Clinical Development of Anti-VEGF Therapy - Long

http://www.medscape.com/viewarticle/522095_2
Nat Clin Pract Oncol. 2006;3(1):24-40
Phase III Clinical Trials on Anti-VEGF Therapy for Cancer
Clinical Development of Anti-VEGF Therapy

Vascular endothelial growth factor A (VEGF-A, also called VEGF) is a
potent proangiogenic growth factor expressed by most cancer-cell types and
certain tumor stromal cells.[3,5,14] VEGF stimulates endothelial-cell
proliferation, migration and survival, expression of adhesion molecules,
and potently induces increased vascular permeability.[2,3] VEGF can also
affect new-vessel formation in tumors by acting as a chemoattractant for
bone-marrow-derived progenitor/stem cells.[15] VEGF expression can be
triggered during early stages of neoplastic transformation by
environmental stimuli (e.g. hypoxia or low pH) or by genetic mutations
(e.g. in K-ras, p53, or HER2/ErbB2), and persists during
progression.[2,16] Proteolytic enzymes produced by cancer cells or stromal
cells can also release sequestered VEGF bound to the extracellular
matrix.[2] Treatment itself (e.g. radiation or anti-VEGF
therapy[17,18,19]) may increase VEGF production or accumulation, and
inhibiting its activity might be important in maintaining antitumor
efficacy. Thus, blocking the action of VEGF appears to be a promising
antiangiogenic approach to treating multiple types of solid tumors. Such
inhibition can be achieved by direct or indirect targeting of the ligand
(VEGF) at the mRNA or protein level, direct targeting of its receptors
(VEGFR1, VEGFR2, and neuropilin 1 [NP1]; Table 1 ), or by blocking
downstream signaling pathway components. Each of these strategies is
currently being investigated in clinical trials (Figure 1).


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Figure 1. (click image to zoom)

Schematic representation of direct targeting of cancer, endothelial and
perivascular cells by anti-VEGF agents. Combined and direct targeting of
cancer cells and endothelial and perivascular cells has yielded increased
survival in phase III trials of anti-VEGF agents. This has been achieved
by two approaches. The first combines traditional cytotoxic agents (which
may kill any proliferating cell) with the VEGF-specific antibody
bevacizumab. VEGF blockade will inhibit its signaling pathways in
endothelial cells responsible for cell survival, migration, proliferation
and vascular permeability; VEGF blockade might also affect cancer cells,
when their survival depends on VEGF (e.g. via NP1). The second approach
uses low-molecular-weight tyrosine kinase inhibitors with broad inhibitory
spectra (i.e. active against VEGFRs, EGFRs, PDGFRs, c-Kit receptors,
and/or downstream soluble kinases such as Raf), which may be present in
all these cell populations and on other tumor stromal cells (e.g. immune
cells and fibroblasts). Alternatively, combinations of antibodies that
block the ligands (e.g. VEGF and EGFR/HER2 or PDGF) might be effective in
targeting both cancer and endothelial cells. The intracellular tyrosine
kinase domains are shown in yellow and the extracellular ligand binding
domains are depicted in small pink spheres.

CC, cancer cells; EC, endothelial cells; EGF, epidermal growth factor;
EGFR, EGF receptor; HER2, human epidermal growth factor receptor 2; PC,
perivascular cells; PDGF, platelet-derived growth factor; PDGFR, PDGF
receptor; TKIs, tyrosine kinase inhibitors; TGF-?, transforming growth
factor-?; VEGF, vascular endothelial growth factor; sVEGFR1, soluble VEGF
receptor 1.

Direct treatments for antiangiogenesis include antibodies, soluble
receptors, low-molecular-weight TKIs, antisense oligonucleotides, APTAMERS
and RNA INTERFERENCE ( Table 1 ). Monoclonal antibodies that block VEGFR1
(IMC-18F1, ImClone Systems, New York, NY) or its specific ligand placental
growth factor (PlGF) (TB-403, BioInvent International, Lund, Sweden and
ThromboGenics Ltd, Dublin, Ireland) are also under clinical development.
VEGF-Trap (Regeneron, Tarrytown, NY), a composite decoy receptor based on
VEGFR1 and VEGFR2, fused to an antibody Fc segment, potently blocks VEGF
and PIGF action. RNA-interference-based approaches (e.g. ICS-283;
Intradigm Corporation, Rockville, MD) that target VEGF are currently under
preclinical development. Of interest, aptamer (pegaptanib sodium;
Macugen®, Eyetech Pharmaceuticals, Inc., New York, NY), as well as
antibody fragment (ranibizumab; Lucentis®, Genentech, South San Francisco,
CA) that target VEGF, are FDA-approved for patients with age-related
macular degeneration. Finally, because the VEGF pathway acts downstream of
most oncogenes, treatment with agents that target these oncogenic pathways
can indirectly inhibit VEGF (further information is provided in
Supplementary Table 1; see website for details).

