Economic outcomes of sequences which include monoclonal antibodies against vascular endothelial growth factor and/or epidermal growth factor receptor for the treatment of unresectable metastatic colorectal cancer

Figures & data

Table 1. Studies referenced in SmPCs for bevacizumab, cetuximab, and panitumumab.

Study name/description from SmPC	Study reference
Bevacizumab
NO16966 (1L)	Cassidy et al.27, Saltz et al.17, de Gramont et al.28
E3200 (2L)	Giantonio et al.18,29
AVF2107g	Hurwitz et al.16
AVF0780g	No formal publication
AVF2192g	No formal publication
Cetuximab
EMR 62 202-013 (CRYSTAL 1L)	Van Cutsem et al.5
EMR 62 202-047 (OPUS 1L)	Bokemeyer et al.7
COIN 1L (open label study)	Maughan et al.6
CA225006 (EPIC 2L)	Sobrero et al.9
CA225025 (CO17 2L as single agent)	Jonker et al.10, Karapetis et al.11
EMR 62 202-007 (BOND)	Pfeiffer et al.30,31
Panitumumab
Monotherapy (3L)	Van Cutsem et al.15
1L with FOLFOX	Douillard et al.13, Siena et al.32
2L with FOLFIRI	Peeters et al.14

Table 2. Drug and administration cost data for Germany.

Drug name	Cost/mg (€)	Source
Bevacizumab	€3.59
Cetuximab	€2.45
Panitumumab	€5.34
Fluorouracil	€0.005	WINAPO SQL Lauer Taxe (Version March 2012)
Capecitabine	€0.007
Oxaliplatin	€4.03
Irinotecan	€2.27
Leucovorin (Folinic acid) (400 mg Racemic)	€0.500	Assumption
Leucovorin (Folinic acid) (200 mg)	€0.410	WINAPO SQL Lauer Taxe (Version March 2012)
Administration cost: Intravenous Therapy	€15.60	Kassenärztliche Bundesvereinigung (KBV); Einheitlicher Bewertungsmaβstab (EBM) Version: 1; Quartal 2012. Last change: 2012*

Administration cost per single intravenous administration in Germany applies to a more than 60 min administration; *rounded up to 0.01.

Table 3. Median PFS (proxy health outcome and treatment duration) from pivotal studies.

Drug regimen	Median PFS	Significance	Reference
1L
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	p = 0.0023	Cassidy et al.27, Saltz et al.17, de Gramont et al.28
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	p = 0.0023	Cassidy et al.27, Saltz et al.17, de Gramont et al.28
CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	8.6	Not significant	Maughan et al.6
CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	8.3	p = 0.0064	Bokemeyer et al.7
PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	9.6	Not reported	Douillard et al.13, Siena et al.32
CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	8.6	Not significant	Maughan et al.6
CET 250 mg weekly + FOLFIRI (KRAS WT CRYSTAL Van Cutsem 2009)	9.9	Not reported	Van Cutsem et al.5
2L
BEV 7.5 mg + XELOX (ML 18147)	5.7	p < 0.0001	Arnold et al.19
BEV 5 mg + FOLFOX 6 (ML18147)	5.7	p < 0.0001	Arnold et al.19
BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	p < 0.0001	Arnold et al.19
BEV 10 mg + FOLFIRI (Assumption)*	5.7	Not applicable	Assumption
BEV 10 mg + FOLFIRI (Assumption)*	7.3	Not applicable	Assumption
PAN + FOLFIRI (KRAS WT, Peeters 2010)	5.9	Statistically significant	Peeters et al.14
CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	Not reported	Sobrero et al.9
BEV 10 mg + FOLFOX 4 (E3200, Giantonio 2007)	7.3	p < 0.0001	Giantonio et al.18,29
3L
BSC alone*	1.8	Not applicable	Karapetis et al.11
CET 250 mg weekly + BSC (KRAS WT CO17 Karapetis 2008)**	3.7	p < 0.0001	Jonker et al.10, Karapetis et al.11
PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	8.0	p < 0.0001	Van Cutsem et al.15
CET 250 mg weekly + IRI (Pfeiffer 2008)	5.4	Not applicable	Pfeiffer et al.30,31

*Fill in regimens are those which were required to complete treatment sequences but are not sourced from SmPCs. For more details see assumptions section.

**This study can be interpreted as 2L or 3L.

Table 4. Calculated monthly drug costs by line of therapy.

