Personalizing medicine for metastatic colorectal cancer: Current developments

Table 1 Summary of the main clinical trials regarding anti-angiogenic therapies

Drugs	Ref.	Trial	Summary of the study	Results (PFS; OS)	Toxicity (grade 3 or 4 adverse events)
Aflibercept	[33]	VELOUR trial	aflibercept with irinotecan/5-FU/LV as second line chemotherapy for mCRC	Median PFS for the aflibercept plus FOLFIRI arm was 6.90 mo vs 4.67 mo for the placebo-plus-FOLFIRI arm	Grade 3 or 4 adverse events were more common with the addition of aflibercept (n = 614) or placebo (n = 612), nearly 1/3 of these patients had previously been treated with bevacizumab
				Median OS for the aflibercept-plus-FOLFIRI arm was 13.50 mo vs 12.06 mo for the placebo plus FOLFIRI arm
Sunitinib	[36]	Carrat et al[36]	Double-blinded, phase III study participants were randomly assigned to sunitinib plus FOLFIRI or placebo plus FOLFIRI	Median PFS for the sunitinib arm was 7.8 mo (95%CI: 7.1-8.4 mo) vs 8.4 mo (95%CI: 7.6-9.2 mo) for the placebo arm	Diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia)
Vatalanib	[38-40]	CONFIRM-1/CONFIRM-2	These are multinational, randomized, double-blinded, phase III studies. Patients were randomly assigned to receive vatalanib plus FOLFOX4 or placebo plus FOLFOX4 in 1ª or 2º line respectively for CONFIRM-1 or CONFIRM-2	Vatalanib and placebo, respectively, presented median OS was 13.1 and 11.9 mo (HR = 1.00; 95%CI: 0.87-1.16; P = 0.957). Median PFS was with placebo (5.6 and 4.2 mo, respectively; HR = 0.83; 95%CI: 0.71-0.96; P = 0.013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR = 0.63; 95%CI: 0.48-0.83; P < 0.001)	The incidence of grade 3/4 neutropenia was similar for both groups; however, a higher percentage of patients in the vatalanib group experienced grade 3/4 hypertension, diarrhea, fatigue, nausea, vomiting, dizziness, confused state, deep vein thrombosis, and pulmonary embolism
Semaxanib	[42]		Study conducted with the objective of determining the maximum tolerated dose and dose-limiting toxicities in combination with weekly irinotecan in patients with advanced CRC who had failed at least one prior treatment	NA	There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting
Regorafenib	[44]	CORRECT trial	Patients with mCRC and progression during or within 3 mo after the last standard therapy were randomised to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 wk of each 4 wk cycle	Median OS was 6.4 mo in the regorafenib group vs 5.0 mo in the placebo group (HR = 0.77; 95%CI: 0.64-0.94; one-sided P = 0.0052)	The grade 3 or higher of adverse effects related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%)
Brivanib	[47]	Siu et al[47]	Patients previously treated were assigned 1:1 to receive cetuximab 400 mg/m intravenous loading dose followed by weekly maintenance of 250 mg/m plus either brivanib 800 mg orally daily (arm A) or placebo (arm B)	Median OS in the intent-to-treat population was 8.8 mo in arm A and 8.1 mo in arm B (HR = 0.88; 95%CI: 0.74-1.03; P = 0.12). Median PFS was 5.0 mo in arm A and 3.4 mo in arm B (HR = 0.72; 95%CI: 0.62-0.84; P < 0.001)	Grade ≥ 3 adverse events was 78% in arm A and 53% in arm B
Cediranib	[48]	HORIZON III	Patients randomly assigned 1:1:1 received mFOLFOX6 with cediranib or bevacizumab	There are not significant differences in PFS (HR = 1.10; 95%CI: 0.97-1.25; P = 0.119), OS (HR = 0.95; 95%CI: 0.82-1.10; P = 0.541) and overall response rate (46.3% vs 47.3%)	Cediranib arm adverse events included diarrhea, neutropenia, and hypertension

PFS: Progression free survival; OS: Overall survival; HR: Hazard ratio; 5-FU: 5-fluourouracil; LV: Leucovorin; FOLFIRI: 5-FU, LV and irinotecan; FOLFOX: 5-FU, LV and oxaliplatin; mCRC: Metastatic colorectal cancer; NA: Not available.