A Phase II Study of GW786034 in Patients With Non Small Cell Lung Cancer Who Have Failed at Least Two Prior Chemotherapy Regimens. An Institutional Pilot Study
Better therapies for patients with NSCLC (Non Small Cell Lung Cancer) who progress after
initial chemotherapy is urgently needed.
Besides VEGF (vascular endothelial growth factor), human lung cancers are known to express
PDGFR (platelet-derived growth factor receptors). NSCLC, like most cancers, involves defects
in signal transduction pathways. Receptor tyrosine kinases (RTKs) play a pivotal role in
these signaling pathways, transmitting extracellular molecular signals into the cytoplasm
and/or nucleus of a cell. Among such RTKs are the receptors for polypeptide growth factors
such as epidermal growth factor (EGF), insulin, platelet-derived growth factor (PDGF),
neurotrophins (i.e., NGF), and fibroblast growth factor (FGF). Phosphorylation of such RTKs
activates their cytoplasmic domain kinase function, which in turns activates downstream
signaling molecules. Thus, RTKs are key mediators of cellular signaling as well as
oncogenesis resulting from over-expression and activation of such RTKs and their substrates.
Due to their pivotal role in normal and aberrant signaling, RTKs are the subject of
increasing focus as potential drug targets for the treatment of certain types of cancer. For
example, Herceptin.RTM., an inhibitor of HER2/neu, is currently an approved therapy for a
certain subset of breast cancer. Iressa.TM. (ZD1839) and Tarceva.TM. (OSI-774), both
small-molecule inhibitors of EGFR, have been approved for the treatment of NSCLC.
Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are a family of RTKs that
play an important role in the regulation of normal cell growth and differentiation. PDGFRs
are involved in a variety of pathological processes, including atherosclerosis, neoplasia,
tissue repair, and inflammation. PDGFRs, which consist of two isoforms (alpha and beta), are
membrane protein-tyrosine kinases that, upon binding to PDGF, become activated and, via
recruitment of SH domain-containing effector molecules, initiate distinct or overlapping
signaling cascades that coordinate cellular responses.
Expression of a constitutively active PDGFR leads to cellular transformation and suggests
that, in normal cells, PDGFR activity must be tightly regulated to oppose continuous
activation of its downstream effectors. PDGFR beta, for example, is known to be
over-expressed in a large number of tumors, and PDGF treatment causes transformation and
malignant tumors in a variety of experimental systems. One study reported the apparent
expression of PDGFR alpha in nearly 100% of human lung cancer tumors examined, and reported
the growth inhibition of a lung cancer cell line, A549, by Gleevec, an effect that was
surmised to be mediated via PDGFR inhibition.
Donnem et al evaluated 335 resected patients with stage I to III with NSCLC. Using IHC
(immunohistochemical staining) the expression of PDGF-A, -B, -C and -D along with PDGFR
alpha and beta. In multivariant analysis high tumor cell expression of PDGF-B and PDGF-
alpha were independent negative prognostic predictors. They suggested that PDGF inhibition
may be an option for treatment of NSCLC.
Socinski et al recently described the activity of sunitnib malate (SU11248) an oral,
multitargeted tyrosine kinase inhibitor targeting VEGFR, PDGFR, KIT, FLT3 and RET on tumor
cells, tumor neovasculature and pericytes. In an open-label, two-stage, multicenter phase II
trial evaluating the single-agent activity of sunitinib in refractory NSCLC, patients with
confirmed diagnosis of NSCLC, ECOG PS 0-1, no recent gross hemoptysis, no brain metastases,
patients (pts) previously treated with 1-2 chemotherapy regimens, and adequate end-organ
function, pts received sunitinib at 50 mg/day po for 4 weeks (wks) followed by 2 wks off
treatment (6 wks considered a cycle). A total of 64 pts were enrolled and 63 pts treated.
Six confirmed partial responses have been observed among 63 treated patients. Stable
disease has been observed in an additional 12 pts (19.0% of all treated patients). Based on
this study, Sunitinib appeared to have single-agent activity in previously treated pts with
recurrent and advanced NSCLC, with the level of activity similar to currently approved
agents. Sunitinib was well tolerated in this population. The trial was extended to explore a
continuous dosing strategy of sunitinib at 37.5 mg/day po.
In addition to VEGF and PDGFR, expression of c-kit has been described in NSCLC. Moreover,
it has been found to have an effect on survival. Micke et al, stained the tumor tissue of
95 consecutive patients with adenocarcinoma of the lung, using a polyclonal c-kit antibody.
c-kit expression was correlated with relevant clinical parameters obtained by chart review.
Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%).
Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage
(p < 0.001) as well as of performance status (p = 0.001), surgical resection (p < 0.001),
and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non-
significant (p = 0.913). However, multivariate Cox regression with the influential
parameters revealed a significant effect of c-kit expression on survival. They concluded
that, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the
lung and has a relevant effect on patient survival. They also concluded that the results of
this study support clinical trials targeting the c-kit receptor with specific c-kit
Combined blockade of VEGF, PDGFR and c-kit may result in better outcomes for patients with
Non Small Cell Lung Carcinoma.
Pazopanib is a novel, orally active small molecule inhibitor targeting multiple tyrosine
kinases including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and - beta, and c-kit. An
antitumor effect due to inhibiting of the VEGF driven angiogenic pathway is well
established. In addition to its effects on VEGF receptors, pazopanib targets additional
tyrosine kinases including PDGF receptors and c-kit that have established roles in
tumorigenesis and oncogenic mutations in both have been described. Preliminary data from a
phase I study of pazopanib in patients with solid tumors demonstrated early evidence of
antitumor activity. Among 43 patients enrolled, a minimal response occurred in 4 patients
and stable disease >6 months, was observed in an additional 6 patients.
Pazopanib was well tolerated at doses up to 2000 mg daily. Pazopanib is a potent and
selective, orally available, small molecule inhibitor of VEGFR-1, -2, and -3, PDGF-α,
PDGF-β, and c-kit tyrosine kinases (TKs). The agent selectively inhibits proliferation of
endothelial cells stimulated with VEGF but not with basic fibroblast growth factor. In
non-clinical angiogenesis models, pazopanib inhibited VEGF-dependent angiogenesis in a
dose-dependent manner and in xenograft tumor models, twice-daily administration of pazopanib
significantly inhibited tumor growth in mice implanted with various human tumor cells. Upon
chronic oral dosing, pazopanib is expected to inhibit VEGF driven angiogenesis and as a
consequence, limit solid tumor growth. Because angiogenesis is necessary for the growth and
metastasis of solid tumors, and VEGF is believed to have a pivotal role in this process,
pazopanib treatment may have broad-spectrum clinical utility.
Based on its ability to target multiple tyrosine kinases including VEGFR-1, VEGFR-2,
VEGFR-3, PDGFR-alpha and beta and c-kit, which have been implicated in non small cancer,
investigation of Pazopanib in patients with non small cell lung cancer is warranted.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the disease control rate (CR+PR+SD) of Pazopanib in patients with NSCLC based on the RECIST
Sachdev P. Thomas, M.D.
Illinois CancerCare, P.C.
United States: Food and Drug Administration
ILCC #2 IllinoisCancerCare #2
|Decatur Memorial Hospital||Decatur, Illinois 62526|
|Illinois CancerCare, P.C.||Bloomington, Illinois 61701|