38 28 15 9 2 2

Hazard ratio = 0.79 (95% Cl: 0.67, 0.93)P = 0.0052

Severity of Skin Toxicity in the First 4 Weeks isSeverity of Skin Toxicity in the First 4 Weeks isa Predictive Factor for Overall Survival a Predictive Factor for Overall Survival

ConclusionsConclusions

• In this large combined analysis, severity of skin toxicity throughout treatment In this large combined analysis, severity of skin toxicity throughout treatment was associated withwas associated with aa numerically higher ORR and disease control rate and numerically higher ORR and disease control rate and better PFS and OS. better PFS and OS.

– The association between efficacy outcomes and severity of skin toxicity The association between efficacy outcomes and severity of skin toxicity reported throughout the treatment may have been confounded by the lead-reported throughout the treatment may have been confounded by the lead-time bias.time bias.

• Substantial number of patients developed severe skin toxicity after the first 4 Substantial number of patients developed severe skin toxicity after the first 4 weeks of treatment.weeks of treatment.

• Severity of skin toxicity in the first 4 weeks of treatment was a predictive factor 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.for OS but not for ORR, disease control rate, and PFS.

• Overall, patients with a higher skin toxicity severity appear to have a better Overall, patients with a higher skin toxicity severity appear to have a better prognosis.prognosis.

• The findings of this exploratory analysis suggest that lack of grade 2-4 skin The findings of this exploratory analysis suggest that lack of grade 2-4 skin toxicity at week 4 should not guide the treatment. toxicity at week 4 should not guide the treatment.

– Careful monitoring and early treatment of skin toxicities should be Careful monitoring and early treatment of skin toxicities should be performed while continuing to treatment with panitumumab. performed while continuing to treatment with panitumumab.

ReferencesReferences

1.1. Foon K, et al. Foon K, et al. Int J Radiat Oncol Biol Phys.Int J Radiat Oncol Biol Phys. 2004;58:984-990. 2004;58:984-990.

2.2. VectibixTM Prescribing Information, Amgen Inc. Thousand Oaks CA; 2006.VectibixTM Prescribing Information, Amgen Inc. Thousand Oaks CA; 2006.

3.3. Berlin J, et al. Berlin J, et al. Annals Oncol.Annals Oncol. 2006;17 (supp 9): Abstract #3260. 2006;17 (supp 9): Abstract #3260.

4.4. Van Cutsem E, et al. Van Cutsem E, et al. J Clin Oncol.J Clin Oncol. 2007;25:1658-1664. 2007;25:1658-1664.

5.5. Berlin J, et al. Berlin J, et al. J Clin OncolJ Clin Oncol 2006;24 (suppl 16): Abstract #3548. 2006;24 (suppl 16): Abstract #3548.

6.6. Hecht JR, et al. Hecht JR, et al. Proc Gasterointestinal Cancer Symp.Proc Gasterointestinal Cancer Symp. 2007a: Abstract. 2007a: Abstract.

7.7. Hecht JR, et al. Cancer. 2007b; In press.Hecht JR, et al. Cancer. 2007b; In press.

predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic...

Documents