Cetuximab plus FOLFIRI 1st-line in patients (pts) with metastatic colorectal cancer (mCRC):

A quality of life (QoL) analysis of the CRYSTAL trial

G. Folprecht,* M. Nowacki, I. Lang, S. Cascinu,

I. Shchepotin, J. Maurel, P. Rougier, D. Cunningham,

A. Zubel, E. Van Cutsem*University Hospital Carl Gustav Carus, Dresden, Germany

(Presenting author)

Background (1)

• Cetuximab is an IgG1 monoclonal antibody

• Cetuximab specifically targets the epidermal growth factor receptor (EGFR) with high affinity

• Cetuximab competitively inhibits endogenous ligand binding

Background (2)

• The benefits of combining cetuximab with standard irinotecan- or oxaliplatin-based chemotherapy in the 1st-line treatment of metastatic colorectal cancer (mCRC)– Are suggested in single-arm phase II trials1,2

– Have been confirmed by the randomized CRYSTAL and OPUS trials3,4

1Raoul J-L, et al. BMC Cancer 2009;9:112 [E-pub ahead of print]2Tabernero J, et al. J Clin Oncol 2007;25:5225-5232

3Bokemeyer C, et al. J Clin Oncol 2009;27:663-6714 Van Cutsem E, et al. N Engl J Med 2009;360:1408-1417

Background (3)• Cetuximab in combination with chemotherapy

– Is generally well tolerated– Acne-like rash is the most common side effect

• The impact of treatment on quality of life (QoL) can be an important factor in treatment decision-making

• Cetuximab provided QoL benefits in previously treated mCRC patients– As monotherapy compared with best supportive care1

– In combination with irinotecan compared with chemotherapy alone2

1Au H-J, et al. J Clin Oncol 2009;27:1822-18282Sobrero AF, et al. J Clin Oncol 2008;26:2311-2319

Primary and secondary objectives of the CRYSTAL trial

• Primary objective – To examine differences in progression-free survival

(PFS) between patients receiving cetuximab plus FOLFIRI and those receiving FOLFIRI

• Secondary objectives included – Determination of overall survival (OS) – Assessment of QoL changes

Primary objectives of the QoL analysis

• To assess differences between the treatment groups in QoL

• To pay particular attention to the effects of treatment on global health status and social functioning– The social functioning scale was expected to reflect

any impact of cetuximab-associated acne-like rash on QoL

CRYSTAL trial design

FOLFIRI

Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous

infusion) + FA (every 2 weeks)

Cetuximab + FOLFIRI

Cetuximab (iv 400 mg/m2 on day 1, then 250 mg/m2 weekly)

+ Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous infusion)

+ FA (every 2 weeks)

REGFR-

detectablemCRC

Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent

5-FU, 5-fluorouracil; FA, folinic acid; ECOG, Eastern Cooperative Oncology Group

Stratification by:

Region

ECOG PS

Patients • Main inclusion criteria

– ≥18 years of age

– Histologically confirmed non resectable adenocarcinoma of the colon or rectum

– Immunohistochemical evidence of EGFR expression

– ECOG PS ≤2

• Main exclusion criteria– Previous anti-EGFR therapy or irinotecan-based

chemotherapy

– Previous chemotherapy for mCRC

– Adjuvant treatment that was terminated ≤6 months before start of treatment

EORTC QLQ-C30 questionnaire1

• Five functional scales – Physical, role, emotional, cognitive, and social

functioning

• Three symptom scales – Fatigue, nausea and vomiting, and pain

• Six symptom single-item scales– Dyspnea, insomnia, appetite loss, constipation

diarrhea and financial difficulties

• One global health status QoL scale

1 Fayers PM, et al. 1999. EORTC QLQ-C30 Scoring Manual. EORTC: Brussels

EORTC, European Organisation for Research and Treatment of Cancer

QoL assessments and analysis

• QoL was assessed – At randomization– Every 8 weeks thereafter– At final tumor assessment

• QoL analysis was performed– On the primary analysis population– In a subgroup of patients with KRAS wild-type tumors

QoL statistics (1)

• Descriptive statistics – Were used for each treatment group at each of the

assessment points• For the multi-item scales and for single-item measures

• Primary QoL analysis – A pattern mixture analysis of global health status/QoL

and social functioning scores• Included the drop-out pattern

– A post-hoc analysis on changes from baseline scores was also conducted

QoL statistics (2)

• An ANOVA model was used– To investigate QoL data changes over time

– To generate least squares mean (LSmean) estimates for each timepoint

– A post-hoc analysis of QoL over time as a function of changes from baseline scores was conducted

