EGFR-targeted therapy in metastatic colorectal cancer

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1 EGFR-targeted therapy in metastatic colorectal cancer What do we know and where are we going? Hagen Kennecke, MD, MHA, FRCPC Abstract N umerous Phase III studies have documented the benefit of panitumumab and cetuximab in first-, second-, and third-line treatment of nonmutated/ wild-type (WT) KRAS metastatic colorectal cancer (mcrc). Doublet 5-fluorouracil-based chemotherapy with irinotecan or oxaliplatin (FOLFIRI or FOLFOX) represents the current standard for first-line treatment of eligible patients. Bevacizumab is recommended by the National Comprehensive Cancer Network (NCCN) clinical practice guidelines, as well as provincial formulary protocols such as Cancer Care Ontario and BC Cancer Agency, to be used in combination with these chemotherapy backbones. In Canada, cetuximab is approved as monotherapy or in combination with irinotecan for patients with EGFR-expressing mcrc WT KRAS with disease progression after treatment with irinotecan or oxaliplatin, and panitumumab is approved as monotherapy for the treatment of patients with EGFR-expressing mcrc with WT KRAS after failure of chemotherapy regimens containing fluoropyrimidine, oxaliplatin and irinotecan. This article reviews the benefits of anti-egfr monoclonal antibodies alone or in combination with standard first-line chemotherapy in first-, second-, and third-line settings to treat mcrc. Background The proliferation of new chemotherapies and targeted biologic treatments coupled with advancements in diagnostic and surgical techniques has doubled the median overall survival (OS) for patients diagnosed with metastatic colorectal cancer (mcrc) in the past 15 years. 1-3 The major treatments currently available to treat mcrc are fluoropyrimidines, irinotecan and oxaliplatin, and 2 in the biologic classes: bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), and cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) Doublet 5-fluorouracil (5FU)-based chemotherapy with irinotecan (5FU/leucovorin/irinotecan [FOLFIRI]) or oxaliplatin (5FU/leucovorin/oxaliplatin [FOLFOX]) represents the current standard for first-line treatment of eligible patients Added to these chemotherapy backbones, bevacizumab is recommended in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines, as well as provincial formulary protocols such as those from Cancer Care Ontario and BC Cancer Agency In Canada, cetuximab is approved as monotherapy or in combination with irinotecan for patients with EGFR-expressing Hagen Kennecke, MD, MHA, FRCPC is a Clinical Assistant Professor, UBC Division of Medical Oncology. hkennecke@bccancer.bc.ca Table 1. Randomized studies of anti-egfr therapy in the first-line PRIME 13 FOLFOX4 + panitumumab vs FOLFOX4 (n=656)* CRYSTAL 14,15 FOLFIRI + cetuximab vs FOLFIRI (n=666) OPUS 16 FOLFOX4 + cetuximab vs FOLFOX4 (n=134) COIN FOLFOX/XELOX + cetuximab vs FOLFOX/XELOX (n=729) NORDIC VII 19 Continuous FLOX vs continuous FLOX + cetuximab (n=566) 23.9 mo vs 19.7 mo p= mo vs 20.0 mo p= Not reported 17.0 mo vs 17.9 mo p= mo vs 20.1 mo vs 21.4 mo 9.6 mo vs 8.0 mo p= mo vs 8.4 mo p= mo vs 7.2 mo p= mo vs 8.6 mo p= mo vs 7.9 mo Not reported 5% vs 48% p= % vs 39.7% 61% vs 37% p= % vs 57% p= % vs 46% vs 51% OS=overall survival; PFS=progression-free survival; RR=relative response; FOLFOX=fluorouracil (5FU)/leucovorin/oxaliplatin; FOLFIRI=5FU/leucovorin/irinotecan; XELOX=capecitabine/ oxaliplatin; FLOX=bolus 5FU/leucovorin/oxaliplatin *patients with WT KRAS tumours; primary endpoint e-22 oe VOL. 11, No. 2, May 2012

2 mcrc with nonmutated/wild-type (WT) KRAS with disease progression after treatment with irinotecan or oxaliplatin. Panitumumab is approved as monotherapy for the treatment of patients with EGFR-expressing mcrc with WT KRAS after failure of chemotherapy regimens containing a fluoropyrimidine, oxaliplatin and irinotecan In a retrospective US study, analysis of records for 1655 adult patients with mcrc who were treated from January 1, 2004, to January 31, 2008, revealed that the most commonly used chemotherapy backbones for mcrc treatment were first-line FOLFOX and second-line FOLFIRI, with bevacizumab being the most frequently administered biologic therapy. Continuation and dose escalation with bevacizumab were frequently observed across lines of therapy. During the study period, 68.6%, 22%, and 7% of patients received bevacizumab, cetuximab and panitumumab, respectively. 