What is the role of EGFR in predicting response to panitumumab?

In addition to ascertaining resistance mechanisms, other biomarkers such as EGFR gene copy number and expression levels of EGFR ligands in tumor cells may be useful to further refine the responder population.

What is the significance of the assay used in this study?

while the assay employed in their study is known to detect more than 90% of known activating KRAS mutations in CRC, it would have missed additional mutations in codons 12 and 61.

What is the effect of the KRAS wild-type state on survival?

De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.

how long did panitumumab take to treat a tumor?

What is the effect of the KRAS mutation on the outcome of patients?

The presence of a control arm made it possible to study the relative effect of panitumumab monotherapy by KRAS mutational status independent of the potential prognostic influence of KRAS mutations on outcomes, enabling us to conclude that the clinical benefit observed in the KRAS unselected population was entirely derived from the KRAS WT population.

What is the significance of the results of this study?

To their knowledge, these are the first results arising from a randomized, controlled trial showing that the state of a signaling molecule downstream of a target plays a crucial role in predicting clinical benefit to a targeted therapeutic.

(Open Access) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer (2008) | Rafael G. Amado

Q: What was the incidence of grade 3 or 4 adverse events in the panitumumab?

In the KRAS assessable population, 37% of patients had a grade 3 or 4 event, and 20% of patients had a treatment-related grade 3 or 4 adverse events.

Wild-Type KRAS Is Required for Panitumumab Efﬁcacy in

Patients With Metastatic Colorectal Cancer

Rafael G. Amado, Michael Wolf, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Daniel J. Freeman,

Todd Juan, Robert Sikorski, Sid Suggs, Robert Radinsky, Scott D. Patterson, and David D. Chang

From Amgen Inc, Thousand Oaks, CA;

Ghent University Hospital, Ghent,

Belgium; University Hospital Gasthuis-

berg, Leuven, Belgium; and the Ospe-

dale Niguarda Ca’ Granda, Milan, Italy.

Submitted October 1, 2007; accepted

November 20, 2007; published online

ahead of print at www.jco.org on

March 3, 2008.

Funded by Amgen Inc, Thousand

Oaks, CA.

Presented in part in oral format at

the 14th European Cancer Confer-

ence, Barcelona, Spain, September

23-27, 2007; and the American Soci-

ety of Clinical Oncology Gastrointesti-

nal Cancer Symosium, Orlando, FL,

January 25-27, 2008.

Authors’ disclosures of potential con-

ﬂicts of interest and author contribu-

tions are found at the end of this

article.

Corresponding author: Rafael G.

Amado, MD, Amgen, Inc, One Amgen

Center Dr, MS 38-2-B, Thousand Oaks,

CA 91320-1799; e-mail: ramado@

amgen.com.

Oncology

0732-183X/08/2610-1626/$20.00

DOI: 10.1200/JCO.2007.14.7116

ABSTRACT

Purpose

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has

activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating

mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to

anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in

randomized trials.

Patients and Methods

KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections

collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care

(BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed

by KRAS status.

Results

KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS

mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS

group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was signiﬁcantly greater (P ⬍ .0001) than in

the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3

weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and

0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival

(HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure,

more grade III treatment-related toxicities occurred in the WT KRAS group. No signiﬁcant

differences in toxicity were observed between the WT KRAS group and the overall population.

Conclusion

Panitumumab monotherapy efﬁcacy in mCRC is conﬁned to patients with WT KRAS tumors. KRAS

status should be considered in selecting patients with mCRC as candidates for panitu-

mumab monotherapy.

INTRODUCTION

Epidermal growth factor receptor (EGFR) has been

validated as a therapeutic target in several human

tumors, including colorectal cancer (CRC).

1-4

Li-

gand occupancy of the EGFR activates the RAS/

RAF/MAPK, STAT, and PI3K/AKT signaling

pathways, which together modulate cellular prolif-

eration, adhesion, angiogenesis, migration, and

survival.

5,6

The anti-EGFR targeted antibodies

cetuximab and panitumumab administered as

monotherapy in CRC have shown response and dis-

ease stabilization rates of approximately 10% and

30%, respectively.

2,3

Although EGFR expression is

used for patient selection, clinical experience shows

that the level of EGFR expression as measured by

immunohistochemistry does not predict clini-

cal beneﬁt.