Anti-VEGF-specific monotherapy has been shown to have antivascular effects
on tumor vessels,[19,20] but has yet to yield an OS benefit in phase III
trials. In lung and colorectal carcinoma trials, bevacizumab monotherapy
was discontinued because the primary endpoint (OS) was unlikely to be
achieved based on the inferior responses compared with the chemotherapy
and combination-regimen groups.[8,21]

VEGF blockade by bevacizumab has yielded improved OS or PFS in cancer
patients in four phase III trials when combined with standard chemotherapy
( Table 2 ). These results emphasize the potential benefit of targeting
and killing both endothelial and neoplastic cells to enhance survival in
multiple types of cancer. Impressive results have been achieved by
combining anti-VEGF therapy with contemporary cytotoxic agents or by using
broad-spectrum multitargeted agents that block VEGF and other
growth-factor pathways in both cell types (Figure 1).
Targeting of Cancer and Endothelial Cells by Anti-VEGF Therapy and
Chemotherapy

Bevacizumab, a humanized VEGF-specific antibody with a reported half-life
of 17-21 days,[5] was given to cancer patients in combination with
traditional cytotoxic regimens. Some phase I and II trials demonstrated
objective responses (including a few complete responses[22]) to this
combined therapy.[23] The first randomized placebo-controlled phase III
trial of bevacizumab, however, failed to show increased PFS or OS when
bevacizumab was combined with chemotherapy in previously treated
metastatic breast cancer patients.[10] In this trial, despite an increased
response rate, no survival benefit was seen in patients receiving
bevacizumab with capecitabine versus patients receiving capecitabine
alone.

The clinical breakthrough for antiangiogenic therapy came from a
randomized phase III trial showing a 4.7-month increase in OS (the primary
endpoint) when bevacizumab was used with chemotherapy
(irinotecan/5-fluorouracil/leucovorin) in previously untreated, metastatic
colorectal cancer patients ( Table 2 ).[9] Based on these data,
bevacizumab became the first anti-VEGF agent to be approved by the FDA for
cancer patients. Three other unpublished randomized phase III trials have
shown positive results. One trial investigated the efficacy of bevacizumab
with standard chemotherapy (paclitaxel) in patients with
chemotherapy-naive recurrent or metastatic breast cancer and achieved the
primary endpoint of increased PFS.[8] In another trial, previously treated
patients with advanced colorectal cancer who received bevacizumab in
combination with proven second-line therapy (an
oxaliplatin-5-fluorouracil-leucovorin regimen, FOLFOX 4) had a 2.1-month
increase in OS?the primary endpoint?compared with patients who received
FOLFOX 4 alone ( Table 3 ). Whether combining bevacizumab with FOLFOX 4 or
other chemotherapy regimens will be the best option for first-line therapy
for colorectal cancer is under investigation (see reference [24] for
review and discussion).

Finally, a trial of patients with previously untreated advanced
nonsquamous and non-small-cell lung cancer showed a 2.3-month increase in
median survival (the primary endpoint) when bevacizumab was added to
standard chemotherapy (paclitaxel and carboplatin).[21] This was the first
randomized trial of this agent in combination with chemotherapy that
showed a median survival of greater than 1 year in one of the arms, and
the first to use a targeted agent and demonstrate a survival advantage in
combination with chemotherapy in patients with untreated metastatic lung
cancer. The utility and feasibility of using bevacizumab in previously
treated lung cancer patients is unknown. Even in renal-cell carcinoma,
which is a highly VEGF-dependent malignancy, increase in OS by bevacizumab
monotherapy has yet to be demonstrated in a phase III study. A phase III
trial of bevacizumab and interferon-? versus interferon-? alone for
renal-cell cancer has been completed, but results are not yet available.
Collectively, these phase III trials show that anti-VEGF therapy can
increase OS and/or PFS in colorectal, breast and lung cancer patients when
combined with cytotoxic agents.
Targeting of Cancer and Endothelial Cells by Multitargeted anti-VEGF
Agents with or Without Chemotherapy

