Avid Bioservices Inc (CDMO)

[freethemice]

I thought I would post this to put the bavi NSCLC results in context with what else is going on with NSCLC clinical trials.
Targeted drugs were supposed to be the next great thing, but in many cases they have been a bust.
From this you can see that there is much room for improvement in treatment of NSCLC.
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Journal of Clinical Oncology, August 10, 2012.
Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC):
Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)
Daniel Morgensztern and Roy S. Herbst, Yale Comprehensive Cancer Center, Yale University School of Medicine, New
Haven, CT
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Angiogenesis is a complex and tightly regulated process that is
defined as the growth of new blood vessels, especially those that supply
oxygen and nutrients to cancerous tissue, from existing vasculature. 1
Because of the critical role of angiogenesis in the growth and
metastases from solid tumors, including non–small-cell lung cancer
(NSCLC), its inhibition represents a rational therapeutic strategy.
Vascular endothelial growth factor (VEGF) is a key ligand and
regulator of both physiologic and pathologic angiogenesis, including
that of tumors, with signaling occurring mainly through the
VEGF receptor 2 (VEGFR-2). 2
Bevacizumab, a humanized monoclonal antibody against circulating
VEGF, was the first antiangiogenesis drug to enter clinical practice
for NSCLC. Because of an increased risk of life-threatening
bleeding among patients with squamous cell carcinoma in the phase II
trial, 3 subsequent trials were limited to nonsquamous histology. The
addition of bevacizumab to chemotherapy was associated with improved
response rate (RR) and progression-free survival (PFS) in two
large randomized trials, Eastern Cooperative Oncology Group
(ECOG) 4599 4 and Avastin in Lung (AVAiL) ,5 although only ECOG
4599 was associated with improved overall survival (OS). Unfortunately,
the benefit from bevacizumab in patients with advanced
NSCLC is modest and transient, with essentially all responding patients
developing secondary resistance. One of the mechanisms that is
implicated in the development of resistance is the stimulation of
compensatory proangiogenic factors such as fibroblast growth factor
and platelet-derived growth factor(PDFGR) .6
Tyrosine kinase inhibitors (TKIs) compete with adenosine
triphosphate for the active site of the kinase domain. Because of the
well-conserved adenosine triphosphate binding sites of the kinases,
many TKIs (unlike bevacizumab, which exclusively targets the VEGF
ligand) inhibit multiple receptors. This ability to inhibit multiple angiogenesis
pathways offers the potential for increased efficacy and
decreased development of secondary resistance through redundant
pathways. Nevertheless, the decreased specificity may be associated
with increased toxicity. Given that single-agent TKIs directed against
similar targets such as sorafenib (VEGF-R2, VEGFR-3, PDGFR,
RAF-1, BRAF, c-KIT, FLT-3), 7 sunitinib (VEGFR-2, PDGFR, FLT-3,
c-KIT, RET), 8,9 and axitinib (VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR, c-KIT) 10 have been well tolerated in NSCLC, the next step
would be to pursue their combination with chemotherapy or other
biologic agents.
Several randomized clinical trials comparing chemotherapy
alone or with the addition of TKIs have been conducted (Table 1).

In phase II studies, neither the addition of vandetanib 11 nor cediranib 12
improved the median PFS or OS compared with chemotherapy alone
using carboplatin and paclitaxel. Lack of OS improvement was also
observed in the two randomized phase III studies in the first-line
setting, the Evaluation of Sorafenib, Carboplatin, and Paclitaxel
Efficacy (ESCAPE) 13 and NSCLC Research Experience Utilizing
Sorafenib (NExUS), 14 as well as in previously treated patients. 15,16
Motesanib is a small-molecule targeted antagonist of VEGF receptors
1, 2, and 3, PDGFR, and KIT. In the phase IB study, five (17%)
of 29 patients who were treated with motesanib (50 mg per day, 125
mg per day, or 75 mg twice per day) in combination with carboplatin
and paclitaxel achieved partial response. Because of increased toxicity,
the twice-daily cohort was discontinued. The recommended motesanib
dose for subsequent studies was 125 mg once per day, which had
already been established as the maximum-tolerated dose for singleagent
therapy. 17 In the phase II study, 18 there were no significant
differences in outcomes between patients treated with carboplatin
plus paclitaxel and either bevacizumab or motesanib. In the article that
accompanies this editorial, Scagliotti et al 19 present the results of the
Motesanib NSCLC Efficacy and Tolerability (MONET1) trial, a multicenter,
randomized, double-blind phase III trial comparing carboplatin
and paclitaxel alone or in combination with motesanib 125 mg
per day as first-line therapy for NSCLC. The primary end point was
OS. All tumor types were initially included, but squamous cell carcinoma
was excluded after increasing gross hemoptysis and mortality
among the first 223 patients with this histology; this ultimately left
1,090 randomly assigned patients with nonsquamous histology for
evaluation. Although the overall RR was higher in the motesanib arm
(40% v 26%;P
.001), the median PFS was only minimally improved
(5.6 v 5.4 months; P
.001) and median OS was not significantly
improved (13 months v 11 months; hazard ratio, 0.90; P.14). In a
preplanned analysis, the 287 Asian patients were the only subset of
patients associated with improved survival from motesanib (hazard
ratio, 0.75; 95% CI, 0.59 to 0.97). Toxicity was significantly higher in
the motesanib arm, with incidence of serious adverse effects of 49%
compared with 34% in the chemotherapy alone arm. The motesanib
arm was associated with increased incidence of diarrhea, nausea, vomiting,
abdominal pain, hypertension, proteinuria, stomatitis, gallbladder
disorders, neutropenia, and thrombocytopenia. Levels of placental
growth factor, thought from previous studies to increase in response to
motesanib, were not associated with RR or survival. Therefore, MONET1
joins the growing list of studies that show no significant benefit from the
addition of multitargeted TKIs to chemotherapy.
Although the reason that TKIs failed to improve survival when
combined with chemotherapy is still unclear, this phenomenon has
been previously observed among patients treated with epidermal
growth factor receptor (EGFR) inhibitors; neither gefitinib 20,21 nor
erlotinib 22,23 showed survival improvement when added to chemotherapy.
However, the addition of the monoclonal antibody cetuximab
to chemotherapy produced mixed results, with improved
survival in the Cetuximab Plus Chemotherapy in Patients With Advanced
Non–Small-Cell Lung Cancer (FLEX) study 24 but not in the
Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced
Non–Small-Cell Lung Cancer (BMS-099) study. 25
[snip]
In addition to the lack of survival benefit in NSCLC, multitargeted
antiangiogenic TKIs have been associated with significant
toxicity. Recent meta-analyses evaluating the adverse effects of the
two most commonly used TKIs, sorafenib and sunitinib, in multiple
malignancies showed that these drugs were associated with
increased risk of bleeding (relative risk, 2.0; P  .015), 33 arterial
thrombotic events such as cardiac or cerebrovascular events (relative
risk, 3.03; P  .015), 34 and treatment-related mortality (relative
risk, 2.23; P  .023). 35 Therefore, TKIs to be used in
combination with chemotherapy should be carefully selected to
avoid major adverse effects.
[snip]