2,7-9

KRAS, the human homolog of the Kirsten rat

sarcoma-2 virus oncogene, encodes a small GTP-

binding protein that acts as a self-inactivating signal

transducer by cycling from GDP- to GTP-bound

states in response to stimulation of a cell surface

receptor, including EGFR.

10,11

KRAS can harbor on-

cogenic mutations that yield a constitutively active

protein.

10-13

Such mutations are found in approxi-

mately 30% to 50% of CRC tumors and are com-

mon in other tumor types.

12,14-19

Several studies

have indicated that the presence of mutant KRAS in

lung and CRC tumors correlates with poor progno-

sis,

14,17,18,20

and is associated with lack of response to

EGFR inhibitors.

15,16,19,21,22

These published re-

ports investigating the role of KRAS as a selection

JOURNAL OF CLINICAL ONCOLOGY

ORIGINAL REPORT

VOLUME 26 䡠 NUMBER 10 䡠 APRIL 1 2008

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marker for EGFR inhibitor treatment were based on tumor samples

from uncontrolled studies and included patients treated with anti-

EGFR antibodies alone or in combination with irinotecan. Given the

possible prognostic role of KRAS mutational status, these uncon-

trolled studies could not isolate the relative effect of antibody treat-

ment on outcome by KRAS status from the prognostic implications of

KRAS as a marker of poor clinical outcome in CRC.

We assessed the predictive role of KRAS in a phase III, random-

ized trial comparing panitumumab monotherapy with best support-

ive care (BSC) in patients with chemotherapy-refractory metastatic

CRC.

The primary objective of the biomarker analyses was to deter-

mine whether the effect of panitumumab monotherapy on

progression-free survival (PFS) differed between patients whose tu-

mors contain mutant versus wild-type (WT; ie, nonmutated) KRAS.

PATIENTS AND METHODS

Trial Design and Patient Population

The design of this controlled, panitumumab monotherapy study has

been previously described.

Brieﬂy, patients with metastatic CRC with EGFR

expression in ⱖ 1% of tumor cells (assessed by immunohistochemistry) and

documented evidence of disease progression after failure of ﬂuoropyrimidines

and prespeciﬁed exposure to oxaliplatin and irinotecan were randomly as-

signed to panitumumab 6 mg/kg plus BSC every 2 weeks or BSC alone. BSC

patients could receive panitumumab after disease progression. Tumor status

was assessed radiographically every 4 to 8 weeks from week 8 until disease

progression using the Response Evaluation Criteria in Solid Tumors by

blinded central review. The primary end point was PFS, deﬁned as the interval

from random assignment to radiologic progression or death. Secondary end

points included objective response rate, overall survival (OS), and safety. All

patients, including those with unassessable or missing assessments, were in-

cluded in the response rate analysis. A best response of stable disease was

determined at or after week 8 from random assignment. At enrollment, pa-

tients provided informed consent for study procedures including research on

archived parafﬁn-embedded tumor samples (mostly from primary tumor

resection) for identiﬁcation of predictive biomarkers. The study protocol was

approved by the ethics board at each research center.

Assay to Detect Mutant KRAS

Formalin-ﬁxed, parafﬁn-embedded tumor sections were deparafﬁnized

and air dried, and DNA was isolated using proteinase K and a DNeasy mini-

spin column (Qiagen, Valencia, CA). Mutant KRAS was detected using a

validated KRAS mutation kit (DxS Ltd, Manchester, United Kingdom) that

identiﬁes seven somatic mutations located in codons 12 and 13 (Gly12Asp,

Gly12Ala, Gly12Val, Gly12Ser, Gly12Arg, Gly12Cys, and Gly13Asp) using

allele-speciﬁc real-time polymerase chain reaction.

23-25

A central laboratory

(HistoGeneX, Antwerp, Belgium) validated the assay for analytic and diagnos-

tic performance, established acceptance criteria, included appropriate quality

controls for each assay, and performed the KRAS analysis in a blinded fashion.

