BIBF 1120 for the treatment of non-small cell lung cancer
Martin Reck
Hospital Grosshansdorf, Department of Thoracic Oncology, Grosshansdorf, Germany

Importance of the field: For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy offers modest benefits and outcomes are poor. Angiogenesis, the formation of new blood vessels from the pre- existing vasculature, is a fundamental process for tumor growth and develop- ment. Tumor vasculature is therefore emerging as an important target for cancer therapy.
Areas covered in this review: This expert review will briefly discuss several antiangiogenic agents approved for the treatment of NSCLC, including many more currently being investigated in clinical trials, such as neutralizing antibodies of pro-angiogenic factors and inhibitors of their tyrosine kinase receptors. This review will also provide an overview of BIBF 1120, a novel, potent, triple angiokinase inhibitor that simultaneously acts on three recep- tor families involved in blood vessel formation: vascular endothelial growth factor receptors, platelet-derived growth factor receptors and fibroblast growth factor receptors.
What the reader will gain: Expert opinion on the promising results obtained in Phase I studies demonstrating that BIBF 1120 is well tolerated in patients with advanced solid tumors will be provided. Further experience from a Phase II monotherapy trial also indicates promising efficacy and a favorable safety profile in patients with relapsed advanced NSCLC.
Take home message: Based on these data, the BIBF 1120 Phase III clinical development program is currently underway and will be discussed in further detail.

Keywords: angiogenesis, BIBF 1120, NSCLC, tyrosine kinase inhibitors, VEGFR

Expert Opin. Investig. Drugs (2010) 19(6):789-794

⦁ Introduction

Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) being the most common type [1,2]. Combination chemotherapy remains the standard therapy for patients with advanced or metastatic disease. How- ever, in spite of available treatment options for patients who progress beyond first- line therapy, prognosis remains poor, with median survival times of 7 — 8.3 months, and 1-year survival rates of 29 — 37% [3-5]. Angiogenesis is the process by which new blood vessels are formed from pre-existing vasculature [6]. Although a fundamental process for embryonic growth, wound healing and regeneration, tumors are able to utilize this process to stimulate their own growth and metastasis [6-8]. Angiogenesis is a tightly regulated process controlled by a delicate balance between pro- and antian- giogenic factors and their receptors, which comprise a complex, complementary and overlapping network [6]. Tumors induce angiogenesis by disrupting this balance and secreting various growth factors [8].
Vascular endothelial growth factor (VEGF) is considered to be one of the most important pro-angiogenic factors involved in tumor angiogenesis [9]. VEGF plays

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Box 1. Drug summary.
Drug name BIBF 1120
Phase III
Indication NSCLC
Mechanism of action Angiokinase inhibitor predominantly targeting the VEGF, PDGF and FGF tyrosine kinase receptors Route of administration Oral
Chemical structure O

N N N

N H

O
O N
H
O
Pivotal trials LUME-Lung 1: investigating the efficacy and safety of BIBF 1120 200 mg b.i.d. plus standard docetaxel therapy compared with placebo plus standard docetaxel therapy in patients with Stage IIIB/IV or recurrent NSCLC (all histologies) after relapse or failure of first-line chemotherapy LUME-Lung 2: investigating the efficacy and safety of BIBF 1120 200 mg b.i.d. plus standard pemetrexed therapy compared with placebo plus standard pemetrexed therapy in patients with Stage IIIB/IV or recurrent non-squamous NSCLC after relapse or failure of first-line chemotherapy
Pharmaprojects – Copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline. com) and Citeline (http://informa.citeline.com).
FGF: Fibroblast growth factor; NSCLC: Non-small cell lung cancer; PDGF: Platelet-derived growth factor; VEGF: Vascular endothelial growth factor.