Drug regimen	Month 1 cost	Month 2 cost
1L
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	€4493	€4493
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	€4648	€4648
CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	€6628	€5960
CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	€6636	€5968
CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	€6725	€6057
CET 250 mg weekly + FOLFIRI (KRAS WT CRYSTAL Van Cutsem 2009)	€7253	€6585
PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	€6636	€6636
2L
BEV 7.5 mg + XELOX (ML 18147)	€4648	€4648
BEV 5 mg + FOLFOX 6 (ML18147)	€5088	€5088
BEV 5 mg + simplified FOLFIRI (ML18147)	€5110	€5110
CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	€6999	€6331
BEV 10 mg + FOLFIRI (Required regimen)*	€6632	€6632
PAN + FOLFIRI (KRAS WT, Peeters 2010)	€6929	€6929
BEV 10 mg + FOLFOX 4 (E3200, Giantonio 2007)	€7223	€7223
3L
BSC alone (Required regimen)*	€100	€100
CET 250 mg weekly + BSC (KRAS WT CO17 Karapetis 2008)**	€5007	€4339
PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	€5007	€5007
CET 250 mg weekly + IRI (Pfeiffer 2008)	€6521	€5853

Initial CET doses incur an incremental drug cost for month 1 based on the higher upfront dose; therefore, results are arranged in ascending order of cost for month 2.

*Required regimens are those which were required to complete treatment sequences but which are not sourced from SmPCs.

**This study can be interpreted as 2L or 3L.

Table 5. Potential treatment sequences based on studies referenced in SmPCs.

First line drug regimen	Median PFS (months)	Second line drug regimen	Median PFS (months)	Third line drug regimen	Median PFS (months)	Sum of PFS
Anti-EGFR 1L
CET 250 mg weekly + FOLFOX 4 (KRAS WT,  OPUS BOKEMEYER PII, 2011)	8.3	BEV 10 mg + FOLFIRI (Assumption)	5.7	BSC (KRAS WT Karapetis CO17)	1.8	15.8
CET 250 mg weekly + FOLFOX (KRAS WT  COIN Maughan 2011)	8.6	BEV 10 mg + FOLFIRI (Assumption)	5.7	BSC (KRAS WT Karapetis CO17)	1.8	16.1
CET 250 mg weekly + XELOX (KRAS WT  COIN Maughan 2011)	8.6	BEV 10 mg + FOLFIRI (Assumption)	5.7	BSC (KRAS WT Karapetis CO17)	1.8	16.1
PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	9.6	BEV 10 mg + FOLFIRI (Assumption)	5.7	BSC (KRAS WT Karapetis CO17)	1.8	17.1
CET 250 mg weekly + FOLFOX 4 (KRAS WT,  OPUS BOKEMEYER PII, 2011)	8.3	BEV 10 mg + FOLFIRI (Assumption)	7.3	BSC (KRAS WT Karapetis CO17)	1.8	17.4
CET 250 mg weekly + FOLFOX (KRAS WT  COIN Maughan 2011)	8.6	BEV 10 mg + FOLFIRI (Assumption)	7.3	BSC (KRAS WT Karapetis CO17)	1.8	17.7
CET 250 mg weekly + XELOX  (KRAS WT COIN Maughan 2011)	8.6	BEV 10 mg + FOLFIRI (Assumption)	7.3	BSC (KRAS WT Karapetis CO17)	1.8	17.7
PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	9.6	BEV 10 mg + FOLFIRI (Assumption)	7.3	BSC (KRAS WT Karapetis CO17)	1.8	18.7
CET 250 mg weekly + FOLFIRI (KRAS WT CRYSTAL  Van Cutsem 2009)	9.9	BEV 10 mg + FOLFOX 4 (E3200, Giantonio 2007)	7.3	BSC (KRAS WT Karapetis CO17)	1.8	19.0
Anti-EGFR 2L
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	BSC (KRAS WT Karapetis CO17)	1.8	15.2
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	BSC (KRAS WT Karapetis CO17)	1.8	15.2
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	PAN + FOLFIRI (KRAS WT, Peeters 2010)	5.9	BSC (KRAS WT Karapetis CO17)	1.8	17.1
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	PAN + FOLFIRI (KRAS WT, Peeters 2010)	5.9	BSC (KRAS WT Karapetis CO17)	1.8	17.1
Anti-EGFR 3L
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	CET 250 mg weekly + BSC (KRAS WT CO17 Karapetis 2008)*	3.7	18.8
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	CET 250 mg weekly + IRI (Pfeiffer 2008)	5.4	20.5
BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	8.0	23.1
BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	8.0	23.1

*This study can be interpreted as 2L or 3L.

