KRAS status (wild-type vs mutant) correlates with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients with metastatic colorectal cancer A Cervantes*, T Macurulla, E Martinelli, E Vega-Villegas, E Rodriguez-Braun, F Ciardiello, C Story, J NIppgen, J Baselga, J Tabernero*Hospital Clinico Universitario, Valencia, Spain (Presenting author)

Background (1)

• Cetuximab is an IgG1 monoclonal antibody vs epidermal growth factor receptor (EGFR)1

– Targets the extracellular domain – Competitively inhibits ligand binding to disrupt EGFR

signalling• Cetuximab is active in metastatic colorectal

cancer (mCRC)– First-line as monotherapy or with chemotherapy2–5

– In other lines following cytotoxic chemotherapy1,6,7

1Cunningham D, et al. N Engl J Med 2004;351:337–345; 2Folprecht G, et al. Ann Oncol 2006;17:450–456; 3Tabernero J, et al. J Clin Oncol 2007;25:5225–5232; 4Peeters M, et al. Eur J Cancer Suppl. 2005;3 (Abstract

664); 5Scheithauer W, et al. Eur J Cancer Suppl. 2007;5(S4) (Abstract O-3003) (updated information presented at meeting); 6Wilke H, et al. J Clin Oncol 2006;24(18S):(Abstract 3549) (updated information presented at meeting);

7Sobrero AF, et al. J Clin Oncol 2008;26:2311–2319

Background (2)

• KRAS is a central downstream mediator of EGFR signaling– It links EGFR activation to cell proliferation and survival

• Cetuximab’s activity in mCRC may correlate with somatic mutations in codons 12/13 of KRAS1–6

1 Liévre A, et al. J Clin Oncol 2008;26:374–379; 2Benvenuti S, et al. Cancer Res 2007;67:2643–2648; 3De Roock W, et al. Ann Oncol 2008;19:508–515; 4Finocchiaro G, et al. J Clin Oncol 2007;25(18S) (Abstract 4021); 5Di Fiore

F, et al. Br J Cancer 2007;96:1166–1169; 6Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237

Background (3)

• Many mCRC chemotherapy regimens are once every 2 weeks

• We assessed the feasibility of a q2w cetuximab dosing regimen in patients with mCRC in a phase I, open-label, multicenter study

• Comparison with standard once-weekly (qw) regimen

Study objectives

• Primary objective– To determine maximum tolerated dose (MTD)a of

cetuximab q2w regimen

• Secondary objectives – To evaluate safety, clinical efficacy, PK and PD– To investigate the relationship between KRAS mutation

status and efficacy outcomes

aIn this case equivalent to recommended dose : q2w; pharmacodynamics, PD; pharmacokinetics, PK

Study design: Eligibility criteria

• Main inclusion criteria– Adults with measurable EGFR-expressinga mCRCb

– ECOG PS ≤2; life expectancy ≥12 weeks– Adequate bone marrow, liver, and renal function

• Main exclusion criteria– Prior EGFR-targeted agents, or mCRC chemotherapyc

– Surgery or irradiation within 4 weeks of study onset– Brain metastases

aEGFR status confirmed by immunohistochemistry; bconfirmed by histology and with at least one tumor accessible for biopsy and ≥1 bi-dimensionally measurable lesion (not in an irradiated area; cincluding adjuvant,

within 6 months of study onset; ); Eastern Cooperative Oncology Group performance status, ECOG PS

Study design: Phase I studya

Group A (control arm) n=10

Cetuximab 400 mg/m2

initial dose then 250 mg/m2 qw

Group B (test arm) n=10

Escalating cetuximab doses:

400, 500, 600 mg/m2 q2w

6 weeks’ treatment

Complete PK profile obtained during this periodPart IPrimary endpoint:

DLT assessment

FOLFIRI added to patients’ current cetuximab regimen

Secondary

endpoints

Evaluate best overall response

Progression-free survival

Part II

a20─50 patients planned depending on no. dose-limiting toxicities (DLTs); FOLFIRI: irinotecan 180 mg/m2 over 30─90 min; FA 400 mg/m2 over 2 hours; 5-fluorouracil 200 mg/m2 as bolus and 2400 mg/m2 over 46 hours, q2w