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a fundamental role in angiogenesis by mediating vasculogene- sis, angiogenic remodeling and angiogenic sprouting [9]. VEGF increases vascular permeability, thereby causing a greater delivery of oxygen and nutrients, and additionally may facilitate tumor dissemination via the circulation; it recruits circulating endothelial precursor cells, and also acts as a survival factor for immature tumor blood vessels. Specif- ically, activities of the VEGF family are mediated through the VEGF-specific tyrosine kinase receptors, VEGF receptor (VEGFR)1, VEGFR2 and VEGFR3 [9,10]. VEGFR2 is
considered to be the crucial receptor involved in initiating the formation as well as the maintenance of tumor vas- culature; it is associated with mitogenic signaling and permeability-enhancing effects [9-11].
Platelet-derived growth factor (PDGF) signaling is impor- tant for pericyte survival and maintaining pericyte–endothelial cell contact; PDGF receptor (PDGFR) tyrosine kinases are expressed on the surface of pericytes and smooth muscle cells, and contribute to pericyte recruitment and the stability of blood vessel walls [6]. Recently, Rikova and colleagues reported
the involvement of receptor tyrosine kinase dysregulation (i.e., PDGFR-a) in lung cancer development [12].
Fibroblasts, which are associated with cancer cells at all
stages of cancer progression, are responsible for the synthesis, deposition and remodeling of much of the extracellular matrix in tumor stroma. Basic fibroblast growth factor

(bFGF) is secreted by tumors to stimulate the proliferation of endothelial and smooth muscle cells; elevated levels of fibroblast growth factor (FGF) directly correlate with tumor angiogenesis and growth [6,13].
As multiple proangiogenic factors contribute to angio- genesis and extensive redundancy exists, other angiogenic factors, including bFGF, are thought to play a role in the development of resistance against certain treatment modali- ties (e.g., VEGF and VEGFR2 therapeutic antibodies) [14]. Tumor vasculature is therefore emerging as an important tar- get for anticancer therapy. Specifically, inhibitors of ligands and receptors involved in mediating the signals that drive tumor angiogenesis offer the potential for targeted therapy.

⦁ Overview of the antiangiogenic agents

The first approved antiangiogenic agent, bevacizumab, a monoclonal antibody, blocks the binding of VEGF to its high-affinity receptors. Two pivotal Phase III studies have demonstrated the activity of bevacizumab in chemotherapy- naive patients with NSCLC [15,16]. Although bevacizumab demonstrates promising antitumor activity, its clinical use is limited by the observed side-effect profile, namely the increased risk of fatal or life-threatening bleeding events and hemorrhages. Therefore, a proportion of patients are deemed ineligible for bevacizumab treatment, such as those

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with squamous histology, tumors infiltrating central blood vessels, active cardiovascular disease, or relevant history of hemoptysis/bleeding.
A large number of small-molecule, multi-targeting tyrosine kinase inhibitors (TKIs) are currently undergoing development for the treatment of NSCLC, including: sunitinib, an oral inhibitor of VEGFR, PDGFR, c-kit and -
Flt-3; sorafenib, an oral inhibitor of C-Raf, B-Raf, VEGFR, PDGFR-b, c-kit and Flt-3; and vandetanib, an oral inhibitor of VEGFR, EGFR and rearranged during
transfection (RET) receptor tyrosine kinase activity. These novel agents have the advantages of hitting multiple tar- gets, convenient oral administration, and the potential for lower cost.
A recent Phase II study demonstrated the therapeutic potential of continuous daily sunitinib in patients with previously treated advanced NSCLC. Although response rates were modest, sunitinib treatment was associated with an acceptable safety profile and promising time-to-event data [17]. However, for sorafenib, a Phase III, randomized, placebo-controlled trial designed to assess the efficacy and safety of sorafenib in combination with carboplatin and paclitaxel in chemotherapy-naive NSCLC patients was recently terminated after demonstrating no clinical bene- fit [18]. Despite any potential improvements in patient survival seen with these agents, prognosis continues to be poor for patients with advanced NSCLC, and tolerability remains an issue.

⦁ BIBF 1120

BIBF 1120 (Box 1) is a novel, oral, potent, triple angiokinase inhibitor, which simultaneously acts on three key receptor families involved in angiogenesis: VEGFRs, PDGFRs and FGF receptors (FGFRs) [19]. Co-crystallization with recombi- nant VEGFR2 kinase and X-ray diffraction demonstrated that BIBF 1120 competitively binds to the adenosine- 5-triphosphate (ATP) binding site of receptor tyrosine kinases and inhibits downstream intracellular signaling [19].

