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Several new drugs, such as the recently approved panitumumab, could change standards for frontline treatment of colorectal cancer. Here, evidence for the drug’s use in managing mCRC is summarised
Department of Oncology
University of Navarra
Advanced colorectal carcinoma (aCRC) remains a major public health concern worldwide. It represented the second most common cancer type among men and women in Europe in 2006 (412,900 new cases). Furthermore, aCRC constituted
the second-leading cause of death in cancer patients in Europe during the same year (207,400 deaths).
On the one hand, several surgical approaches provide low recurrence rates and high survival expectancy in localised-stage colorectal tumour patients. In addition, adjuvant chemotherapy regimens have been shown to effectively improve those rates.
On the other hand, however, metastatic colorectal cancer (mCRC) is still far from curable. The ultimate aims in treating stage IV colorectal cancer are to decrease tumour-related symptoms and prolong progression-free survival (PFS) with acceptable toxicity. In the frontline setting, the highly selective therapeutic monoclonal antibodies bevacizumab and cetuximab have been incorporated into the chemotherapy arsenal and have definitely improved prognoses for aCRC subjects, reaching an overall survival (OS) over two years.
This has dramatically encouraged the search for other therapies targeted at various fundamental checkpoints in colorectal carcinogenesis in first- and second-line scenarios. The epidermal growth factor receptor (EGFR) signalling pathway is a major target for several drugs being developed. The EGFR inhibitor most recently approved by the FDA6 for refractory aCRC is
panitumumab (VectibixTM), in 2006. This article summarises
some of the new evidence supporting use of panitumumab in the systemic management of mCRC.
The EGFR family as a cancer treatment target
The EGFR signalling pathway constitutes an attractive and effective target for developing cancer therapies, since the molecular structure of the receptor and its tyrosine kinases are well determined. In fact, one of the first targeted therapies shown to be effective against cancer was trastuzumab, a humanised antierbB2 (EGFR family member) monoclonal antibody. In 1998, trastuzumab was approved in the USA for
use in combination with chemotherapy against erbB2- expressing metastatic breast tumours. The addition of trastuzumab to chemotherapy (paclitaxel or doxorubicin and cyclophosphamide) was associated with a longer time to disease progression (median, 7.4 vs 4.6 months; p<0.001), a higher rate of objective response (50% vs 32%, p<0.001), a longer duration of response (median, 9.1 vs 6.1 months; p<0.001), a lower rate of death at one year (22% vs 33%, p=0.008), longer survival (median survival, 25.1 vs 20.3 months; p=0.01) and a 20% reduction in the risk of death.
Other successfully developed EGFR signalling pathway inhibitors are cetuximab (against erbB1), commonly used in colorectal and head and neck cancer, lapatinib, approved for metastatic breast cancer (against erbB1 and erbB2), and gefitinib (against erbB1) or erlotinib (against erbB1), fundamentally active against non-small-cell lung cancer. There are two basic types of EGFR inhibitors – monoclonal antibodies against the receptor and small molecules that inhibit the receptor tyrosine kinases (TKIs), as shown in Figure 1.
Panitumumab for colorectal cancer treatment
Panitumumab, the first fully human IgG2 monoclonal antibody directed against EGFR, binds to EGFR (erbB1) and prevents receptor dimerisation, EGFR-tyrosine autophosphorylation and activation of downstream signalling molecules, inhibiting cellular
proliferation and tumour growth, and inducing apoptosis (see Figure 1).
In September 2006 the FDA approved panitumumab for treating patients affected by EGFR-expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. In addition, the European Committee for Medicinal Products for Human Use has recommended conditional marketing authorisation for panitumumab in the EU for patients with refractory mCRC with nonmutated (wild-type) KRAS genes.