The second approach is to target both cancer cells and endothelial cells
with small molecules that inhibit signaling pathways for VEGF and other
factors by blocking tyrosine kinase activity with or without chemotherapy.
Similar to bevacizumab, VEGFR receptor kinase-selective multitargeted
agents have been used in combination with chemotherapeutic agents in phase
III clinical trials ( Table 3 ). A randomized phase III study of semaxinib
(SU5416; Pharmacia, San Francisco, CA), which primarily targets VEGFR1,
VEGFR2 and VEGFR3, and secondarily targets PDGFR-? and c-Kit, with
5-fluorouracil/leucovorin and 5-fluorouracil/leucovorin/irinotecan in
patients with metastatic colorectal carcinoma, failed to show, at interim
analysis, any survival benefit for the SU5416-containing regimens,
resulting in the cessation of further development of this compound.[25]
Vatalanib (PTK787/ZK 222584; Novartis, Basel, Switzerland) also primarily
targets VEGFR1, VEGFR2, and VEGFR3, and secondarily targets PDGFR-? and
c-Kit, and can decrease blood flow at doses greater than 750 mg/day.[26]
One trial (CONFIRM 1) compared the efficacy of oral vatalanib in
combination with FOLFOX 4 versus FOLFOX 4 alone for first-line treatment
of metastatic colorectal cancer. The primary endpoint of this trial,
improvement in PFS as judged by an independent central review, was not
met. A secondary endpoint of the trial, OS, is perhaps just as clinically
relevant, and these data may be available in early 2006.[27] Interim
results from a phase III trial of vatalanib in combination with FOLFOX 4
chemotherapy as second-line treatment for metastatic colorectal cancer
(CONFIRM 2), however, suggested no significant benefit in OS. Thus,
multitargeted TKIs are yet to show survival benefit in phase III trials
when combined with chemotherapeutics. Questions about the efficacy of
these classes of agents and their scheduling can only be answered with
additional pharmacokinetic and correlative clinical studies.

Conversely, monotherapy with other multitargeted broad-spectrum TKIs has
shown efficacy in two randomized phase III trials for tumors with limited
treatment options. Sorafenib (BAY 43-9006; Nexavar®, Bayer
Aktiengesellschaft, Leverkusen-Bayerwerk, Germany, and Onyx
Pharmaceuticals Inc., Emeryville, CA) targets VEGFR2 and VEGFR3, PDGFR-?,
Raf, c-Kit and FLT3 (fms-related tyrosine kinase 3), and efficiently
inhibits both tumor-cell proliferation and angiogenesis in preclinical
models.[28] Interim data from a randomized, placebo-controlled phase III
trial (with OS as the primary endpoint) showed that renal-cell-carcinoma
patients taking 400 mg sorafenib twice daily (sorafenib's half-life is
about 20-27 h) had a significant improvement in PFS,[12,13] despite a
marginal (2%) partial-response rate. Thus, patients on the placebo arm
were allowed to cross over to sorafenib after unblinding. A new drug
application has been filed with the FDA for sorafenib for use in patients
with advanced renal-cell carcinoma. Another recent success was obtained
with sunitinib (SU11248; Pfizer, New York, NY) in patients with GIST. In
addition to targeting VEGFR2, sunitinib targets c-Kit, PDGFR-?, and FLT3.
The activated form of the c-Kit receptor is often expressed in GISTs, and
is thus a good candidate for treatment with TKIs that inhibit c-Kit
activity, such as the FDA-approved agent imatinib mesylate (Gleevec®;
Novartis, Basel, Switzerland), which also targets PDGFR-? and PDGFR-? and
BCR/ABL1. A randomized phase III study assessing sunitinib in the
treatment of imatinib-resistant GIST successfully met its predetermined
efficacy endpoint, time-to-progression ( Table 4 ).[29] Sunitinib has a
half-life of 40 h and was given daily at a dose of 50 mg in 4-week cycles
with 2-week breaks to patients randomized 2:1 to patients receiving
placebo. A planned interim analysis of the phase III study data led to the
recommendation that the study be 'unblinded' to give all enrolled patients
access to sunitinib. Sunitinib showed high response rates in refractory
metastatic renal cancers in a large phase II trial.[30] An application for
FDA approval of sunitinib has also been submitted. Both sorafenib and
sunitinib are expected to increase OS in patients in these trials. These
contrasting outcomes for multitargeted TKIs when used in monotherapy
versus combined with chemotherapeutics call for further investigations on
the importance of each target and their mechanisms of action.
Inhibiting Tumor Angiogenesis Indirectly

The use of approved targeted agents?that can indirectly inhibit
angiogenesis?in combination with chemotherapy has also shown increased
survival in breast cancer patients. In a pivotal phase III trial,
trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA)
administered in combination with chemotherapy
(anthracycline/cyclophosphamide or paclitaxel) was compared with
chemotherapy alone.[31] The combination was found to produce significant
OS benefit in HER2-positive metastatic breast cancer patients. These
results led to the approval of trastuzumab for clinical use in the US and
elsewhere. Recently, two phase III trials showed that breast cancer
patients with HER2-positive tumors who received trastuzumab in combination
with doxorubicin, cyclophosphamide and paclitaxel had a 52% decrease in
disease recurrence compared with patients treated with chemotherapy
alone.[32,33] This difference was statistically significant. Most of the
patients enrolled in these studies had lymph-node-positive disease.[32,33]
Whether improved OS can be achieved by combining direct and indirect
inhibitors of angiogenesis in cancer patients awaits the outcome of the
ongoing phase III trials.
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