⦁ Pharmacodynamics
In vitro, BIBF 1120 is a potent inhibitor of VEGFR, FGFR and PDGFR in enzymatic and cellular assays. Biochemical assays demonstrate that BIBF 1120 inhibits a narrow range of kinases at pharmacologically relevant concentrations: VEGFR types 1, 2 and 3 (IC50 values of 34,
21 and 13 nmol/l, respectively), PDGFR-a and PDGFR-b (IC50 values of 59 and 65 nmol/l), FGFR types 1, 2 and
3 (IC50 values of 69, 37 and 108 nmol/l, respectively), Flt-3 and members of the Src family (Src, Lyn and Lck) [19]. BIBF 1120 has a sustained duration of cellular action; in vitro pulse-chase experiments with VEGFR2-transfected NIH3T3 cells demonstrate that after 1 h exposure with 50 nmol/l BIBF 1120, the autophosphorylation of VEGFR2
was blocked for ‡ 32 h [19]. Sustained blockade of the
receptor may indicate the potential for a long-lasting antiangiogenic effect.
Observations from cellular cultures showed that the treatment of VEGF-stimulated endothelial cells derived from umbilical veins (HUVEC) and skin microvessels (HSMEC) with BIBF 1120 resulted in inhibition of cell proliferation (EC50 < 10 nmol/l) [19]. In agreement with the biochemical kinase inhibition data, BIBF 1120 also inhibited the proliferation of PDGF-stimulated smooth muscle cells and pericytes, with EC50 values of 69 and 79 nmol/l, respectively. In vivo, BIBF 1120 demonstrates antitumor activity in all xenograft models tested to date, including human renal cell carcinoma (Caki-1), colorectal carcinoma (HT-29), ovarian carcinoma (SKOV-3), NSCLC (Calu-6), prostate carcinoma (PAC-120) and a syngeneic rat glioblastoma model (cell line GS-9L) [19]. In tumor xenografts, BIBF 1120 reduces tumor microvessel density and the number of PDGFR-ß-expressing perivascular cells, as measured by immunohistochemistry [19]. Mice with established FaDu xenografts were treated for
4 consecutive days with either the vehicle control or BIBF 1120 at a dose of 100 mg/kg. When tumors were dissected and analyzed, vessel density was reduced by 76% in BIBF 1120-treated mice compared with the control group. BIBF 1120 also induces rapid changes in tumor perfusion and permeability in FaDu HNSCC xenografts, as measured by dynamic contrast-enhanced magnetic reso- nance imaging (DCE-MRI) [19]. These nude mice were ana- lyzed before and 72 h after initiation of daily treatment with BIBF 1120 at 100 mg/kg, with vascular permeability significantly reduced after 3 days of treatment. In addition to BIBF 1120 monotherapy, preclinical studies investi- gating BIBF 1120 in combination with chemotherapeutic agents have reported improved antitumor activity compared with single-agent treatment [20]. Furthermore, the concept of combining a cytotoxic drug with an antiangiogenic agent, which has the potential to facilitate cytotoxic drug delivery to the tumor by reorganizing the tumor vessel system, seems promising.

⦁ Pharmacokinetics and metabolism
Clinical studies demonstrate that after oral administration, maximum BIBF 1120 plasma concentrations occurred mainly 1 -- 4 h after administration [21]. No deviation from dose proportionality in the pharmacokinetics of BIBF 1120 has been observed. BIBF 1120 showed a high apparent volume of distribution during the terminal phase, both after single dose and at steady state, which might indicate a high tissue distribution of the drug. In addition, there was no decrease in exposure over time during continuous daily treatment with BIBF 1120. From clinical investigation, the cleavage of [14C]BIBF 1120 by esterase-catalysed hydrolysis is the prevalent metabolic reaction; CYP450-dependent metabolism was found to be minor. The terminal half-life of BIBF 1120 was determined to be 19 h. BIBF 1120 is mainly excreted via the liver.

