Tabernero_edit_Layout 1 01/10/2009 13:37 Page 66
Colorectal Cancer
and OS (median 12.5, 10.7 and 10.7, respectively; p<0.0024). advantage in median PFS was not met (7.7 versus 7.6 months in the
Bevacizumab has been approved in the second-line setting in PTK/ZK and placebo arms, respectively; p=0.11). Nevertheless,
combination with chemotherapy in patients with mCRC. patients with high levels of lactate dehydrogenase (LDH) who
received valatinib achieved a significant improvement in median PFS
When oxaliplatin-based chemotherapy was combined with compared with patients with high levels of LDH who received
bevacizumab (FOLFOX or CAPOX) in the first-line setting the placebo (7.7 versus 5.8 months, respectively; p=0.010), suggesting
expected benefit was proved too, albeit to a lesser magnitude. A that LDH could be a predictive marker. The second trial was
randomised 2x2 factorial phase III trial was presented by Cassidy.
12
In performed in previously treated mCRC patients with identical
this study, 1,401 untreated mCRC patients were randomised to one of randomisation, but the primary end-point was to demonstrate an
four arms: CAPOX (capecitabine plus oxaliplatin) plus placebo, improvement in median OS (CONFIRM 2).
16
While the primary
CAPOX plus bevacizumab, FOLFOX plus placebo or FOLFOX plus objective was not met (12.1 versus 11.8 months in the valatinib and
bevacizumab. The results of the study met the primary end-points: placebo arms, respectively; p=0.511), median PFS was significantly
CAPOX was non-inferior to FOLFOX with a similar safety profile and longer in the valatinib-containing arm (5.5 versus. 4.1 months,
offered the advantage of oral fluoropyrimidine administration. respectively; p=0.026). Patients with higher levels of LDH showed the
Bevacizumab added clinically meaningful and statistically superior greatest benefit in median PFS with the addition of valatinib (5.6
benefit in terms of PFS (eight months in the placebo arms versus 9.4 versus 3.8 months, respectively; p<0.001). A meta-analysis of these
months in the bevacizumab arms; p=0.0023). two randomised phase III trials aimed at determining clinical benefit
in PFS in patients with high LDH levels was conducted. The study
The observational cohort study Bevacizumab Regimens: suggests that valatinib improves PFS in this subgroup of patients.
17
Investigation of Treatment Effects and Safety (BRITE) has recently More recently, an early press release has announced that the phase
been published suggesting that continuation of VEGF inhibition with III study SUN1122 that was evaluating sunitinib plus FOLFIRI versus
bevacizumab beyond initial progression could prolong OS.
13
Two FOLFIRI alone in the first-line treatment of mCRC was discontinued,
ongoing prospective randomised trials (ML18147 and SWOG S0600) having failed to achieve its primary end-point.
18
are comparing the value of adding bevacizumab to second-line
chemotherapy after failing first-line chemotherapy in combination Targeting Epidermal Growth Factor Receptor
with bevacizumab in patients with mCRC. The epidermal growth factor receptor (EGFR) is a member of the
family of transmembrane protein kinase receptors known as the erbB
The efficacy demonstrated in mCRC with bevacizumab generates the or HER receptor family. EGFR is overexpressed in 75–90% of CRC and
question of its usefulness in the adjuvant setting. At the last it seems to confer a poor prognosis.
19
While multiple strategies of
American Society of Clinical Oncology (ASCO) meeting, Wolmark targeting the EGFR are under development, two modalities have been
presented the results of the National Surgical Adjuvant Breast and the most developed: small molecule inhibitors of the intra-cellular
Bowel Project (NSABP) C-08 trial.
14
The objective of this two-arm kinase domain of the EGFR and molecular antibodies designed to
randomised, prospective study was to determine whether block the extra-cellular ligand-binding domain of EGFR. Currently,
mFOLFOX6 plus bevacizumab was superior to the chemotherapy several trials have reported that K-Ras mutations are associated with
alone in terms of disease-free survival (DFS). A total of 2,672 patients lack of response to anti-EGFR monoclonal antibodies. K-Ras mutations
with stage II (24.9%) and III CRC were included in the study. The HR are found in about 40% of CRC and a high concordance between
was 0.89 (95% CI 0.76–1.04; p=0.15), the study failing to demonstrate primary tumour and related metastases has been reported.
statistically significant prolongation of DFS. The international
community is awaiting the results of some other trials that are Cetuximab, the most advanced anti-EGFR agent in clinical development,
evaluating the role of bevacizumab in the adjuvant setting, such as and panitumumab, a fully human monoclonal antibody against EGFR,
the AVANT and the QUASAR2 studies. In the AVANT trial, patients with have been approved in the US and in Europe for the treatment of mCRC
high-risk stage II and stage III colon cancer after radical surgery are K-Ras wild-type patients. The approval for cetuximab is in combination
randomised to one of three arms: FOLFOX4 alone (control arm), with chemotherapy in first-line and in the refractory setting whereas
FOLFOX4 plus bevacizumab or XELOX plus bevacizumab. panitumumab has only been approved as a single-agent treatment in
the refractory setting. Nevertheless, the FDA has not yet positioned on
The inhibition of tyrosine kinase (TKI) signalling of VEGFR is another the K-Ras mutation status-based indication for both compounds.
strategy to hinder tumour-induced angiogenesis. A variety of small-
molecule tyrosine TKIs targeting the VEGF receptors are being Both anti-EGFR monoclonal antibodies were originally developed in the
developed such as PTK-787 (valatanib), SU-5416 (semaxanib), SU- refractory setting. The pivotal study for the approval of cetuximab in
11248 (sunitinib), AZD-2171 (cediranib), BAY-43-9006 (sorafenib) and the refractory setting was the BOND randomised phase II study.
20
In this
ZD-6474 (vandetanib). Of these compounds, three drugs have failed study, patients refractory to irinotecan-based chemotherapy (and half
so far to demonstrate additional clinical benefit when combined with of them also previously treated with oxaliplatin-based chemotherapy)
standard chemotherapy schedules. Semaxanib was the first to fail with EGFR-expressing tumours were randomised to receive cetuximab
clinical development, with an early interruption of the registrational plus irinotecan (218 patients) versus cetuximab alone (111 patients).
20
studies. More recently, valatanib was the first TKI to complete the The combination arm was the most effective, with a RR of 23% (11%
clinical evaluation. Two randomised phase III studies have evaluated with cetuximab alone; p=0.007), and a median TTP of 4.1 months (1.5
the efficacy of valatinib in combination with standard chemotherapy months with cetuximab as single agent; p<0.001). The mOS was 8.6
in patients with mCRC. In the first, 1,168 patients with untreated months for cetuximab plus irinotecan and 6.9 months in the cetuximab
mCRC were randomised to receive FOLFOX4 plus valatinib or arm (p=0.48). The switch to the combination arm was allowed for the
FOLFOX4 plus placebo (CONFIRM 1).
15
The primary end-point for an patients who progressed in the monotherapy arm.
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