Optimizing sequential treatment with anti-EGFR and VEGF mAb in metastatic colorectal cancer: current results and controversies

Figures & data

Table 1 Anti-EGFR vs -VEGF mAb in first-line treatment for patients with RAS WT mCRC

	RAS WT population (n)	ETS (%)	Median DpR (%)	ORR (%)	Median PFS months	Median OS months
FIRE-3^Citation16
Cetuximab + FOLFIRI	199	68.2	48.9	65	10.3	33.1
Bevacizumab + FOLFIRI	201	49.1	32.3	58.7	10.2	25
HR or OR (95% CI)		2.22 (1.41–3.47) P=0.0005	NA; P<0.001	1.33 (0.88–1.99) P=0.18	0.97 (0.78–1.20) P=0.77	0.70 (0.54–0.90) P=0.0059
CALGB/SWOG 80405^Citation17,Citation20
Cetuximab + chemotherapy	270	NR	NR	69	11.2	32
Bevacizumab + chemotherapy	256	NR	NR	54	11.0	31.2
HR or OR (95% CI)				NR; P<0.01	1.03 (0.86–1.24) P=0.71	0.88 (0.72–1.08) P=0.24
PEAK^Citation21
Panitumumab + FOLFOX	88	64	65	65	12.8	36.9
Bevacizumab + FOLFOX	82	45	46.3	60	10.1	28.9
HR or OR (95% CI)		1.99 (0.99–4.10); P=0.052	NA; P=0.0018	1.12 (0.56–2.22); P=0.86	0.68 (0.48–0.96); P=0.029	0.76 (0.53–1.11); P=0.15

Note: ETS was defined as having ≥30% tumor shrinkage at week 8 in PEAK and 20% tumor shrinkage at week 6 in FIRE-3.

Abbreviations: DpR, depth of response; ETS, early tumor shrinkage; mCRC, metastatic colorectal cancer; NA, not available; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; WT, wild-type.

Table 2 ETS and outcomes according to the primary tumor location

Trials	Treatment arms		Median PFS (months), HR (95% CI)	Median OS (months), HR (95% CI)
Left-sided colorectal cancer
FIRE-3^Citation22	FOLFIRI + cet FOLFIRI + bev	ETS ≥20% (30%)	NR	NR
PEAK^Citation23	FOLFOX + pani FOLFOX + bev		16.2 vs 12.9 months	55.4 vs 48.5 months
FIRE-3	FOLFIRI + cet FOLFIRI + bev	ETS <20% (30%)	NR	NR
PEAK	FOLFOX + pani FOLFOX + bev		11.6 vs 12.4 months	34.2 vs 27.7 months
Right-sided colorectal cancer
FIRE-3	FOLFIRI + cet FOLFIRI + bev	ETS ≥20% (30%)	7.8 vs 13.4 months 1.718 (0.83–3.55) P=0.137	27.9 vs 23.2 months 1.054 (0.45–2.45) P=0.903
PEAK	FOLFOX + pani FOLFOX + bev		10.8 vs 18.4 months	24.6 vs 26.2 months
FIRE-3	FOLFIRI + cet FOLFIRI + bev	ETS <20% (30%)	2.8 vs 5.2 months 1.743 (0.84–3.61) P=0.129	11.7 vs 15.9 months 1.902 (0.89–4.06) P=0.0902
PEAK	FOLFOX + pani FOLFOX + bev		5.8 vs 12.6 months	15.3 vs 23.3 months

Notes: (30%) represent percentage value for PEAK trial. ETS was defined as having ≥30% tumor shrinkage at week 8 in PEAK and 20% tumor shrinkage at week 6 in FIRE-3.

Abbreviations: bev, bevacizumab; cet, cetuximab; ETS, early tumor shrinkage; NR, not reported; OS, overall survival; pani, panitumumab; PFS, progression-free survival.

Table 3 Anti-EGFR vs -VEGF mAb in second-line treatment after progression on first-line bevacizumab for patients with KRAS WT mCRC

	Primary end-point	KRAS WT population
		N	ORR (%)	Median PFS months	Median OS months
SPIRITT^Citation18	OS
Panitumumab + FOLFIRI		91	32	7.7	18
Bevacizumab + FOLFIRI		91	19	9.2	21.4
HR or OR (95% CI)			NR	1.01 (0.68–1.50); P=0.97	1.06 (0.75–1.49); P=0.75
WJOG6210G^Citation36	ORR
Panitumumab + FOLFIRI		59	46.20	6	16.2
Bevacizumab + FOLFIRI		58	5.70	5.9	13.4
HR or OR (95% CI)			NR; P<0.001	1.14 (0.78–1.66)	1.16 (0.76–1.77)
PRODIGE-18^Citation19	PFS
Bevacizumab + chemotherapy		65	NR	7.1	15.8
Cetuximab + chemotherapy		67	NR	5.6	10.4
HR or OR (95% CI)			NR	0.71 (0.50–1.02); P=0.06	0.69 (0.46–1.04); P=0.08

Abbreviations: mCRC, metastatic colorectal cancer; NR, not reported; OS, overall survival; ORR, objective response rate; PFS, progression-free survival; WT, wild-type.

Table 4 Different sequence strategy for anti-EGFR mAb after progression on first-line bevacizumab

Trial	Treatment arms	n	Prior bevacizumab (%)	PFS II months	PFS III months	Median PFS months	Median OS months
COMET^Citation37	FOLFOX4 followed by cetuximab + irinotecan	55	100	6.1	4.7	11.3	18.6
	Cetuximab + irinotecan followed by FOLFOX4	53	100	5.3	4	9.9	12.3
	HR or OR (95% CI)			0.97 (0.65–1.45); P=0.881	1.00 (0.58–1.70); P=0.986	1.04 (0.69–1.56); P=0.854	0.84 (0.55–1.28); P=0.4114
REVERSE^Citation38	Regorafenib followed by cetuximab + irinotecan	51	96	2.4	5.2	NR	17.4
	Cetuximab + irinotecan followed by regorafenib	50	98	4.2	1.8	NR	11.6
	HR or OR (95% CI)			0.97 (0.62–1.54); P=0.91	0.29 (0.17–0.50); P<0.0001		0.61 (0.39–0.96); P=0.029

Notes: PFS was defined as the time from the date of randomization up to the date of progression after third-line treatment or death from any cause. PFS II was defined as the time from the date of randomization up to the date of first progression after second-line or death from any cause. PFS III was defined as the time from the third-line starting date up to the date of first progression after third-line or death from any cause. In REVERSE trial, PFS II was defined as the time from the date of randomization up to the date of first progression after first treatment (R in R-C arm or C in C-R arm) or death from any cause. PFS III was defined as the time interval between the first progression after first treatment and second progression after second treatment (C in R-C arm or R in C-R arm).

Abbreviations: OS, overall survival; PFS, progression-free survival.

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