12 Anti-EGFR in first-line setting Numerous Phase III studies have reported on the benefit of adding anti-egfr monoclonal antibodies (mabs) to standard firstline chemotherapy In the PRIME study, patients were treated with FOLFOX4 + panitumumab vs FOLFOX4 in a first-line setting WT KRAS patients with mcrc experienced an OS of 23.9 months vs 19.7 months (p=0.072), progression-free survival (PFS) of 9.6 months vs 8.0 months (p=0.02), and response rate (RR) of 55% vs 48% (p=0.068), respectively. Metastastectomy of any site was attempted in 10.5% of patients treated with FOLFOX4 + panitumumab and 9.4% of patients treated with FOLFOX4 with WT KRAS status. 13 In an analysis of WT KRAS patients in the CRYSTAL the trial, the combination of FOLFIRI + cetuximab vs FOLFIRI in the firstline setting demonstrated an OS of 23.5 months vs 20.0 months (p=0.0093), PFS of 9.9 months vs 8.4 months (p=0.0012), and RR of 57.3% vs 39.7% (), respectively In contrast to this, the COIN study was a large trial evaluating anti-egfr treatment in first-line advanced CRC in a prospective OS analysis by KRAS mutation status. The study demonstrated that while the addition of cetuximab to oxaliplatin-based chemotherapy did increase the RR in patients with WT KRAS (p=0.049), it did not improve PFS or OS among KRAS WT patients Another randomized Phase III trial, NORDIC-VII, evaluated the use of bolus FU/leucovorin/oxaliplatin (FLOX) given alone, continuously or intermittently with cetuximab in first-line treatment of mcrc. With a median PFS of 8 months, OS of 20 months and overall response rate (ORR) >40%, cetuximab did not provide a significant additional benefit when combined with Nordic FLOX. While BRAF mutation was a strong negative prognostic factor, KRAS mutation status was not found to be predictive for cetuximab effect, althought the study was not powered to investigate KRAS subpopulations. 19 The lack of benefit of anti-egfr therapy in the latter two Phase III studies is difficult to explain. It has been postulated that chemotherapy schedule may play a role. In the COIN study, benefit of cetuximab therapy was observed among FOLFOX (HR=0.72) but not in the capecitabine/oxaliplatin (XELOX) Table 2. Randomized studies of anti-egfrs in the second-line FOLFIRI + panitumumab vs FOLFIRI 25 (n=597) EPIC 26 Irinotecan + cetuximab vs irinotecan (n=1298)* PICCOLO 27 Irinotecan + panitumumab vs irinotecan (n=460) 14.5 mo vs 12.5 mo p= mo vs 10.0 mo p=0.71 HR=0.91 p= mo vs 3.9 mo p= mo vs 2.6 mo HR=0.78 p= % vs 10% 16.4% vs 4.2% 34% vs 12% OS=overall survival; PFS=progression-free survival; RR=relative response; FOLFIRI=5FU/leucovorin/irinotecan * Unselected patient population; primary/co-primary endpoint (HR=1.04) subgroups, 18 while the FLOX regimen used in the NOR- DIC-VII study represents an unconventional regimen that includes bolus but not infusional 5-FU. A high proportion of BRAF mutant tumours (20%) was documented among patients with KRAS WT mcrc in the NORDIC-VII study. This may have mitigated any benefit of cetuximab, as BRAF mutant tumours have not been consistently shown to benefit from anti-egfr therapy and are associated with significantly shorter OS durations. 19 Overall, results point to a benefit of combining anti-egfr mab to standard, first-line chemotherapy. This has led to the approval of panitumumab and cetuximab in first-line therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Hepatic resection A consistent observation in the Phase II and III anti-egfr studies has been the significant improvement in response rate when cetuximab or panitumumab are added to chemotherapy. Increased RRs are associated with an increased rate of hepatic resection, 20 which is particularly relevant among patients with potentially resectable, liver-only mcrc. Such patients represent approximately 15-25% of all patients with mcrc and have been shown to achieve 5-year OS rates of 40-60% when resection can be achieved. 21 Rate of hepatic resection was higher with cetuximab than chemotherapy alone in the CRYSTAL study (5 vs 2%), and in the OPUS study (4.7% vs 2.4%). 16 Very high response rates and hepatic resection rates have also been described among a series of single-arm and randomized Phase II studies. 16,20,24 While randomized studies are awaited to define the optimal first-line biologic therapy in combination with chemotherapy, combination anti-egfr therapy represents an attractive option among patients with liver-only mcrc when downstaging is required prior to hepatic resection. oe VOL. 11, No. 2, May 2012 e-23