Table 6. Sequences arranged in ascending order of health outcomes (sum of median PFS).

Line	1L drug regimen	PFS	Total cost 1L	2L drug regimen	PFS	Total cost 2L	3L regimen	PFS	Total cost 3L	SUM PFS	Total sequence cost	Average monthly cost
2L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	€42,233	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	€28,664	BSC (KRAS WT Karapetis CO17)	1.8	€180	15.2	€71,076	€4676
2L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	€43,694	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	€28,664	BSC (KRAS WT Karapetis CO17)	1.8	€180	15.2	€72,537	€4772
1L	CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	8.3	€55,744	BEV 10 mg + FOLFIRI (Assumed regimen minimum efficacy)*	5.7	€37,801	BSC (KRAS WT Karapetis CO17)	1.8	€180	15.8	€93,726	€5932
1L	CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	8.6	€57,668	BEV 10 mg + FOLFIRI (Assumed regimen minimum efficacy)*	5.7	€37,801	BSC (KRAS WT Karapetis CO17)	1.8	€180	16.1	€95,650	€5940
1L	CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	8.6	€58,503	BEV 10 mg + FOLFIRI (Assumed regimen minimum efficacy)*	5.7	€37,801	BSC (KRAS WT Karapetis CO17)	1.8	€180	16.1	€96,484	€5992
1L	PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	9.6	€63,703	BEV 10 mg + FOLFIRI (Assumed regimen minimum efficacy)*	5.7	€37,801	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.1	€101,684	€5946
2L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	€43,694	PAN + FOLFIRI (KRAS WT, Peeters 2010)	5.9	€40,883	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.1	€84,757	€4956
2L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	€42,233	PAN + FOLFIRI (KRAS WT, Peeters 2010)	5.9	€40,883	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.1	€83,296	€4871
1L	CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	8.3	€55,744	BEV 10 mg + FOLFIRI (Assumed regimen maximum efficacy)**	7.3	€48,412	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.4	€104,337	€5996
1L	CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	8.6	€57,668	BEV 10 mg + FOLFIRI (Assumed regimen maximum efficacy)**	7.3	€48,412	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.7	€106,261	€6003
1L	CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	8.6	€58,503	BEV 10 mg + FOLFIRI** (Assumed regimen maximum efficacy)	7.3	€48,412	BSC (KRAS WT Karapetis CO17)	1.8	€180	17.7	€107,095	€6050
1L	PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	9.6	€63,703	BEV 10 mg + FOLFIRI** (Assumed regimen maximum efficacy)	7.3	€48,412	BSC (KRAS WT Karapetis CO17)	1.8	€180	18.7	€112,295	€6005
3L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	€42,233	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	€29,129	CET 250 mg weekly + BSC (KRAS WT CO17 Karapetis 2008)^a	3.7	€19,193	18.8	€90,555	€4816
1L	CET 250 mg weekly + FOLFIRI (KRAS WT CRYSTAL Van Cutsem 2009)	9.9	€72,475	BEV 10 mg + FOLFOX 4 (E3200, Giantonio 2007)	7.3	€52,726	BSC (KRAS WT Karapetis CO17)	1.8	€180	19.0	€125,381	€6599
3L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	€43,694	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	€29,129	CET 250 mg weekly + IRI (Pfeiffer 2008)	5.4	€35,880	20.5	€108,702	€5302
3L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	9.4	€42,233	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	€29,129	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	8.0	€40,053	23.1	€111,415	€4823
3L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	9.4	€43,694	BEV 5 mg + simplified FOLFIRI (ML18147)	5.7	€29,129	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	8.0	€40,053	23.1	€112,876	€4886

*BEV efficacy estimate minimum; ** BEV efficacy estimate maximum.

Table 7. Sequences arranged in ascending order of cost outcomes with standardized treatment duration.

