TABLE 1.

Pivotal advanced mCC clinical trials

Author Trial Name^a	Journal	Regimen Tested	Number of Patients	Line of Therapy	Previous Treatments	Primary Endpoint^b	Significance
IRINOTECAN TRIALS
Cunningham et al²⁴	Lancet, 1998	Irinotecan vs BSC	189 Vs 90	Second	5-FU	OS 9.2 vs 6.5	p<0.0001
Rougier et al²⁵	Lancet, 1998	Irinotecan vs 5-FU/LV	133 vs 134	Second	5-FU	OS 10.8 vs 8.5	p<0.035
Saltz et al²⁶	NEJM, 2000	Irinotecan vs IFL vs 5-FU/LV	226 vs 231 vs 226	First	-	PFS 7 (IFL) vs 4.3 (5-FU) vs 4.2 (irinotecan) OS 14.8 (IFL) vs 12.6 (5-FU) vs 12 (irinotecan)	p<0.04
Douillard et al²⁷	Lancet, 2000	FOLFIRI vs 5-FU/LV	199 vs 188	First	-	RR 35% v 22% OS 17.4 vs 14.1	p<0.005
OXALIPLATIN TRIALS
de Gramont et al²⁹	JCO, 2000	Oxali+ LV5FU2 vs LV5FU2	210 vs 210	First	-	PFS 9 vs 6.2 OS 16.2 vs 14.7 NS	p<0.0001
Rothenberg et al³⁰	JCO, 2003	Oxali vs FOLFOX4 vs LV5FU2	156 vs 152 vs 151	Second	5FU Irinotecan (IFL)	RR 1.3% vs 9.9% vs 0% OS not reported	p<0.0001
Goldberg et al³¹ NCCTG 9741	JCO, 2004	FOLFOX vs IFL vs IROX	267 vs 264 vs 264	First	-	TTP 8.7 vs 6.9 vs 6.5 OS 19.5 vs 15 vs 17.4	p<0.0014
FOLFOXIRI TRIALS
Souglakos et al³²	Br J Cancer, 2006	FOLFOXIRI vs FOLFIRI	137 vs 146	First	-	OS 21.5 vs 19.5	p=0.337 NS
Falcone et al³³	JCO, 2007	FOLFOXIRI vs FOLFIRI	122 vs 122	First	-	RR 66% v 41% OS 22.6 v 16.7	p<0.0002
CAPECITABINE
Van Cutsem et al³⁸	JCO, 2001	Cape vs 5-FU/LV	301 vs 301	First	-	RR non-inferiority 18.9% vs 15% OS 13.2 vs 12.1 NS	NS 95% CI, 14.7%–23.8% vs 95% CI, 11.1%–19.5%
Hoff et al³⁹	JCO, 2001	Cape vs 5-FU/LV	302 vs 303	First	-	RR non-inferiority 25.8% vs 11.6% OS 12.5 vs 13.3 NS	NS 95% CI, 21.0%–31.2% vs 95% CI, 8.2%–15.7%
Diaz-Rubio et al⁴⁰	JCO, 2007	CapeOx vs FUOX	174 vs 174	First	-	TTP non-inferiority 8.9 vs 9.5 OS 18.1 vs 20.8 NS	p=0.153 NS
Porschen et al⁴¹	JCO, 2007	CapeOx vs FUFOX	242 vs 234	First	-	PFS non-inferiority 7.1 vs 8 OS 16.8 vs 18.8 NS	p=0.117 NS
Cassidy et al⁴²	JCO, 2008	CapeOx vs FOLFOX4 CapeOx-bev vs FOLFOX- bev	767 vs 351 vs 349	First	-	PFS non-inferiority 8 vs 8.5 OS 19.8 vs 19.6 NS	NS HR = 1.04; 97.5% CI, 0.93 to 1.16
Kohne et al⁴⁴ EORTC 40015	Ann Oncol, 2008	CapeIRI vs FOLFIRI	44 vs 41	First	-	PFS non-inferiority Early termination	Early Termination
Fuchs et al⁴⁵ BICC-C	JCO, 2007	CapeIRI vs FOLFIRI vs mIFL	145 vs 144 vs 141	First	-	PFS 5.8 vs 7.6 vs 5.9 OS 18.9 vs 23.1 vs 17.6 NS	FOLFIRI vs mIFL p<0.004
OPTIMAL SEQUENCE TRIALS
Tournigand et al⁷	JCO, 2004	FOLFIRI then FOLFOX vs Reverse	113 vs 113	First, then Second	-	Second PFS 14.2 vs 10.9 OS 21.5 vs 20.6 NS	p=0.64
Koopman et al⁴⁸ CAIRO	Lancet, 2007	Cape then irinotecan, then CapeOX vs CapeIRI then CapeOX	336 339	First, Second +/− Third	-	OS 16.3 vs 17.4	p<0.3281 NS
Seymour et al⁴⁹ MRC-FOCUS	Lancet, 2007	A. 5FU/LV then Irinotecan vs B. 5FU/LV then Combo -FOLFIRI -FOLFOX vs C. Combo -FOLFIRI -FOLFOX	710 (712) 356 356 (713) 356 357	First, then Second		OS A. 13.9 vs B. FOLFIRI 15.0 FOLFOX 15.2 vs C. FOLFIRI 16.7 FOLFOX 15.4	p=NS
OPTIMAL DURATION TRIALS
Tournigand et al⁵⁰ OPTIMOX-1	JCO, 2006	FOLFOX4 vs Drop oxali FOLFOX7	310 vs 310	First	-	OS 19.3 vs 21.2	p=NS
Chibaudel et al⁵¹ OPTIMOX-2	JCO, 2009	FOLFOX4 vs Chemo-free FOLFOX7	108 vs 108	First	-	DDC 13.1 vs 9.2 OS 23.8 vs 19.5	p=0.046