3 Table 3. Randomized studies of anti-egfrs in third-line Cetuximab vs cetuximab + irinotecan 28 (n=329)* Cetuximab vs BSC 29 (n= 394) Panitumumab vs BSC 30 (n=463) 6.9 mo vs 8.6 mo p= mo vs 4.8 mo 8.1 mo vs 7.6 mo p=n/s 1.5 mo vs 4.1 mo 3.7 mo vs 1.9 mo 12.3 weeks vs 7.3 weeks * KRAS unselected patients; primary endpoint; BSC=best supportive care 10.8% vs 22.9% P= % vs 0% 17% vs 0% Anti-EGFR in second-line setting The benefit of EGFR-targeted therapy has also been evaluated in the second-line setting Combination FOLFIRI and panitumumab vs FOLFIRI in the treatment of WT KRAS patients with mcrc demonstrated OS of 14.5 months vs 12.5 months (p=0.12), PFS of 5.9 months vs 3.9 months (p=0.004), and RR of 35% vs 10% (), respectively. 25 In another study, EPIC, the use of irinotecan + cetuximab combination vs irinotecan in the treatment of KRAS-unselected patients with mcrc demonstrated OS of 10.7 months vs 10.0 months (p=0.71), PFS of 4.0 months vs 2.6 months (), and RR of 16.4% vs 4.2 (), respectively. 26 In the PICCOLO study, 1198 patients with advanced colorectal cancer previously treated with fluoropyrimidines +/- oxaliplatin were randomized to irinotecan with or without panitumumab. Of 1198 randomized, 460 were found to be KRAS12,13,61-WT and were included in the primary analysis. The study did not meet its primary objective of improved OS (HR=0.91, p=0.44), but it showed major improvements in PFS (HR=0.78, p=0.01) and RR (12% vs 34%, ). 27 In further subgroup analysis, there was a trend toward shorter OS with panitumumab among patients with WT KRAS but a mutation in BRAF, NRAS, KRAS146 or PIK3CA (n=133; OS HR=1.47, p=0.057). This was significant in BRAF-mutated patients (n=63, OS HR=2.03, p=0.02). 27 Anti-EGFR in third-line setting The use of anti-egfrs in the third-line setting has been shown to improve survival of patients with mcrc in Phase II and III randomized controlled trials Cetuximab + irinotecan vs cetuximab in the treatment of KRAS unselected patients with mcrc demonstrated OS of 8.6 months vs 6.9 months (p=0.48), PFS of 4.1 vs 1.5 months (), and RR of 22.9% vs 10.8% (p<0.007), respectively. 28 Cetuximab vs best supportive care (BSC) in the treatment of WT KRAS patients with mcrc demonstrated OS of 9.5 months vs 4.8 months (), PFS of 3.7 months vs 1.9 months (), and RR of 12.8% vs 0% (), respectively. 29 Panitumumab vs BSC in the treatment of WT KRAS patients with mcrc resulted in improved PFS of 12.3 weeks vs 7.3 weeks () and RR of 17% vs 0% (), respectively. OS was not improved, as the majority of patients in the control arm crossed over to panitumumab. 30 What biomarkers should be used to select for anti-egfr therapy? The identification of KRAS as a strong predictive marker for anti-egfr therapy was a belated discovery 30 such that virtually all reported Phase III studies with cetuximab or panitumumab have included both KRAS mutant and WT tumours. It has been a consistent observation that when KRAS mutations in codon 12 or 13 are considered together, no benefit of cetuximab or panitumumab therapy is seen. However, 2 recent studies have pointed to potentially differing behaviour in KRAS codon 13D mutations, suggesting an inferior prognosis when treated with chemotherapy alone but a potential benefit with cetuximab, with an effect size similar to that of patients with KRAS WT tumours. 27,31,32 The studies were limited by their relatively small sample sizes. These findings were not reproduced in a combined analysis of the 3 reported RPH III trials of panitumumab. A total of 2,877 patients with known KRAS status in the first- (PRIME), 13 second- and thirdline studies of panitumumab therapy in mcrc were included. 25,27,30 In comparison to other codon 12 and 13 KRAS mutations, KRAS 13D did not confer an inferior prognosis when treated with chemotherapy or BSC alone. There was no benefit of panitumumab therapy in any of the 3 treatment lines in KRAS 13D mutant patients. The KRAS 12V but not the 13D mutation was associated with improved OS when treated with panitumumab in the first-line PRIME study. 13 Given these results, at this time there is insufficient evidence to warrant the use of cetuximab or panitumumab in patients with any codon 12 or 13 mutations. Further analysis may become available from the COIN and NORDIC studies. Other RAS and BRAF mutations Numerous studies have reported on the prognostic effect of other KRAS, NRAS and BRAF mutations. KRAS mutations in codons 61 and 146 have been reported and appear to have a similar, negative predictive effect, but numbers are too small to draw statistically significant conclusions. 17,18,31,27 V600 BRAF mutations have been documented with a frequency of 6-20% exclusively among patients with KRAS WT tumours and confer a significantly inferior OS. 19,31,33 It is not clear whether there is a benefit in treating these patients with anti-egfr therapy. In a combined analysis of BRAF mutant patients in the OPUS and CRYSTAL studies, there was a nonstatistically significant trend to improved OS, PFS and RR among patients treated with cetuximab vs chemotherapy alone. 14,15,34 However, subsequent randomized studies (NORDIC, COIN, PICCOLO) have demonstrated no benefit (or potential harm) of anti-egfr therapy in BRAF-mutant mcrc ,27 It is likely that BRAF-mutant mcrc represents a distinct molecular subtype 35,36 that responds poorly to most currently available therapies and for which alternate treatments are urgently required. e-24 oe VOL. 11, No. 2, May 2012

