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Anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab) and chemotherapy in the treatment of metastatic colorectal cancer: the role of KRAS gene mutational status.

Introduction

Recently, Van Cutsem et al. reported the results of a Phase III trial (the CRYSTAL study) in metastatic colorectal cancer (mCRC) patients in first-line therapy [1]. The combination of cetuximab plus FOLFIRI showed a statistically significant increase in response rate (RR) and progression-free survival (PFS) in the KRAS wild-type (wt) population. These results confirm the fact that the addition of cetuximab to first-line chemotherapy in metastatic colorectal cancer (mCRC) improves the clinical outcomes in KRAS wt population.

CRC is the third most common cancer worldwide, with approximately 1 million new cases diagnosed yearly, 25% of patients with CRC present with overt metastatic disease, and metastatic disease develops in 40-50% of newly diagnosed patients [2]. Standard first-line treatments including fluorouracil (5-FU) with leucovorin (LV) and irinotecan or oxaliplatin, alone or combined with bevacizumab, have resulted in a median overall survival (mOS) greater than 20 months [3-9].

The epidermal growth factor receptor (EGFR) is a member of the family of transmembrane protein kinase receptors known as the erbB or HER receptor family: EGFR (HER1 or erbB1), erbB2 (HER2), erbB3 (HER3) and erb4 (HER4). When activated, EGFR phosphorylates and activates two main signalling pathways. These include the RAS-RAF-MAPK axis, which is mainly involved in cell proliferation, and the PI3K-PTEN-AKT pathway, which is mainly involved in cell survival and motility [10,11] (Figure 1). EGFR is overexpressed in 75-95% of CRC and it confers a poor prognosis [12].

While multiples strategies of targeting the EGFR are under development, two modalities are best developed: small-molecule inhibitors of the intracellular kinase domain of the EGFR and monoclonal antibodies (MoAbs) designed to block the extracellular ligandbinding domain of EGFR.

Cetuximab (a chimeric monoclonal immunoglobulin G1 antibody), the most advanced anti-EGFR agent in clinical development, and panitumumab (a fully human monoclonal immunoglobulin G2 antibody) are approved in Europe and in the United States (US) for the treatment of mCRC patients [13,14]. Both molecules bind to the extracellular domain of EGFR, thus leading to inhibition of its downstream signalling. They have proven to be effective in providing clinical benefit in approximately 10-20% of chemorefractory mCRC patients [13-16].

Initially cetuximab and panitumumab were registered for mCRC patients whose tumours expressed EGFR protein as determined by immunohistochemistry. However, it has been clearly demonstrated that this method is not predictive of treatment efficacy [13,15,17]. On the contrary, recent data indicate that EGFR gene status evaluated by fluorescent in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) may predict response to these MoAbs [18-22]. Therefore, the selection or exclusion of patients for cetuximab based on EGFR status is not justified. However, recent results of first-line therapy of cetuximab in combination with chemotherapy have shown effectiveness only in KRAS wt patients [1,23,24].

The KRAS oncogene controls the transduction of signals required for proliferation, differentiation and survival, mainly acting as GDP/GTP-regulated binary switches located at the inner surface of the plasma membrane. Interestingly the KRAS oncogene may harbour activating mutations yielding proteins with reduced GTPase activity [25]. KRAS mutations are found in about 40% of CRC and a high concordance between primary tumour and related metastases has been reported [26,27].

Predictive role of KRAS status in chemorefractory patients

The predictive power of the KRAS mutation status of tumours with regard to their responsiveness to cetuximab or panitumumab has been shown previously in studies with cetuximab/panitumumab alone or in combination with chemotherapy, administered to patients with mCRC that had progressed after previous treatment.

[FIGURE 1 OMITTED]

Lievre et al. screened for KRAS, BRAF, and PI3KCA mutations from 30 mCRC patients treated with cetuximab [28]. KRAS mutant-type (mt) was found in 13 tumours (43%) and was significantly associated with the absence of response to cetuximab (KRAS mt in 0% of the 11 responder patients versus 68.4% of the 19 non-responder patients; P=0.0003). The OS of patients without KRAS mt in their tumour was significantly higher compared with those patients with a mutated tumour (P=0.016; median, 16.3 versus 6.9 months).

Di Fiore et al. studied 59 patients with a chemotherapy-refractory mCRC treated with cetuximab plus chemotherapy [29]. KRAS mutation was detected in 22 out of 59 tumours. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and time to progression (TTP) was significantly decreased in KRAS mt patients.

De Roock et al. studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with cetuximab in clinical trials [30]. mOS was significantly better in KRAS wt versus mutants (43.0 versus 27.3 weeks; P=0.020). Within KRAS wt patients, OS was significantly better in patients with an initial decrease compared with those without (mOS: 74.9 versus 30.6 weeks).