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⦁ Clinical efficacy
⦁ Phase I studies
Several Phase I, BIBF 1120 monotherapy, dose-escalation trials have been performed in patients with a variety of advanced solid tumors [22-24]. Based on these studies, the MTD of BIBF 1120 was defined as 250 mg b.i.d. in Caucasian patients and 200 mg b.i.d. in Japanese patients. Splitting the cumulative daily dose into two daily adminis- trations allowed an increase in the tolerable total daily dose without additional toxicity, increasing exposure to BIBF 1120. BIBF 1120 was generally well tolerated in these studies, with the most frequent adverse events (AEs) being nausea, diarrhea, vomiting, abdominal pain and fatigue of a mild-to-moderate intensity. With regard to dose-limiting AEs, Common Toxicity Criteria (CTC) Grade 3 or 4 rever- sible liver enzyme elevations (alanine aminotransferase and aspartate aminotransferase) constituted the majority; no drug-related bleeding events were observed. Furthermore, BIBF 1120 demonstrated encouraging signs of efficacy, with one complete and two partial responses observed in patients with colorectal cancer and renal cell cancer [22].
Two Phase I dose-escalation studies investigating BIBF 1120 in combination with standard chemotherapy regimens have also been conducted [25,26]. One investigated the MTD of continuous oral treatment with BIBF 1120 in combination with standard-dose pemetrexed (500 mg/m2) in patients with recurrent NSCLC who had been treated with one prior platinum-based chemotherapy regimen. The second investigated the safety, tolerability and MTD of BIBF 1120 in combination with carboplatin (AUC 6) and paclitaxel (200 mg/m2) in previously untreated pat- ients with advanced-stage (IIIB/IV) NSCLC. In these studies, the recommended dose of BIBF 1120 was deter- mined to be 200 mg b.i.d. when combined with standard regimens for NSCLC. Although these studies were predo- minantly designed to evaluate the safety, tolerability and pharmacokinetics of BIBF 1120 when used in combination with chemotherapy, promising efficacy signals were obser- ved. One patient, who was treated with 100 mg b.i.d. of BIBF 1120 and pemetrexed, had a complete response for more than 3 years. Furthermore, DCE-MRI results dem- onstrated an antiangiogenic effect of BIBF 1120 in a substan- tial number of patients. The AE profiles observed in these studies were comparable to those observed in the BIBF 1120 monotherapy trials, except for toxicities commonly related to the chemotherapy agent.

⦁ Phase II in NSCLC
The key Phase II evidence for BIBF 1120 in NSCLC has been obtained from a double-blind, two-arm, randomized mono- therapy study [27]. This study evaluated the efficacy of BIBF 1120 in patients with relapsed, advanced NSCLC of any histology. The primary end points were progression- free survival (PFS) and objective response rate (ORR). Secondary end points included characterization of the safety
and pharmacokinetic (PK) profiles of BIBF 1120, as well as overall survival (OS). In total, 73 patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 -- 2 with locally advanced or metastatic (stage IIIB/IV) relapsed NSCLC after failure of first- or second-line chemo- therapy were randomized to continuous twice-daily treatment with 150 or 250 mg BIBF 1120 until disease progression. The median PFS of all patients (n = 73) was 1.6 months, with no significant difference between the two groups; stable disease rate was 48%; the disease control rate was 59%. However, a stratified analysis reported that patients with an ECOG performance status of 0 or 1 (n = 57) had a median PFS of 2.9 months. One partial response was observed and 20 patients showed tumor shrinkage as best response. The median OS of patients with an ECOG performance status of 0 or 1 was 9.5 months. The majority of AEs reported in this study were mild-to-moderate in nature and predominantly related to the gastrointestinal tract (nausea, diarrhea and vomiting). No severe drug-related bleeding was observed, and there were no major differences in toxicity with regards to histology. No hypertension events exceeding CTC Grade 2 AEs were observed. In general, BIBF 1120 tolerability was comparable between the two doses, with the exception of a higher frequency of liver enzyme elevations in the higher dose group. These Phase II data confirmed the promising single-agent activity of BIBF 1120 in patients suffering from recurrent NSCLC, warranting further development of BIBF 1120 in the Phase III setting.