Statistical Analysis

The primary objective of the biomarker analyses was to examine whether

the relative effect of panitumumab compared with BSC on PFS differed in

patients with tumors bearing mutant versus WT KRAS. Additional objectives

included examining whether panitumumab improved PFS, OS, and response

rate in the WT KRAS group compared with the BSC group. Safety was assessed

in both KRAS groups. Analyses were limited to patients with known KRAS

status and were categorized by randomized treatment for efﬁcacy and safety.

Adverse events were graded per the National Cancer Institute Common Tox-

icity Criteria version 2.0 with the exception of selected skin toxicities, which

were graded using version 3.0. Statistical analyses were performed at Amgen

Inc. All analyses were prespeciﬁed in a statistical analysis plan before KRAS

mutation assessment.

A quantitative-interaction test

at a two-sided 5% level was used to

compare the PFS log-hazard ratio (HR; panitumumab relative to BSC) from a

Cox model with covariates for the randomization factors between the WT and

mutant KRAS groups. Based on an assessable sample size of 380 patients and

assuming 60% WT prevalence, power was estimated at more than 99% if the

HR was 1.0 in the mutant KRAS group and at 87% if the HR was 0.80 in the

mutant KRAS group, assuming an overall HR of 0.54 among all patients.

Kaplan-Meier methods were used to estimate PFS and OS. Conditional on a

signiﬁcant interaction test, sequential testing at a 5% level of PFS, followed by

OS and overall response rate, were planned within the WT KRAS group

between panitumumab versus BSC. A log-rank test was used for PFS, Wil-

coxon for OS, and a generalized Cochran-Mantel-Haenszel test for response

rate, each stratiﬁed by the randomization factors.

Maximum change in tumor burden per blinded central radiology review

was summarized by treatment in each KRAS group. Propensity-score sensitiv-

ity analyses were performed to assess bias due to exclusion of patients with

unknown KRAS status.

RESULTS

Patients

Of the 463 patients originally enrolled,

427 (92%) were included

in the KRAS analyses (208 and 219 in the panitumumab and BSC

arms, respectively; Fig 1). KRAS status could not be determined in 18

patients because of unavailable samples and in an additional 18 pa-

tients whose samples had insufﬁcient or poor-quality DNA. KRAS

mutations were identiﬁed in 184 (43%) of 427 patients (84 [40%] and

100 [46%] in the panitumumab and BSC arms, respectively). In the

BSC arm, 76% of patients with WT KRAS and 77% of patients with

mutant KRAS received panitumumab in a cross-over protocol, after a

median PFS time in the original study (investigator assessment) of 7.1

weeks (95% CI, 7.0 to 7.6) and 6.3 weeks (95% CI, 5.1 to 7.1) for

patients in the WT and mutant KRAS groups, respectively.

Baseline patient characteristics were balanced between the WT

and mutant KRAS groups for both panitumumab and BSC (Table 1).

The distribution of speciﬁc KRAS mutations was similar between

treatment arms (Table 2).

Efﬁcacy

Primary end point: PFS. Similar to previously described results

in the intent-to-treat population,

a statistically signiﬁcant improve-

ment in PFS was observed in the KRAS assessable group between

panitumumab and BSC (HR, 0.59; 95% CI, 0.48 to 0.72). Median PFS

time was 8.0 weeks for panitumumab and 7.3 weeks for BSC. The

relative effect of panitumumab versus BSC on PFS was signiﬁcantly

greater among patients with WT KRAS (HR, 0.45; 95% CI, 0.34 to

0.59; median PFS of 12.3 weeks for panitumumab v7.3 weeks for BSC)

compared with patients with mutant KRAS, in whom no panitu-

mumab beneﬁt was observed (HR, 0.99; 95% CI, 0.73 to 1.36; median

PFS of 7.4 weeks for panitumumab v 7.3 weeks for BSC; Fig 2). The

quantitative-interaction test comparing the magnitude of the relative

treatment effect on PFS between WT and mutant KRAS groups was

statistically signiﬁcant (P ⬍ .0001). Consistent results were obtained

with propensity-score adjusted HRs. PFS was signiﬁcantly greater for

panitumumab versus BSC in the WT KRAS group (stratiﬁed log-rank

test P ⬍ .0001; Fig 2). In all sensitivity analyses performed in the WT

KRAS subset, PFS favored the panitumumab arm. In particular, to

compensate for potential tumor-ascertainment bias in favor of the

BSC arm, an interval-censored sensitivity analysis was performed

KRAS Is a Selection Marker for Panitumumab Beneﬁt in mCRC Patients

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whereby radiologic event times were moved to the closest assessment

