Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Table 1 Clinical trials investigating the impact of epidermal growth factor receptor blockades in colorectal cancer patients

Ref.	Year	Sample size	Mutation status	Treatment groups	Special considerations	Summarized findings
Saltz et al[46]	2001	120	EGFR +	Cetuximab plus Irinotecan		22.5% major objective response rate 17% radiologic response rate
Saltz et al[47]	2004	57	EGFR +	Cetuximab		9% (CI: 3% to 19%) partial response Median survival of 6.4 mo. P value ??
Cunningham et al[48]	2004	329	EGFR +	Cetuximab plus irinotecan vs cetuximab alone		22.9% partial response in combination arm, 10.8% partial response in the cetuximab monotherapy arm No difference in OS
Jonker et al[49]	2007	572	EGFR +	Cetuximab compared to best supportive care		6.1 mo OS in treatment arm vs 4.6 mo with supportive care. P = 0.005 Quality of life was better preserved in the cetuximab group (P < 0.05)
Van Cutsem et al[56]	2007	463	EGFR+	Panitumumab vs best supportive care		Median PFS 8 wk in treatment arm compared to 7.3 wk in patients receiving supportive care (HR 0.54; P < 0.0001)
Amado et al[57]	2008	427	EGFR+ Wild type KRAS vs mutant KRAS	Panitumumab vs best supportive care	Reanalysis of Van Cutsem 2007	In patients with wild type KRAS median PFS was 12.3 wk for panitumumab vs 7.3 wk for supportive care Response rates to panitumumab was 17% for patients with wild type KRAS compared to 0% in patients with mutant KRAS
Van Cutsem et al[51] CRYSTAL Trial	2009	1198	EGFR +	Cetuximab plus FOLFIRI vs FOLFIRI alone		HR for PFS in combination therapy 0.85 (P = 0.048) when compared to FOLFIRI alone There was no difference in OS (HR 0.93; P = 0.31) Although not significant PFS was improved with cetuximab in patients with wild-type-KRAS (HR 0.68; P = 0.07)
Folprecht et al[55] CELIM trial	2010	113	Wild type KRAS vs mutant KRAS	Cetuximab plus FOLFOX vs Cetuximab plus FOLFIRI vs historical controls	Neoadjuvant setting	No survival difference between the two groups Higher response rates compared to historical controls (FOLFOX and FOLFIRI) Total 36 of 116 patients were able to receive R0 resection Improved outcomes limited to patients with wild type KRAS
Van Cutsem et al[52]	2011	1198	EGFR+ Wild type KRAS vs mutant KRAS	Cetuximab plus FOLFIRI vs FOLFIRI alone Wild type KRAS vs mutant KRAS	Reanalysis of data from CRYSTAL trial	Patients with wild type KRAS had improvements in OS from 20 to 23.5 mo PFS from 8.4 to 9.9 mo and response rates 39.7% to 57.3% with addition of Cetuximab to FOLFIRI
Bokemeyer et al[53] OPUS study	2011	315	Wild type KRAS/BRAF vs mutant KRAS/BRAF	Cetuximab plus FOLFOX		Improved PFS (HR 0.567) and response (OR 2.55) in patients with KRAS wild-type tumors
Alberts et al[54] N0137 trial	2012	2686	Wild type KRAS vs mutant KRAS	Cetuximab plus FOLFOX vs FOLFOX alone	Locally advanced disease	No additional benefit of Cetuximab when added to FOLFOX-6 regimen in the setting of locally advance disease

EGFR: Epidermal growth factor receptor; PFS: Progression free survival; OS: Overall survival.