⦁ The BIBF 1120 Phase III development programme The BIBF 1120 Phase III clinical development programme is currently underway, with patients being recruited into two pivotal studies, LUME-Lung 1 and 2. The LUME-Lung study program is investigating the potential benefit of adding BIBF 1120 to standard chemotherapy in patients with advanced NSCLC in the second-line setting. LUME-Lung 1 is a multicenter, randomized, double-blind study to investigate the efficacy and safety of BIBF 1120
200 mg b.i.d. plus standard docetaxel therapy compared with placebo plus standard docetaxel therapy in patients with Stage IIIB/IV or recurrent NSCLC (all histologies) after relapse or failure of first-line chemotherapy [28]. LUME-Lung 2 is a multicenter, randomized, double-blind study to investigate the efficacy and safety of BIBF 1120 200 mg b.i.d. plus standard pemetrexed therapy compared with placebo plus standard pemetrexed therapy in patients with Stage IIIB/IV or recurrent non-squamous NSCLC after relapse or failure of first-line chemotherapy [29]. Based on the overall safety profile from Phase I and II investigation, BIBF 1120 200 mg b.i.d. is the recommended Phase III dose for a combination of BIBF 1120 with pemetrexed and docetaxel. Besides the primary end point of PFS, both trials are statistically powered to give adequate information on OS.

⦁ Expert opinion

The potential clinical benefit of BIBF 1120, or any other anti- angiogenic agent, is driven by the need to fully understand its mode of action, identify suitable combination regimens and identify patients who will benefit from treatment. The number of antiangiogenic agents demonstrating clinical interest continues to grow. Motesanib (AMG 706), a novel, oral, multi-targeting small-molecule inhibitor of VEGFR types 1, 2 and 3, PDGFR and c-kit, is currently undergoing Phase II investigation across a variety of indications, including non-squamous NSCLC. In addition, axitinib, another potent, oral, selective inhibitor of VEGFR types 1, 2 and 3, PDGFR and c-kit is also undergoing investigation in a similar patient population.
BIBF 1120 differs from other angiogenesis inhibitors not only in its distinctive VEGFR-, PDGFR-, and FGFR- targeting profile, but also with regard to its sustained cellular duration of action and its PK profile [19]. BIBF 1120 also has
tumor growth and dissemination, while also avoiding prob- lems such as redundancy or resistance across the complex sig- naling networks. Clinical trials have demonstrated that, due to the non-CYP450 mediated metabolism of BIBF 1120, drug--drug interactions are not expected and, to date, no co- medications have been excluded from BIBF 1120 trials. This is of potential benefit both in considering combination with other cancer therapeutics and in taking into account medication being taken for co-morbidities, which is a key issue for the majority of late-stage NSCLC patients.
The future of antiangiogenic treatment in NSCLC will focus on establishing biomarkers of response and resistance to antiangiogenic therapies, which is increasingly becoming an unmet need in NSCLC. The discovery of specific patient populations that will derive benefit from these agents will offer a strategy to maximize patient benefit and encourage truly personalized therapy.

Acknowledgements

the advantage of a convenient oral application and good

tolerability, with no severe bleeding, skin reactions, hyperten- sion or hematological side effects observed in patients suffer- ing from all histologies. This is particularly important for patients with squamous cell NSCLC who are ineligible for treatment with bevacizumab. The potential use of BIBF 1120 in patients with squamous histology will be investigated as part of the pivotal Phase III LUME-Lung 1 study, which will therefore provide more substantial data regarding the efficacy and safety of BIBF 1120 in this key patient population.
Due to its unique and multiple targeting profile, BIBF 1120 has the potential to effectively prevent both
The author wishes to thank F Halbug of Boehringer Ingelheim for medical input.

Declaration of interest

Medical writing assistance was provided by Ogilvy Health- world, as funded by Boehringer Ingelheim. M Reck has received honoraria from Hoffmann-La Roche, Eli Lilly, AstraZeneca, Merck and Pfizer for lectures and serving on advisory boards.

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Affiliation
Martin Reck
Hospital Grosshansdorf, Department of Thoracic Oncology, Grosshansdorf, Germany
Tel: +49 4102 601 188; Fax: +49 4102 691 317;
E-mail: [email protected]