time prespeciﬁed in the protocol. These analyses showed HR ⫽ 0.44

(95% CI, 0.30 to 0.63) and median PFS times of 16 and 8 weeks for

panitumumab and BSC, respectively. Across all subsets examined, the

treatment effect of panitumumab on PFS in the WT KRAS group was

consistent with the primary analysis (Fig 3). Of 168 BSC patients

receiving panitumumab after progression, PFS was signiﬁcantly

longer among patients with WT versus patients with mutant KRAS

(HR, 0.32; 95% CI, 0.22 to 0.45; median PFS time of 16.4 weeks for

WT and 7.9 weeks for mutant; online-only Fig A1A).

Response rate. Best overall response data were unassessable or

missing for 35 of 231 patients receiving panitumumab and for 53 of

232 BSC patients (this included 16 of 124 patients receiving panitu-

mumab with WT KRAS, 16 of 119 BSC patients with WT KRAS,15of

84 patients receiving panitumumab in the mutant KRAS group, and

32 of 100 BSC patients in the mutant KRAS group). In the KRAS

assessable group, response rate for panitumumab was 10%, stable

disease was 25%, and disease progression was 50%. For KRAS assess-

able patients in the BSC arm, 0% had a response, 10% had stable

disease, and 68% had disease progression. No responders were iden-

tiﬁed in the panitumumab mutant KRAS group (100% positive pre-

dictive value for nonresponse in the mutant group). In contrast, in the

panitumumab WT KRAS group 21 of 124 patients had a partial

response (17%; 95% CI, 11% to 25%; Fig 4). Median time to response

was 7.9 weeks (range, 7.0 to 15.6 weeks), and median duration of

response was 19.7 weeks (range, 7.9 to 88.7 weeks).

In the WT KRAS group, 42 patients receiving panitumumab

(34%) and 14 BSC patients (12%) had stable disease (Fig 4). In the

mutant KRAS group, stable disease was observed in 10 (12%) and

eight patients (8%) in the panitumumab and BSC arms, respectively.

Consistent results with PFS and response were observed when exam-

ining the magnitude of effect on target lesions for individual patients.

For the WT KRAS group, 61% of patients receiving panitumumab

with available target lesion measurements (62 of 101 in the WT group)

had a target lesion decrease, including the majority of patients with

stable disease (Fig 4). In contrast, in the mutant KRAS group, only 5%

of patients receiving panitumumab (three of 62) had minor tumor

reductions. For the BSC patients in both KRAS groups, 3% of patients

(six of 178) had some degree of tumor reduction.

Of 168 BSC patients in the KRAS assessable group that crossed

over to receive panitumumab on progression, 20 (12%) experienced a

response (including one patient with a complete response), and 55

(33%) had stable disease. All responders had WT KRAS, for a response

rate of 20 of 91 (22%; 95% CI, 14% to 32%).

OS. At the time of these analyses, a total of 391 KRAS assessable

patients (92%) had died (186 [89%] patients receiving panitumumab

and 205 [94%] BSC patients). Median follow-up time was 14.1

months for the remaining 36 patients. No statistically signiﬁcant OS

difference was observed between treatment arms among all patients

(HR, 0.97; 95% CI, 0.79 to 1.18), or in either of the KRAS groups; the

HR for OS was 1.02 (95% CI, 0.75 to 1.39) and 0.99 (95% CI, 0.75 to

1.29) for the mutant and WT KRAS groups, respectively. OS was

longer overall in the WT group than in the mutant group adjusting

for stratiﬁcation factors and randomized treatment (HR, 0.67; 95%

CI, 0.55 to 0.82; both arms combined; Fig 5). Multivariate analysis

showed that WT KRAS status was a predictor for OS in both the

Randomly assigned

(n = 463)

Screened for eligibility

(N = 1,040)

Excluded (did not meet

inclusion criteria, n = 577)

Randomly assigned to

BSC alone

(n = 232)

Randomly assigned to

panitumumab + BSC

(n = 231)

Excluded from

KRAS analyses

(missing or unassessable

samples, n = 36)

Identified as

mutant KRAS

(n = 84)

Identified as

WT KRAS

(n = 124)

Received panitumumab

under cross-over

protocol

(n = 77)

Received panitumumab

under cross-over

protocol

(n = 90)

Identified as

mutant KRAS

(n = 100)

Identified as

WT KRAS

(n = 119)

Fig 1. CONSORT diagram. BSC, best

supportive care; WT, wild-type.