Line	1L drug regimen	PFS	Total cost 1L	2L drug regimen	PFS	Total cost 2L	3L drug regimen	PFS	Total cost 3L	SUM PFS	Total sequence cost	Average monthly cost
2L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	6.1	€27,406	PAN + FOLFIRI (KRAS WT, Peeters 2010)	4.0	€27,717	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€55,394	€4327
2L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	6.1	€27,406	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	€28,664	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€56,340	€4401
2L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	6.1	€28,354	PAN + FOLFIRI (KRAS WT, Peeters 2010)	4.0	€27,717	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€56,342	€4401
2L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	6.1	€28,354	CET 250 mg weekly + IRI (EPIC, Sobrero 2008 2L)	4.0	€28,664	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€57,288	€4475
3L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	6.1	€27,406	BEV 5 mg + simplified FOLFIRI (ML18147)	4.0	€20,441	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	2.7	€13,518	12.8	€61,366	€4794
3L	BEV 5 mg + FOLFOX 4 (NO16966 Saltz 2008)	6.1	€27,406	BEV 5 mg + simplified FOLFIRI (ML18147)	4.0	€20,441	CET 250 mg weekly + BSC (KRAS WT CO17 Karapetis 2008)^a	2.7	€14,186	12.8	€62,034	€4846
3L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	6.1	€28,354	BEV 5 mg + simplified FOLFIRI (ML18147)	4.0	€20,441	PAN + BSC Van Cutsem 2007 (KOL regimen PAN alone)	2.7	€13,518	12.8	€62,314	€4868
3L	BEV 7.5 mg + XELOX (NO16966; Saltz 2008 P2)	6.1	€28,354	BEV 5 mg + simplified FOLFIRI (ML18147)	4.0	€20,441	CET 250 mg weekly + IRI (Pfeiffer 2008)	2.7	€18,274	12.8	€67,070	€5239
1L	PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	6.1	€40,478	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,275	€5255
1L	PAN + FOLFOX 4 (KRAS WT, Prime, Douillard 2011)	6.1	€40,478	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,275	€5255
1L	CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	6.1	€41,098	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,896	€5304
1L	CET 250 mg weekly + FOLFOX (KRAS WT COIN Maughan 2011)	6.1	€41,098	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,896	€5304
1L	CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	6.1	€41,146	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,943	€5308
1L	CET 250 mg weekly + FOLFOX 4 (KRAS WT, OPUS BOKEMEYER PII, 2011)	6.1	€41,146	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€67,943	€5308
1L	CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	6.1	€41,691	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€68,488	€5350
1L	CET 250 mg weekly + XELOX (KRAS WT COIN Maughan 2011)	6.1	€41,691	BEV 10 mg + FOLFIRI (Assumption)	4.0	€26,527	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€68,488	€5350
1L	CET 250 mg weekly + FOLFIRI (KRAS WT CRYSTAL Van Cutsem 2009)	6.1	€44,913	BEV 10 mg + FOLFOX 4 (E3200, Giantonio 2007)	4.0	€28,891	BSC (KRAS WT Karapetis CO17)	2.7	€270	12.8	€74,074	€5787

Figure 1. One-way deterministic sensitivity analysis for drug regimen BEV 5 mg + FOLFOX4.

Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-12

 PubMed Web of Science ®Google Scholar

Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013-19

 PubMed Web of Science ®Google Scholar

de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47

 PubMed Web of Science ®Google Scholar

Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44

 PubMed Web of Science ®Google Scholar

Giantonio BJ, Catalano PJ, O'Dwyer PJ, et al. Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group's Study E3200. J Clin Oncol 2006;ASCO Annual Meeting Proceedings Part I 2006;24:3538

 Google Scholar

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42

 PubMed Web of Science ®Google Scholar

Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17

 PubMed Web of Science ®Google Scholar

Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011;22:1535-46

 PubMed Web of Science ®Google Scholar

Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011;377:2103-14

 PubMed Web of Science ®Google Scholar

Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311-19

 PubMed Web of Science ®Google Scholar

Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-8

 PubMed Web of Science ®Google Scholar

Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65

 PubMed Web of Science ®Google Scholar

Pfeiffer P, Nielsen D, Yilmaz M, et al. Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Acta Oncol 2007;46:697-701

 PubMed Web of Science ®Google Scholar

Pfeiffer P, Nielsen D, Bjerregaard J, et al. Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol 2008;19:1141-5

 PubMed Web of Science ®Google Scholar

Van Cutsem E, Peeters M, Siena S, et al. 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. J Clin Oncol 2007;25:1658-64

 PubMed Web of Science ®Google Scholar

Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697-705

 PubMed Web of Science ®Google Scholar

Siena S, Cassidy J, Tabernero J, et al. Randomized phase 3 study of Panitumumab with FOLFOX4 compared with FOLFOX4 alone as fist-line treatment in patients with metastatic colorectal cancer: the PRIME Trial. ASCO Annual Meeting 2010.

 Google Scholar

Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-13

 PubMed Web of Science ®Google Scholar

Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). 48th Annual ASCO Meeting 2012. Journal of Clinical Oncology 2012;30:suppl:abstr CRA3503). http://www.asco.org. Accessed June 1, 2012

 Google Scholar