• Summary best and worst patient QoL scores were generated– For each scale

– For the change to these scores from baseline

– For the changes from baseline to final tumor assessment

Patient results

• Between July 2004 and November 2005, 2020 patients were screened at 189 centers– 1217 patients underwent randomization

• 1198 patients were treated at 184 centers– Primary analysis population– Each treatment arm contained 599 patients

• Tumor KRAS mutation analysis was available for 540 patients– 348 patients (64.4%) were KRAS wild-type– 192 patients (35.6%) were KRAS mutant

Clinical efficacy

• Adding cetuximab to FOLFIRI significantly reduced the risk of disease progression– By 15% in the primary analysis population (HR=0.85;

95% CI 0.72–0.99; p=0.048)1

– By 32% among patients with KRAS wild-type disease (HR=0.68; 95% CI 0.50–0.94, p=0.02)1

1Van Cutsem E, et al. N Engl J Med 2009;360:1408-1417

QoL analysis for the primary analysis population (1)

• Evaluability and compliance– 1125 patients completed evaluable questionnaires

• 566 in the cetuximab plus FOLFIRI group• 559 in the FOLFIRI group

– Questionnaire evaluability rates• 78.1% in the cetuximab plus FOLFIRI group• 76.4% in the FOLFIRI group

– Compliance rates • Decreased from 70–80% at baseline and week 8 to around

30% at final tumor assessment• Were similar between treatment groups

QoL analysis for the primary analysis population (2)

• Multi-item scales– Statistically significant differences in the LSmeans

between treatment groups for the multi-item scales were found for• Global health status/QoL• Role functioning• Fatigue• Nausea/vomiting

– Adjusting for between-group baseline differences• None of the multi-item scales displayed significant results in

favor of FOLFIRI

EORTC QLQ-C30 global health status/QoL scores: changes over timea

Cetuximab + FOLFIRI

n=556

FOLFIRI

n=559

Difference in LSmeans

95% CI pb

Baseline nLSmean

43058.9

42360.3 -1.45 (-4.06–1.16) 0.2767

Week 8 nLSmean

42159.0

39061.8 -2.81 (-5.44– -0.18) 0.0360

Week 16 nLSmean

31260.8

30963.3 -2.52 (-5.43– 0.39) 0.0897

Week 24 nLSmean

25561.8

24464.1 -2.23 (-5.48–1.02) 0.1794

Week 32 nLSmean

16459.7

15465.1 -5.39 (-9.37– -1.41) 0.0080

Week 40 nLSmean

12263.4

9664.0 -0.60 (-5.51– 4.32) 0.8125

aScores not adjusted for between-group baseline differences bt-testHigher scores for the global health/QoL scale indicate a better QoL

CI, confidence interval; LSmean/s, least squares mean/s;QoL, quality of life

EORTC QLQ-C30 role functioning scores: difference in LSmeans between treatment groupsa,b

over timea,b

aScores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated ascetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0221; **p=0.0482 (t-test) bA higher score for role functioning/QoL indicates a better QoL

6.00

4.00

2.00

0.00

-2.00

-4.00

-6.00

-8.00

-10.00

Time (weeks)

Baseline 8 16 24 32 40

Cetuximab+ FOLFIRI, n 435

427

423

395

317

313

259

251

168

159

125

99FOLFIRI, n

* **

EORTC QLQ-C30 fatigue scores: difference in LSmeans between treatment groups over timea,b

aScores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated ascetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0281 (t-test) bA higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL

8.00

6.00

4.00

2.00

0.00

-2.00

-4.00

-6.00

-8.00

Time (weeks)

Baseline 8 16 24 32 40

438

427

424

395

318

314

259

252

168

159

125

99

*

Cetuximab+ FOLFIRI, n

FOLFIRI, n

EORTC QLQ-C30 nausea/vomiting scores: difference in LS means between treatment groups over timea,b

aScores not adjusted for between-group baseline differences; difference in LSmeans at each timepoint calculated as cetuximab/FOLFIRI LSmean minus FOLFIRI LSmean; *p=0.0202; **p=0.0283 (t-test) bA higher score for symptom/QoL represents increased symptoms and generally indicates a poorer QoL

4.00

2.00

0.00

-2.00

-4.00

-6.00

-8.00

-10.00

Time (weeks)

Baseline 8 16 24 32 40

437

426

423

394

318

314

259

252

168

158

125

99

* **

Cetuximab+ FOLFIRI, n

FOLFIRI, n

QoL analysis for the primary analysis population (3)

• Analysis of changes from baseline– The Wei-Lachin analysis of the global health

status/QoL score over time revealed no significant differences between groups overall or at any visit