Khambata-Ford et al. published the results of a prospective trial conducted to identify biomarkers associated with disease control in patients treated with cetuximab as a single agent [31]. Gene expression profiles showed that patients with tumours that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab. Additionally, patients whose tumours do not have KRAS mutations have a significantly higher disease control rate than patients with KRAS mutations.

Cappuzzo et al. recently published the results of a study aimed at assessing the impact of KRAS mutations on cetuximab sensitivity in EGFR FISH+ mCRC [32]. This study analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations 52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated patients had a significantly lower RR than EGFR FISH+/KRAS wt patients.

Amado et al. published the predictive effect of the KRAS mutational status in patients included in a Phase III randomised controlled trial of panitumumab plus best supportive care (BSC) versus BSC alone in patients with chemorefractory mCRC [33]. The treatment effect on PFS in the KRAS wt group was significantly greater P<0.0001) than in the mutant group. The RR to panitumumab was 17% and 0%, for the wt and mt groups, respectively. KRAS wt patients had longer OS.

Given the apparent correlation of response to cetuximab with the severity of rash, investigators examined an approach of cetuximab dose escalation in patients with mCRC who had no or slight skin reaction to cetuximab at standard doses (the Evaluation of Various Erbitux Regimens by Means of Skin Tumor Biopsies or EVEREST trial) [34]. Patients were required to have tumours that expressed EGFR and must have progressed through an irinotecan-containing regimen. Three weeks after they started cetuximab, patients who had not experienced greater than a grade 1 skin reaction were randomised either to continue standard-dose cetuximab or to receive dose-escalated cetuximab. Additional evaluation of this study has been conducted to assess if dose escalation can induce response in patients with KRAS mutation [35]. The RR among patients with KRAS wt was 21.1% (4 of 19) for standard-dose cetuximab and 46.4% (13 of 28) for escalating-dose cetuximab. No patients with KRAS mt responded to either regimen. Patients with KRAS mt did not benefit from irinotecan-plus-cetuximab treatment, and cetuximab dose escalation did not increase responses in this population of patients.

All the above studies confirm the ineffectiveness of administering EGFR-targeting MoAbs, such as cetuximab or panitumumab, to chemorefractory mCRC patients with activating mutations in KRAS.

Predictive role of KRAS status in the first-line setting

As in the chemorefractory mCRC population, EGFR inhibitors have been widely studied in the first-line setting and correlated with KRAS status.

At the 2008 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, Tabernero et al. presented the first series in which the KRAS mutational status was correlated with efficacy in patients with mCRC treated in the first-line setting with cetuximab as a single agent and with the irinotecan-based chemotherapy schedule FOLFIRI (5-FU/LV/ irinotecan) [23]. In this Phase I / II study, 48 patients were initially treated with cetuximab as a single agent for 6 weeks and thereafter with cetuximab combined with FOLFIRI. KRAS mutation was detected in 16 (41%) of the tumours. In the cetuximab-alone part of the study, patients with KRAS wt tumours had an objective RR (ORR) of 27.6% compared with 0% for patients with KRAS mt tumours (P=0.015). In the combination part of the study (cetuximab plus FOLFIRI), patients with KRAS wt tumours had an ORR of 55.2% compared with 31.6% for patients with KRAS mt tumours. Conversely, median PFS was 9.4 months in patients with KRAS wt tumours versus 5.6 months in patients with KRAS mt tumours (P=0.0475).

Similar results have also been observed with the combination of cetuximab plus FOLFOX. The influence of KRAS mutation status was investigated in a randomised study that assessed whether the best ORR of cetuximab combined with oxaliplatin, LV and 5-FU (FOLFOX-4) was superior to FOLFOX-4 alone as first-line treatment for mCRC [24]. KRAS mutation status was assessed in the subset of patients with assessable tumour samples (n=233). The ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% versus 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established. In patients with KRAS wt tumours, the addition of cetuximab to FOLFOX-4 was associated with a clinically and statistically significant increased chance of response (ORR: 61% versus 37%; P=0.011) and a lower risk of disease progression compared with FOLFOX-4 alone (Table 1).

The CAIRO2 study evaluated the effect of adding cetuximab to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of mCRC [36]. Additional evaluation of this study has been conducted to assess the influence of KRAS mutation status on clinical outcome. There were no differences in baseline characteristics between patients with KRAS wt or KRAS mt (except higher serum lactate dehydrogenase in the wt population). KRAS mutations were detected in 39% of patients (196 of 502) with evaluable samples. The mPFS was equivalent in both arms of treatment in patients with KRAS wt (10.7 months and 10.5 months). In contrast, the mPFS of patients with KRAS mt treated without cetuximab was 12.5 months compared with 8.6 months for patients treated with cetuximab. The OS was not significantly influenced by KRAS status. This study suggests that, in patients with KRAS mutation, the addition of cetuximab to oxaliplatin-based chemotherapy and bevacizumab results in a significant decrease in PFS.