Study endpoints

• Primary endpoint– DLTs to determine MTD

• Secondary endpoints– Adverse events (AEs)– Clinical efficacy (best overall response; PFS)– PK– PD– Biomarker analyses including relationship between

KRAS mutation status and efficacy outcomesProgression-free survival, PFS

Definition of DLTs and MTD

• DLTs– Grade 3/4 AE (except hypersensitivity reactions or grade 3

skin toxicity) – Or administration of <66% of assigned cetuximab dose due

to toxicity

• MTD– Was reached if 2/10 patients in a cohort had a DLT– If ≥3/10 patients had a DLT, the previous cetuximab dose

level was considered the MTD– Dose escalation continued if DLTs in ≤1/10 patients

Results: Patients

• N=62 enrolled between September 2004 and August 2006

• KRAS mutation analysis– 50 blocks of archived tumor material analyzed– n=2 paraffin-embedded specimen slide sets analyzed– 48/52 contained tumor tissues and were evaluablea

– 19 specimens had KRAS mutation (40% of all evaluable)

aBy independent histologic evaluation

Results: Baseline patient and disease characteristics (n=62 evaluable)

Group A (control)

250 mg/m2

qw

Group B (test) cetuximab mg/m2 q2w Total

400 500 600 700

N 13 13 14 12 10 62Male/female, % 46/54 69/31 79/21 75/25 40/60 63/37Median age, years (range)

67 (55–75)

66 (47–77)

69 (42–80)

59 (41–78)

64 (39–73)

65 (39–80)

<65 years, % 46 46 29 75 50 48

≥65 years, % 54 54 71 25 50 52

ECOG PS, %0 54 85 93 83 80 79

1 39 15 7 17 0 16

2 8 0 0 0 20 5Percentages have been rounded to nearest whole number so might not total 100%

Results: DLTs

• One DLT in cetuximab 700 mg/m2 q2w group – Grade 4 dyspnea– Patient died due to progressive disease– Also included AEs considered not related to cetuximab

• Grade 3 anemia • Grade 3 liver enlargement • Grade 1 productive cough• Grade 4 bad general status

Tolerability results: AE overviewGroup A (control)

250 mg/m2 qw

Group B (test) cetuximab mg/m2 q2w Totalb

400 500 600 700a

N

Any AE, n (%)

13 13 14 12 10 62

Part I 13 (100) 13 (100) 14 (100) 12 (100) 10 (100) 62 (100)Part IIAny grade 3/4 AE, n (%)

13 (100) 13 (100) 14 (100) 11 (92) 9 (100) 60 (98)

Part I 3 (23) 1 (8) 1 (7) 1 (8) 2 (20) 8 (13)Part II 13 (100) 10 (77) 12 (86) 7 (58) 8 (89) 50 (82)No deaths due to cetuximab-related AEs in either Part I or Part II; an=9 in Part II; bn=61 in Part II

• Most common grade 3/4 AEs: diarrhea (31%), neutropenia (24%), and rash (16%)

Tolerability results: Cetuximab-related AE overview

Group A (Control)

250 mg/m2 qw

Group B (test) cetuximab mg/m2 q2w Totalb

400 500 600 700a

N

Any AE, n (%)

13 13 14 12 10 62

Part I 13 (100) 13 (100) 14 (100) 11 (92) 9 (90) 60 (97)Part IIAny grade 3/4 AE, n (%)

13 (100) 11 (85) 12 (86) 10 (83) 8 (89) 54 (89)

Part I 0 (0) 1 (8) 0 (0) 0 (0) 0 (0) 1 (2)Part II 3 (23) 0 (0) 7 (50) 1 (8) 4 (44) 15 (25)No deaths due to cetuximab-related AEs in either Part I or Part II; an=9 in Part II; bn=61 in Part II

• Treatment-related grade 4 AEs: neutropenia (8%); febrile neutropenia, hypocalcemia, and pulmonary embolism (all 2%)

Efficacy results: Overall response (Part II)a

Group A250 mg/m2

qw

Group B (test) cetuximab mg/m2 q2w Total400 500 600 700

N 13 13 14 12 10 62BOR, n (%)CR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)PR 4 (31) 5 (39) 8 (57) 4 (33) 5 (50) 26 (42)

