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

Abstract

Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named "vascular disrupting agents," tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.

Keywords: FGF; NSCLC; PDGF; VEGF; angiogenesis; oral antiangiogenic agents.

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.

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.

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.