– For best and worst post-baseline scores for the symptom, functioning and global health status QoL scales only physical functioning was significantly worse in the cetuximab plus FOLFIRI group (p=0.0432)

EORTC QLQ-C30 social functioning scores: changes from baseline scores over timea

Boxes show the 25%-75% percentile, whiskers show the 10%-90% percentile and the lines connect the mean scores at each timepoint. Data for outliers (n≤7 at each time point) not shownaA positive change score represents an improvement in social functioning whereas a negative change score represents a worsening

50

25

0

-25

-50

Timepoint

Week 8

310

298

239

231

192

188

130

112

94

77

59

41

Week 16 Week 24 Week 32 Week 40 Week 48 Week 56 Week 64

31

18

13

8

Cetuximab + FOLFIRI

FOLFIRI

Cetuximab+ FOLFIRI, n

FOLFIRI, n

QoL analysis for the primary analysis population (4)

• Single-item scales– Only minor between-group differences in the mean

changes from baseline to worst post-baseline values were found• Consistent with the incidence of adverse events reported in

each group

• Multivariate analysis among all QoL scales– Only fatigue was considered as a prognostic scale for

survival• Patients with lower fatigue score at baseline had significantly

longer survival (p<0.0001)

Pattern-mixture analysis: change from baseline scores

Variable Treatment effect pa

Global health status/QoL -1.497 0.2917

Social functioning -1.396 0.3914

ap value is an overall test of treatment effect; test used is the F statisticThe treatment effect represents the adjusted difference in the LSmeans in the two treatment groups

QoL analysis in the KRAS wild-type population (1)

• 330 patients completed evaluable questionnaires– 161 in the cetuximab plus FOLFIRI group

– 169 in the FOLFIRI group

– Questionnaire evaluability rates were 79% in each group

• Compared with the QoL primary analysis population the QoL KRAS wild-type population had– Favorable age and ECOG PS values

– Fewer disease sites involved

– Fewer numbers of liver metastases

QoL analysis for the KRAS wild-type population (2)

• The results of the QoL analysis in the KRAS wild-type group confirmed the findings from the primary analysis population

• There were no statistically significant differences between the treatment groups for any multi-item scales at any time point– Including global health status/QoL

EORTC QLQ-C30 global health status/QoL LSmeans over time: KRAS wild-type subgroupa,b

aScores not adjusted for between-group baseline differencesbA higher score for global health status/QoL indicates a better QoL

CI, confidence interval

80

60

40

20

0

-20

Timepoint

Baseline

118

123

123

125

96

104

84

87

64

61

Cetuximab + FOLFIRI

FOLFIRI

Week 8 Week 16 Week 24 Week 32

95% CI for difference in treatment groups

Cetuximab+ FOLFIRI, n

FOLFIRI, n

QoL analysis for the KRAS wild-type population (3)

• According to changes from baseline– There were no significant differences found between

the treatment groups in the global health status/QoL at any timepoint

– There were similar best and worse post-baseline scores for symptom, functioning and global health status/QoL scales in the two treatment groups• The only significant difference was in physical functioning,

which was lower in the cetuximab plus FOLFIRI group (p=0.0172)

EORTC QLQ-C30 social functioning scores in the KRAS wild-type population: changes from baseline scores over

timea

Boxes show the 25%-75% percentile, whiskers show the 10%-90% percentile and the lines connect the mean scores at each timepoint; data for outliers (n≤4 at each timepoint) not shown aA positive change score represents improvement of social functioning whereas a negative change score represents worsening

Timepoint

Week 8

92

98

77

78

66

64

51

42

36

32

24

14

Week 16 Week 24 Week 32 Week 40 Week 48 Week 56 Week 64

14

8

8

5

Cetuximab + FOLFIRI

FOLFIRI

Cetuximab+ FOLFIRI, n

FOLFIRI, n

50

25

0

-25

-50

Conclusions (1)

• Adding cetuximab to FOLFIRI in the 1st-line treatment of mCRC significantly reduced the risk of disease progression in patients with KRAS wild-type tumors compared with FOLFIRI alone

• In both the primary and KRAS wild-type subgroup QoL analyses– There was no significant difference between cetuximab plus

FOLFIRI and FOLFIRI alone in the global health status/QoL and social functioning scores, when analyzed according to changes from baseline levels

Conclusions (2)

• These results support the QoL findings from trials in patients with previously treated mCRC1,2

• The data confirm that cetuximab increases the efficacy of standard 1st-line chemotherapy without any real impact on QoL

1Au H-J, et al. J Clin Oncol 2009;27:1822-18282Sobrero AF, et al. J Clin Oncol 2008;26:2311-2319