Van Cutsem et al. reported the results of a Phase III trial (the CRYSTAL study) in mCRC patients in first-line therapy according to the KRAS status [1]. A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The addition of cetuximab to FOLFIRI increases RR [hazard ratio (HR): 1-40; P=0.004]. The hazard ratio for PFS in the cetuximab-FOLFIRI group compared with the FOLFIRI group was 0.85 [95%confidence interval (CI): 0.72-0.99; P=0.048]. There was no significant difference in the OS between the two treatment groups (HR: 0.93; 95%CI: 0.81-1.07; P=0.31). A total of 540 patients were suitable for the analysis of KRAS mutation status, and the incidence of KRAS mutations (36%) was in keeping with previous reports. There was a significant interaction between treatment groups and KRAS mutation status for tumour response (P=0.03) but not for PFS (P=0.07) or OS (P=0.44). The RR in the cetuximab-FOLFIRI group was 59.3%and in the FOLFIRI group 43.2%(OR: 1.91; 95%CI: 1.24-2.93). Among those with KRAS mt, the RR was 36.2%in the cetuximab-FOLFIRI group and 40.2%in the FOLFIRI group (OR: 0.80; 95%CI: 0.44-1.45) The hazard ratio for PFS among patients with KRAS wt tumours was 0.68 (95%CI: 0.50-0.94), in favour of the cetuximab-FOLFIRI group. This study demonstrates that the administration of first-line cetuximab plus FOLFIRI improves RR and reduced the risk of progression of mCRC compared with FOLFIRI alone, and that this benefit is seen mainly in patients with KRAS wt.

These studies show that KRAS mutational status is a highly predictive selection criterion for the treatment decision regarding the addition of cetuximab to chemotherapy for previously untreated patients with mCRC. However, to quantify the benefit of adding cetuximab/panitumumab to chemotherapy, prospective randomised studies are needed.

Conclusions

In the past 5 years, cancer therapy has undergone a major revolution characterised by the introduction of targeted drugs that inhibit specific molecules. Among these, MoAbs (cetuximab and panitumumab) targeting the EGFR have shown remarkable efficacy in the treatment of patients with mCRC. Similar to the other targeted therapies, anti-EGFR drugs are active in only a fraction of patients, and most of them subsequently become resistant to treatments. These recent clinical data confirm that the efficacy of cetuximab and panitumumab is confined to patients bearing KRAS wt in second- and first-line therapy. Administering EGFR-targeting monoclonal antibodies, such as cetuximab or panitumumab, to unselected mCRC patients can no longer be considered the standard of care, as those agents will be ineffective in patients with activating mutations in KRAS.

References

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[31.] Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol, 2007, 25, 3230-3237.

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[36.] Punt CJ, Tol J, Rodenburg CJ et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch colorectal cancer Group (DCCG). J Clin Oncol, 2008, 26, 180s (Abstract LBA4011).

Correspondence to: Josep Tabernero (email: jtabernero@vhebron.net)

Manuel Ruiz-Echarri, Francisco Javier Ramos, Teresa Macarulla, Jaume Capdevila, Elena Elez and Josep Tabernero

Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain
Table 1: Relating KRAS status to efficacy: cross-study comparison
between the CRYSTAL and OPUS studies with
response rate and progression-free survival [1-24].

                      CRYSTAL                   OPUS

               Cetuximab+FOLFIRI (A)     Cetuximab+FOLFOX (A)
                versus FOLFIRI (B)        versus FOLFOX (B)

KRAS status    Wild-type   Mutant-type   Wild-type     Mutant-type

               A     B      A     B       A       B    A        B

PFS (months)   9.9   8.7   7.6   8.1     7.7    7.2   5.5      8.6

HR               0.684        1.07          0.57         1.83

P value          0.02         0.46          0.14         0.0192

RR (%)          59   43     36   40       61     37    33      49

P value          0.003        0.46          0.01         0.11

FOLFIRI, 5-FU/leucovorin/irinotecan; FOLFOX, 5-FU/leucovorin/
oxaliplatin; HR, hazard ratio; PFS, progression-free survival; RR,
response rate.
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Title Annotation:Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
Author:Ruiz-Echarri, Manuel; Ramos, Francisco Javier; Macarulla, Teresa; Capdevila, Jaume; Elez, Elena; Tab
Publication:Advances in Gastrointestinal Cancer
Article Type:Report
Geographic Code:4EUSP
Date:Mar 1, 2009
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Previous Article:How can we treat elderly patients with colorectal cancer?
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