Panitumumab’s approval is based on the results of a single phase III open-label randomised multinational study. This study enrolled 463 patients with EGFR-expressing (at least 1+ membrane staining in >1% of tumour cells) mCRC. The main results of this study are set out in Table 1. Patients were assigned to best supportive care with or without panitumumab, 6mg/kg IV, every other week. The primary study endpoint was PFS. Best supportive care patients who progressed were eligible to receive panitumumab. All patients enrolled were refractory to standard chemotherapy regimens containing fluoropyrimidines
and oxaliplatin or irinotecan (FOLFOX/FOLFIRI). Median PFS was
eight weeks in the panitumumab arm and 7.3 weeks in the best supportive care group, and mean PFS was 13.8 weeks and 8.5 weeks, respectively. Response rate (RR) was 10% in the panitumumab group, whereas no responses were observed in the best supportive care arm. The main toxicities seen were rash, diarrhoea and hypomagnesaemia, all considered mild. No advantage was found in overall survival due to the crossover,
but it resulted in a 46% reduction in risk of tumour progression.
Similar efficacy results were obtained from those 176 patients assigned to best supportive care who, after progression, were administered panitumumab, according to a later communication by the same authors.
In addition to this encouraging study, several other trials have tested panitumumab’s role in monotherapy for pretreated aCRC patients, as shown in Table 1. A phase II open-label multicentre study recruited 148 advanced EGFR-positive CRC individuals, after progression on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients received panitumumab 2.5mg/kg weekly for eight of
every nine weeks, until disease progression. Hecht et al showed a 9% RR with 29% of stable disease (SD). Median PFS was 14 weeks, and median overall survival was nine months. In total, 95% of patients appeared with skin toxicity, but only 5% showed grade 3 or 4. In a different clinical trial, panitumumab
was also administered as a single agent to 91 aCRC pretreated patients with negative or low EGFR expression by immunohistochemistry. They showed 36-42% of disease control, with a median duration of response of 20-22 weeks
and a median PFS of eight weeks. Skin rash and hypomagnesaemia were the main toxicities.
These results have prompted other investigators to test panitumumab’s efficacy in combination with chemotherapeutic compounds and other targeted therapies.[17,18]
For instance, a two-part multicentre study of panitumumab
2.5mg/kg weekly with irinotecan, 5-fluorouracil (5-FU) and leucovorin used bolus 5-FU (IFL) in part one and infusional 5-FU (FOLFIRI) in part two (see Table 1). Objective response rates observed were 46% and 42% in parts one and two, respectively. Respective disease control rates were 74% and 79%; median PFS (95% confidence interval) was 5.6 months
(4.4-8.3 months) and 10.9 months (7.7-22.5 months); median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) and 22.5 months (14.4 months to not estimable). However, panitumumab showed better tolerability combined with FOLFIRI than with IFL. In fact, grade 3/4 diarrhoea occurred in 11 patients (58%) treated with IFL but only six (25%) treated with FOLFIRI. All patients had a skinrelated toxicity (no grade 4 events).
Another study compared panitumumab in combination with standard chemotherapy and bevacizumab with standard chemotherapy and bevacizumab without panitumumab. Preliminary results seem promising, but potential higher toxicity should be evaluated in a larger series of patients. Especially interesting is a recent suggestion of significantly prolonged PFS
and overall survival in patients with more severe skin toxicity.
In recent years, the addition of new targeted therapies to the armamentarium against cancer has been reflected in quality-of-life improvement, enhanced PFS and even overall survival advantage for patients diagnosed with aCRC. In fact, since 2004, three new “technological” drugs – cetuximab, bevazumab and panitumumab – have been approved for this indication. The most recent arrival, panitumumab, has shown substantial benefit for refractory patients regarding PFS when employed as a single agent in CRC. Differences in overall survival were not observed compared with best supportive care,
but this might be inferred by crossover of 76% of the best supportive care patients to the treatment arm after progression.
Nevertheless, it is well known that adding these therapies to standard chemotherapy regimens usually results in response rate and overall survival improvements. Actually, this effect has been partially observed in a recent study with panitumumab combined with IFL and FOLFIRI regimens in colorectal cancer. Ongoing controlled clinical trials are aimed at resolving this
question. The next few years will show us the proper way to combine and the best subset of patients to whom these novel different combinations of therapies should be offered as a first-line regimen.
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