Amado et al

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panitumumab (HR, 0.64; P ⫽ .004) and BSC (HR, 0.68; P ⫽ .007)

arms. Similar results for OS were observed among the 168 BSC pa-

tients receiving panitumumab after progression (HR, 0.65; 95% CI,

0.47 to 0.90; median OS time of 6.8 months for WT v 4.5 months

for mutant; online-only Fig A1B). For the 51 BSC patients who did

not cross-over to panitumumab, no difference in OS was observed

between WT and mutant KRAS groups (median OS time of 1.9 and

2 months, respectively).

Exposure and Safety

The mean number of panitumumab infusions was 10.0 (median,

8.0) and 4.9 (median, 4.0) in WT and mutant KRAS groups, respec-

tively. In the mutant KRAS group, 100% of patients receiving panitu-

mumab and 84% of BSC patients had an adverse event. In the WT

KRAS group, these numbers were 100% and 90%, respectively. By

maximum grade and by KRAS group, a higher incidence of grade 3 or

4 adverse events (44% v 28%) and treatment-related grade 3 adverse

events (25% v 12%) was observed in the panitumumab WT versus

mutant KRAS groups, respectively. In the KRAS assessable popula-

tion, 37% of patients had a grade 3 or 4 event, and 20% of patients had

a treatment-related grade 3 or 4 adverse events. The incidence of

adverse events leading to withdrawal in the panitumumab arm was

7% and 5% for the WT and mutant KRAS groups, respectively; 2% of

WT KRAS patients and 1% of mutant KRAS patients withdrew for

panitumumab-related events.

Grade 3 integument-related events occurred in 20% of all KRAS

assessable patients (in 25% of WT KRAS patients and in 13% of

mutant KRAS patients). In the mutant KRAS group, 1% of patients

Table 1. Patient Demographics and Baseline Characteristics by KRAS Status

Characteristic

Mutant Wild-Type

Panitumumab BSC Panitumumab BSC

No. % No. % No. % No. %

No. of patients 84 100 124 119

Sex

Male 47 56 64 64 83 67 76 64

Race/ethnicity

White 84 100 97 97 122 98 118 99

Baseline age, years

Median 62.0 62.0 62.5 63.0

Minimum 27 27 29 32

Maximum 79 83 82 81

Primary diagnosis

Colon cancer 53 63 65 65 86 69 82 69

Rectal cancer 31 37 35 35 38 31 37 31

ECOG performance status

0 43 51373753434034

1 28 33474756456252

ⱖ 2

13 15 16 16 15 12 17 14

Cells with EGFR membrane staining

1% to ⬍ 10% 20 24 23 23 31 25 29 24

10% to 100% 63 75 77 77 93 75 89 75

Highest membrane staining intensity

3⫹ (strong) 17 20 17 17 25 20 22 18

2⫹ (moderate) 42 50 51 51 69 56 58 49

1⫹ (weak) 24 29 32 32 30 24 39 33

0 1 1000000

Prior adjuvant chemotherapy

Yes 27 32 40 40 50 40 32 27

Prior lines of chemotherapy

2 54 64747479646353

3 23 27242441334941

Abbreviations: BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.

Of patients treated with BSC, one patient with wild-type KRAS status and one patient with mutant KRAS status had an ECOG performance status score of 3.

Table 2. Distribution of KRAS Mutations By Treatment Arm

KRAS

Mutation

Total

(N ⫽ 184)

Panitumumab

(n ⫽ 84)

BSC

(n ⫽ 100)

No. % No. % No. %

12Ala 15 8.2 8 9.5 7 7.0

12Asp 70

38.0 34 40.5 36 36.0

12Arg 3

1.6 0 0.0 3 3.0

12Val 40 21.7 15 17.9 25 25.0

12Cys 14 7.6 7 8.3 7 7.0

12Ser 14 7.6 5 6.0 9 9.0

13Asp 29 15.8 15 17.9 14 14.0

Abbreviations: BSC, best supportive care; Ala, alanine; Asp, aspartic acid;

Arg, arginine; Val, valine; Cys, cysteine; Ser, serine.