SD 7 (54) 7 (54) 6 (43) 6 (50) 3 (30) 29 (47)PD 2 (15) 0 (0) 0 (0) 1 (8) 1 (10) 4 (7)UE 0 (0) 1 (8) 0 (0) 1 (8) 1 (10) 3 (5)

ORR, % (95% CI)

31 (9–61) 39 (14–68) 57 (29–82) 33 (10–65) 50 (19–81) 42 (30–55)

DCR, % (95% CI)

85 (55–98) 92 (64–100) 100 (77–100) 83 (52–98) 80 (44–98) 89 (78–95)

aITT safety population; percentages have been rounded to nearest whole numbers; best overall response, BOR; complete response, CR; disease control rate, DCR (PR+CR+SD); overall response rate, ORR (PR+CR); partial response, PR; progressive disease, PD; stable disease, SD; unevaluable, UE

Efficacy results: Progression-free response (ITT safety population)

Group A (Control)

250 mg/m2

qw

Group B (test) cetuximab mg/m2 q2w Total

400 500 600 700a

N 13 13 14 12 10 62Number of events, n (%)a

12

(92)

9

(69)

4

(29)

5

(42)

8

(80)

38

(61)

Median PFS, months (95% CI)

4.4 (3.2–9.5)

7.0 (4.6–12.2)

17.4 (9.2–17.4)

6.9 (4.3– ND )

6.3 (2.7–8.4)

7.2 (6.3–9.8)aProgression or death; not yet determined, ND

Efficacy results: Tumor response stratified by KRAS status

Res

pons

e ra

te (%

)

27.6

(12.7─47.2)

0

(0─17.7)

55.2

(35.7─73.6)

31.6

(12.6─56.6)

p=0.015

p=0.144

KRAS wild-type (n=29)

0

10

20

30

40

50

60

Monotherapy (Part I) Combination (Part II)

KRAS mutation (n=19)

Efficacy results: PFS by KRAS statusPr

obab

ility

of P

FS

1.0

0.8

0.6

0.2

0.0

Time (days)0 100 200 300 400

aA PFS hazard ratio <1 indicates a lower risk of progression in patients with wild-type KRAS

0.4

KRAS wild-type (n=29) KRAS mutation (n=19)

Median PFS, (95% CI) 9.4 (7.0–11.3) 5.6 (3.3–12.2)

PFS hazard ratioa 0.47 (p=0.0475)

+

++++

+++

++++

+

+

+

MutationWild-type

PK results: Mean (± SD) cetuximab concentration vs time profile at Week 5

Con

cent

ratio

n (µ

g/m

L)

600

500

400

200

0

Time (h)0 48 144 240 336

300

400/250 mg/m2 q1w (n=13)400 mg/m2 q2w (n=8)500 mg/m2 q2w (n=9)600 mg/m2 q2w (n=10)700 mg/m2 q2w (n=6)

100

96 192 288

• Cetuximab had a predictable PK profile at all doses; t1/2 and CLSS values were similar for qw and each q2w dosing regimen

PK results: Cetuximab median trough concentrations during weeks 1–29

Con

cent

ratio

n (µ

g/m

L)

180160140

100

0

Time (weeks)1 5 13 21 29

120

80

9 17 25

400/250 mg/m2 q1w400 mg/m2 q2w500 mg/m2 q2w600 mg/m2 q2w700 mg/m2 q2w

3 11 19 277 15 23

604020

• Cetuximab 500 and 600 mg/m2 q2w Cmin values similar to qw; Cmin & time to steady state much higher at 700 mg/m2 q2w

PD results: Other biomarker findings

• Evaluation of skin biopsy samples – Substantial changes from baseline in pEGFR,

pMAPK, Ki67, p27, and pSTAT3 with cetuximab– No apparent major differences between dosing

schedules

Conclusions

• Cetuximab 400–700 mg/m2 q2w was safe and well tolerated; the MTD was not reached

• t1/2 and CLSS values similar for qw and q2w doses

• Cmin values were much higher at q2w 700 mg/m2 – 500 or 600 mg/m2 may be most appropriate q2w dosage

• Outcomes improved for wild-type vs mutant KRAS tumors• Other potential biomarkers warrant further study• Study supports feasibility of cetuximab q2w as a

convenient alternative to weekly regimen in mCRC