Labianca et al GISCAD- FOLFIRI	JCO, 2006 abstr. 3505	FOLFIRI vs On off every 2 months	Total = 336	First	-	OS 16.9 vs 17.6	p=NS
Tabernero et al MACRO	JCO, 2010 abstr. 3501	CapeOX- bev vs CapeOX- bevX6 then bev alone	239 vs 231	First	-	PFS non-inferiority 11 vs 10.3 OS 25.3 vs 20.7 NS	p=0.59 HR 1.07 95% CI, 0.84–1.36^*
Adams et al MRC-COIN	JCO, 2010 Abstr. 3525	ARM A: OX-Fp vs ARM C: Stop and go	Total= 1640	First	-	OS 15.6 vs 14.3	HR 1.084 80% CI, 1.008–1.165
DREAM- OPTIMOX-3		FOLFOX or CapeOX with bev X6 then bev+ erlotinib maintenace		First	-	ongoing
ANTI-ANGIOGENESIS: BEVACIZUMAB
Hurwitz et al⁵²	NEJM, 2005	IFL-bev vs IFL	402 vs 411	First	-	OS 20.3 vs 15.6	p<0.001
Saltz et al⁵³ N016966	JCO, 2008	FOLFOX or XELOX + /− bev	Total= 1401	First	-	PFS 9.4 vs 8 OS 21.3 vs 19.9 NS	p<0.0023
Grothey et al⁵⁴ BRiTE Observational	JCO, 2008	BBP vs No BBP vs No therapy	642 vs 531 vs 253	First, then with Second	-	OS 31.8 vs 19.9 vs 12.6	P<0.001
ANTI-EGFR: CETUXIMAB AND PANITUMUMAB
Cunningham et al⁶¹ BOND	NEJM, 2004	Irinotecan- cetuximab vs cetuximab	218 vs 111	Second and Third	Irinotecan (100%) Oxali (63%)	RR 22.9% vs 10.8% OS 8.6 v 6.9 NS	P=0.007
Jonker et al⁶²	NEJM, 2007	Cetuximab vs BSC	287 vs 285	Third	5-FU irinotecan oxaliplatin	OS 6.1 vs 4.6	p<0.001
Van Cutsem et al⁶³	JCO, 2007	p-MAb vs BSC	231 vs 232	Third	5-FU irinotecan oxaliplatin	PFS 8wk vs 7.3 wk OS NS – cross over design	0.0001
Bokemeyer et al⁶⁶ OPUS Phase II	JCO, 2009	FOLFOX- cetuximab vs FOLFOX	169 vs 168	First	-	RR 46% v 36% OS not reported	p=0.64
Maughan et al MRC-COIN	JCO, 2010 Abstr. 3502	FOLFOX/ CapeOX +/− cetuximab	Total= 1640 KRAS wt + mt	First	-	OS Not reported for total population (only KRAS wt)
Douillard et al PRIME	JCO, 2010 Abstr. 3528	FOLFOX+ p-MAb vs FOLFOX	593 vs 590	First	-	PFS Not reported for total population (only KRAS wt)
Van Cutsem et al⁶⁵ CRYSTAL	NEJM, 2009	FOLFIRI+ cetuximab vs FOLFIRI	599 vs 599	First	-	PFS 8.9 vs 8 OS 19.9 vs 18.6 NS	p=0.048
COMBINED BIOLOGICS: BEVACIZUMAB and ANTI-EGFR
Saltz et al⁷¹ BOND-2 Phase II	JCO, 2007	Irinotecan Bev and cetuximab vs Bev + Cetuximab	43 vs 40	Second and Third	Irinotecan (100%) Oxaliplatin (84–93%)	TTP 7.3 vs 4.9 OS 14.5 vs 11.4 NS	not reported
Hecht et al⁷² PACCE	JCO, 2009 ARM A	FOLFOX and bev + p-MAb vs FOLFOX and bev	413 vs 410	First	-	PFS 10 vs 11.4 OS 19.4 vs 24.5	p=0.004
Hecht et al⁷² PACCE	JCO, 2009 ARM B	FOLFIRI and bev + p-MAb vs FOLFIRI and bev	115 vs 115	First	-	PFS (2^nd endpt) 10.1 vs 11.9 OS 20.7 VS 20.5 NS	p=NS
Tol et al⁶⁸ CAIRO-2	NEJM, 2009	CapeOx-bev + cetuxmab vs CapeOx-bev	378 vs 377	First	-	PFS 9.4 vs 10.7 OS 20.4 vs 20.3 NS	p=0.01

Randomized Phase III trials unless otherwise specified.

Units indicated in months unless otherwise indicated.

MACRO trial failed to meet primary endpoint of noninferiority (CI with upper limit HR<1.32)

BSC, best supportive care; OS, overall survival; PFS, progression free survival; RR, response rate; TTP, time to progression; DDC, duration of disease control; Cape, capecitabine; NS, not significant; Bev, bevacizumab; BBP, bevacizumab beyond progression; p-MAb, panitumumab; wt, wild type; mt, mutant.