4 Current clinical trials Given the documented benefit of anti-egfr therapy in first-, second- and third- line therapy, a relevant question is: What is the optimal time to introduce panitumumab or cetuximab in the management of mcrc? 37,38 CALGB 80405/CRC05 is a randomized Phase III study comparing first-line therapy with bevacizumab vs cetuximab with either FOLFOX or FOLFIRI among KRAS WT patients with previously untreated mcrc. The study initially included a dual biologic arm, which was subsequently closed due to inferior outcomes with combination panitumumab/bevacizumab in the PACCE study. 39 The primary objectives are to compare OS of patients treated with cetuximab and/or bevacizumab in combination with either FOLFOX or FOLFIRI. Secondary objectives are to compare response, PFS, time to treatment failure, and the proportion of patients with unresectable disease who become eligible for surgical resection after treatment with these regimens. 37 The randomized Phase II PEAK study, which has recently completed accrual, was designed to compare the efficacy and safety of panitumumab + mfolfox6 vs current standard of care of bevacizumab + mfolfox6 as first-line treatment in patients with mcrc tumours expressing WT KRAS. The primary objective is to estimate the effect on PFS of panitumumab + mfolfox6 vs bevacizumab + mfolfox6. 38 Conclusions Numerous Phase III studies have documented the benefit of panitumumab and cetuximab in the treatment of first-, second-, and third-line KRAS WT mcrc. Improvements in PFS and OS were demonstrated, and a high proportion of patients experienced dermatologic toxicities. Based on the available evidence, these agents should be considered for eligible patients in all 3 treatment settings. When used in combination with chemotherapy, suitable regimens include FOLFIRI, FOLFOX or irinotecan. Until further evidence is published, it may be prudent to avoid combination therapy with XELOX or nonconventional chemotherapy regimens. KRAS WT status in codon 12 and 13 remains a valid biomarker for use of anti-egfr therapy while the predictive value of BRAF mutation status is not fully established. High RRs are seen in Phase II/III studies and point to a particular relevance of anti-egfr combination therapy in patients with potentially resectable, liver-limited mcrc. Head-to-head trials of standard chemotherapy with cetuximab/panitumumab vs bevacizumab will help answer the question of which biologic therapy should be used in the first-line setting. Given the heterogeneity among patients and tumour subtypes, it seems unlikely that a single regimen will be suitable for all patients. Previous studies of mcrc have demonstrated that populationbased gains in OS occur when patients are treated with all effective chemotherapy agents 40,41 and that this principle applies to biologic therapies as well. 42,43 At the current time in Canada, panitumumab and cetuximab are restricted to patients previously treated with irinotecan, oxaliplatin and fluorouracil. A population-based Canadian study found that in 2006 only 35% of chemotherapy treated patients with mcrc received both irinotecan and oxaliplatin. 42 As approximately 60% of these will have KRAS WT tumours, it is likely that in the current Canadian setting, only an estimated 20% of patients with mcrc receive anti-egfr therapy. If EGFR-directed therapy is to result in population-based improvements in OS similar to those seen with bevacizumab, oxaliplatin and irinotecan, 40,42,43 it may be necessary to expand access to panitumumab and cetuximab in all advanced treatment settings. This will allow better patient access to individualized and evidence-based therapy. Acknowledgments The author wishes to thank the medical writer, Flora Krasnoshtein, MSc, for her writing assistance on the manuscript. References 1. Goldberg RM, Rothenberg ML, Van Cutsem E et al. The continuum of care: A paradigm for the management of metastatic colorectal cancer. Oncologist 2007;12: Gruenberger T, Schuell B, Puhalla H et al. Changes in liver surgery for colorectal cancer liver metastases under neoadjuvant treatment strategies. Eur J Surg 2004;36: Falcone A, Fornaro L, Loupakis F et al. Optimal approach to potentially resectable liver metastases from colorectal cancer. 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