New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond

Figures & data

Figure 1 Triple mechanism of action of BIBF-1120: it inhibits all three VEGFR subtypes, PDGFR-α and PDGFR-β and FGFR types 1, 2, and 3. Other targets of this drug are the FLT-3 (inhibition of acute myelogenous leukemia cell proliferation), and members of the Src-family (Src, Lyn, and Lck).

Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor; FLT-3, fms-like tyrosine kinase 3; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Table 1 Kinase inhibition: comparing BIBF 1120 with other small-molecule VEGFR inhibitors

Drug	Half-life (h)	IC50(nM)
		VEGFR1	VEGFR2	VEGFR3	PDGFR α/β	FGFR1/3	KIT	EGFR
Sunitinib	44	15	38	30	69/65	675	10	NR
Sorafenib	~27	NR	90	20	NR/57	580	68	>10,000
Vandetanib	~120	1600	40	110	NR/1100	3600	>20,000	500
Cediranib	13–25	5	<1	<3	36/5	26	2	>1000
AMG 706	5–7	2	3	6	84	>2800	8	>3000
Axitinib	2–5	1.2	0.25	0.29	2/NR	230	NR	NR
Vatalanib	3–6	54	39	195	567	NR	364	NR
BIBF 1120*	7–19	34	21	13	59/65	69/108	NR	>50,000

* Note: Biochemical IC₅₀ values were determined using slightly different methods between the studies and are not directly comparable.

Abbreviations: EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; IC₅₀, half-maximal inhibitory concentration; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.

Figure 2 Demographic distribution of population from a Phase II randomized double-blind study with BIBF 1120 as monotherapy in advanced non-small cell lung cancer.

Abbreviations: ECOG, Eastern Cooperative Oncology Group score; LN, lymph node.

Figure 3 Demographic distribution by overall clinical response status from Phase II randomized double-blind study with BIBF 1120 as monotherapy in advanced non-small cell lung cancer.

Abbreviation: ECOG, Eastern Cooperative Oncology Group score.

Table 2 Most frequent adverse events linked to different doses of BIBF 1120 as monotherapy from Phase II randomized doubleblind study in advanced non-small cell lung cancer

	Grade 3 CTCAE, %		Grade 4 CTCAE, %
	150 mg bid	250 mg bid	150 mg bid	250 mg bid
Nausea	2.7	11.1	0	0
Vomiting	2.7	5.6	0	0
Diarrhea	5.4	11.1	0	0
Fatigue	0	2.8	0	0
Abdominal pain	0	5.6	0	0
ALT increase	0	19.4	0	0
AST increase	0	2.8	0	0
GI bleeding	0	0	0	0
Hemoptysis	0	0	0	0
GI perforation	0	0	0	0
Hypertension	0	0	0	0
Dizziness	2.7	0	0	0

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice daily; CTCAE, Common Terminology Criteria for Adverse Events.

Figure 4 Phase III trials ongoing with BIBF 1120 in combination with chemotherapy: actually the LUME-Lung 1 trial stopped to recruit new patients, while the LUME-Lung 2 is continuing recruitment.

Abbreviation: NSCLC, non-small cell lung cancer.