Surrogate endpoints in second-line treatment for mCRC: A systematic literature-based analysis from 23 randomised trials

Figures & data

Figure 1. PRISMA diagram/literature search.

Table I. Trials included in the analysis.

Trial	Treatment	Number of patients	Overall response rate (%)	Disease control rate (%)	Progression free survival (months)	Overall survival (months)
Bendell et al. 2011 [27]	FOLFIRI + Axitinib	49	25.5		5.7	12.9
	FOLFIRI + Bevacizumab	51	23.5		6.9	15.7
	FOLFOX + Axitinib	36	22.2		7.5	17.1
	FOLFOX + Bevacizumab	35	20.0		6.4	14.1
Bennouna et al. 2013 [19]	Chemotherapy + Bevacizumab	409	5.0		5.7	11.2
	Chemotherapy	411	4.0		4.1	9.8
Cohn et al. 2013b [28]	FOLFIRI + Conatumumab	51	14.0	69.0	6.5	12.3
	FOLFIRI + Ganitumab	52	8.0	67.0	4.5	12.4
	FOLFIRI + Placebo	52	2.0	65.0	4.6	12.0
Cohn et al. 2013a [20]	FOLFIRI + Panitumumab	91	28.0		7.7	18.0
	FOLFIRI + Bevacizumab	91	16.0		9.2	21.4
Cunningham et al. 2004 [29]	Iriotecan + Cetuximab	218	22.9		4.1	8.6
	Cetuximab	111	10.8		1.5	6.9
Eng et al. 2013 [21]	Irinotecan + Cetuximab + Tivantinib	62	45.0	81.7	8.3	19.8
	Irinotecan + Cetuximab + Placebo	60	33.0	71.9	7.3	16.9
Fuchs et al. 2003 [30]	Irinotecan weekly	95			4.0	9.9
	Irinotecan q21d	196			3.0	9.9
Giantonio et al. 2007 [31]	FOLFOX4 + Bevacizumab	286	22.7		7.3	12.9
	FOLFOX4	291	8.6		4.7	10.8
	Bevacizumab	243	3.3		2.7	10.2
Haller et al. 2008 [32]	IROX	317	22.0	78.0	5.3	13.4
	Irinotecan	310	7.0	55.0	2.8	11.1
Hoehler et al. 2013 [33]	FOLFOX/FOLFIRI + Sorafenib	50	25.6		5.2	9.6
	FOLFOX/FOLFIRI	51	12.2		5.6	12.7
Kim et al. 2009 [34]	Irinotecan	245	15.5		4.4	14.3
	FOLFOX4	246	28.0		6.2	13.8
Masi et al. 2013 [35]	FOLFOX/FOLFIRI + Bevacizumab	92	21.0		6.7	16.5
	FOLFOX/FOLFIRI	92	18.0		5.2	16.0
Muro et al. 2010 [36]	FOLFIRI	213	16.7		5.1	18.2
	IRIS	213	18.8		5.8	19.5
Peeters et al. 2010 [22]	FOLFIRI + Panitumumab WT	303	35.0	74.0	5.9	14.5
	FOLFIRI WT	294	10.0	65.0	3.9	12.5
	FOLFIRI + Panitumumab MT	238	13.0	68.0	5.0	11.8
	FOLFIRI MT	248	14.0	63.0	4.9	11.1
Peeters et al. 2013 [37]	FOLFIRI + Trebananib	95	14.0	59.0	3.5	11.9
	FOLFIRI + Placebo	49	0.0	69.0	5.2	8.8
Rothenberg et al. 2003 [38]	LV5U2	151	2.6	42.3	2.7	8.7
	Oxaliplatin	156	3.2	39.7	1.6	8.1
	FOLFOX4	152	13.8	69.1	4.6	9.8
Rothenberg et al. 2008 [39]	FOLFOX4	314	18.0		4.8	12.6
	XELOX	313	20.0		4.7	11.9
Rougier et al. 2002 [40]	Irinotecan/LV5FU2	35	11.4	60.0	3.2	12.2
	Oxaliplatin/LV5FU2	33	21.2	79.7	4.7	11.5
	Irnotecan/Oxaliplatin	33	15.2	60.6	4.2	11.0
Schoemaker et al. 2004 [41]	Irinotecan q3w	41	7.0	51.0	2.7	9.4
	Irinotecan weekly	37	5.0	67.0	3.5	7.1
	Irinotecan q2w	46	11.0	65.0	3.8	8.6
	Irinotecan cont. q3w	44	2.0	45.0	1.7	6.4
Sobrero et al. 2008 [23]	Irinotecan + Cetuximab	648	16.4	61.4	4.0	10.7
	Irinotecan	650	4.2	45.8	2.6	10.0
Tsavaris et al. 2003 [42]	Irinotecan q3w	60	22.0		4.5	7.0
	Irinotecan weekly	60	25.0		6.0	9.0
Van Cutsem et al. 2011 [43]	FOLFOX4 + Vatalanib	426	18.5		5.6	13.1
	FOLFOX4 + Placebo	429	17.5		4.2	11.9
Van Cutsem et al. 2012 [44]	FOLFIRI + Aflibercept	612	19.8	85.7	6.9	13.5
	FOLFIRI + Placebo	614	11.1	76.0	4.6	12.1

FOLFIRI, irinotecan + infusional FU/LV, FOLFOX, oxaliplatin + infusional FU/LV; FU, fluorouracil; IRIS, irinotecan + S1; IROX, irinotecan + oxaliplatin; LV, leucovorin; Lv5FU2, leucovorin 200 mg/m², 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m² bolus, 600 mg/m² 22-h continuous infusion, days 1 and 2; Mayo, 5-FU 425 mg/m² + LV 20 mg/m² daily for 5 days every 4–5 weeks; MT, mutant, OS, overall survival; PFS, progression-free survival; XELOX, capecitabine + oxaliplatin; WT, wild-type.

Table II. Descriptive median response rates (ORR, DCR) and median survival rates (PFS, OS).

	No. trials	No. patients	Median	Range
ORR	22	10 509	11.4%	0.0–45.0%
DCR	10	5383	65.0%	39.7–85.7%
PFS	23	10 800	4.5 months	1.6–8.3 months
OS	23	10 800	11.5 months	6.4–19.8 months

DCR, disease control rate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Figure 2. Correlation between PFS and OS. The solid line represents the change in PFS according to a change in OS; dotted lines indicate pointwise 95% confidence intervals. Symbol size is proportional to number of patients.

Table III. Correlation between progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) with overall survival (OS).

	No. trials	No. patients	R	95% CI	p-Value
PFS	23	10 800	0.73	0.61–0.82	< 0.001
ORR	22	10 509	0.58	0.38–0.72	0.003
DCR	10	5383	0.74	0.56–0.86	0.007

95% CI, 95% confidence interval; DCR, disease control rate; ORR, overall response rate; PFS, progression-free survival.

Figure 3. Correlation between ORR and OS. The solid line represents the change in ORR according to a change in OS; dotted lines indicate pointwise 95% confidence intervals. Symbol size is proportional to number of patients.

Figure 4. Correlation between DCR and OS. The solid line represents the change in DCR according to a change in OS; dotted lines indicate pointwise 95% confidence intervals. Symbol size is proportional to number of patients.

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