Two mutations were detected in one specimen.

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had a grade 4 integument-related event; there were no grade 4 events

in the WT group. The time to any integument-related event or to an

event grade 2 or higher was similar in both KRAS groups, suggesting

that incidence differences for integument toxicity were due to differ-

ential exposure. Consistent with previous reports,

2,3

patients with the

worst grade skin toxicity in the WT KRAS group appeared to experi-

ence better PFS and OS (data not shown). In the panitumumab arm, a

higher incidence of diarrhea of any grade was observed (WT KRAS

24%; mutant KRAS 19%) but grade 3 diarrhea was comparable be-

tween groups (WT KRAS 2%; mutant KRAS 1%). The incidence of

hypomagnesemia reported as an adverse event of any grade was 3%

and 0% for WT and mutant KRAS groups, respectively. One grade 2

infusion reaction was reported as an adverse event in a patient with

mutant KRAS.

DISCUSSION

These results show that KRAS mutations predict for lack of clinical

beneﬁt to panitumumab therapy. The presence of a control arm made

it possible to study the relative effect of panitumumab monotherapy

by KRAS mutational status independent of the potential prognostic

inﬂuence of KRAS mutations on outcomes, enabling us to conclude

that the clinical beneﬁt observed in the KRAS unselected population

was entirely derived from the KRAS WT population. Given the cross-

over design, conclusions are limited to the effect of KRAS muta-

tional status on PFS and tumor response end points and not to OS.

Indeed, the majority of BSC patients received panitumumab on

disease progression early in the trial in both KRAS groups (median

Treatment group Events N % Median (weeks)

Panit. + BSC 76 84 90 7.4

BSC alone 95 100 95 7.3

HR = 0.99

(95% CI: 0.73 to 1.36)

Proportion Event Free (%)

Time (weeks)

100

2 4 6 8 10121416182022242628303234363840424446485052

Treatment group Events N % Median (weeks)

Panit. + BSC 115 124 93 12.3

BSC alone 114 119 96 7.3

HR = 0.45

(95% CI: 0.34 to 0.59)

Stratified log-rank P < .0001

Proportion Event Free (%)

Time (weeks)

100

2 4 6 8 10121416182022242628303234363840424446485052

No. of patients at risk

Panit + BSC 84 78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 1

BSC alone 100 91 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2

No. of patients at risk

Panit + BSC 124 119 112 106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10 7 7 6 5 5

BSC alone 119 109 91 81 38 20 15 15 14 11 10 9 9 6 6 6 6 5 4 3 3 2 2 2 2 1

Fig 2. Progression-free survival by treat-

ment within KRAS groups. Progression-

free survival by randomized treatment in

(A) mutant and (B) wild-type KRAS groups.

Hazard ratios (HR) are shown for panitu-

mumab (panit.) versus best supportive

care (BSC) adjusted for randomization fac-

tors (Eastern Cooperative Oncology Group

score, geographic region).

Amado et al

1630

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Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer

Figures

Citations

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.

K-ras mutations and benefit from cetuximab in advanced colorectal cancer.

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

References

Mutations of the BRAF gene in human cancer

Genetic alterations during colorectal-tumor development.

ras Oncogenes in Human Cancer: A Review

Erlotinib in previously treated non-small-cell lung cancer.

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

Related Papers (5)

K-ras mutations and benefit from cetuximab in advanced colorectal cancer.

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer

Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

Frequently Asked Questions (10)

Q1. What contributions have the authors mentioned in the paper "Wild-type kras is required for panitumumab efficacy in patients with metastatic colorectal cancer" ?

Q2. What is the role of EGFR in predicting response to panitumumab?

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Q4. What was the incidence of grade 3 integument-related events in panitumum?

Q5. What was the incidence of grade 3 or 4 adverse events in the panitumumab?

Q6. What is the effect of the KRAS wild-type state on survival?

Q7. how long did panitumumab take to treat a tumor?

Q8. What is the effect of the KRAS mutation on the outcome of patients?

Q9. What is the significance of the results of this study?

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