Integration of panitumumab into the treatment of colorectal cancer

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1 Critical Reviews in Oncology/Hematology 74 (2010) Integration of panitumumab into the treatment of colorectal cancer Cristina Gravalos a,, Javier Cassinello b, Pilar García-Alfonso c, Antonio Jimeno d a Medical Oncology Department, University Hospital 12 de Octubre, Avda. de Andalucía s/n Km 5.400, Madrid, Spain b Medical Oncology Department, University Hospital of Guadalajara, Guadalajara, Spain c Medical Oncology Department, University Hospital of Gregrorio Marañón, Madrid, Spain d University of Colorado Cancer Center, Aurora, CO, USA Accepted 18 June 2009 Contents 1. Introduction Panitumumab as single agent Phase I clinical trials Phase II clinical trials Phase III clinical trials Panitumumab in combination with chemotherapy First line setting Second line setting Tolerance profile Predictive factors KRAS mutation BRAF mutation Number of copies of the EGFR gene Skin rash Comparison between panitumumab and cetuximab Conclusions Conflict of interest Reviewers References Biography Abstract Conventional chemotherapy increases progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mcrc) patients versus best supportive care (BSC). However, the efficacy of chemotherapy is limited. Recently approved monoclonal antibodies (MoAb) have a different mechanism of action, targeting growth factors or their receptors. Panitumumab is a fully human IgG2 MoAb directed against the epidermal growth factor receptor (EGFR). In phase II trials, panitumumab showed preliminary activity in chemorefractory mcrc. This efficacy was confirmed in a randomized pivotal phase III trial, which compared single-agent panitumumab plus BSC versus BSC alone. Several ongoing clinical trials are evaluating panitumumab in combination with different chemotherapy regimens in first- and second-line settings. Skin toxicities, hypomagnesemia, and diarrhea are the most common adverse events associated with anti-egfr therapy. KRAS status and skin rash have been correlated with panitumumab efficacy. Corresponding author. Tel.: ; fax: addresses: cgravalos@telefonica.net, cgravalos@terra.es (C. Gravalos) /$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) This article reviews the preclinical and pharmacokinetics data, activity and tolerance of panitumumab in mcrc patients. Potential predictive factors of response are also discussed Elsevier Ireland Ltd. All rights reserved. Keywords: Panitumumab; Colorectal cancer; EGF receptor; Monoclonal antibodies 1. Introduction Colorectal cancer (CRC) represents the third most commonly diagnosed malignancy after lung and breast cancers worldwide, accounting for an estimated 1,023,256 new cancer cases and 529,020 cancer deaths per year [1]. For more than 40 years, 5-fluorouracil (5FU) was the only antitumoral agent with demonstrated activity in metastatic CRC (mcrc). More recently, newer cytotoxic drugs oxaliplatin, irinotecan and oral fluoropyrimidines were incorporated to the armamentarium against CRC. In the first line setting, bolus and continuous infusion 5FU plus leucovorin (LV) in combination with oxaliplatin (FOLFOX4) or with irinotecan (FOLFIRI) increased response rate (RR) and prolonged survival versus (vs) the same regimen of 5FU alone [2,3]. Lately, FOLFOX and FOLFIRI were compared to each other with similar results [4]. Thus, these two regimens have been accepted as first line chemotherapy (CT). Nevertheless, in spite of significantly improved response rate and survival, it appears that efficacy of CT in mcrc has reached a plateau. There is a need to develop novel therapies, and agents targeting abnormally active biologic pathways are ideal candidates as they tackle the key alterations conferring the cancer phenotype while having a non-overlapping toxicity profile with conventional CT. Monoclonal antibodies (MoAb) are drugs with a mechanism of action based on an antibody epitope interaction and they target growth factors or their receptors [5]. The epidermal growth factor receptor (EGFR), a cell membrane glycoprotein, is a member of the tyrosine kinase receptor family, which includes the epidermal growth factor receptor (HER) 1 (EGFR; HER1 or c-erbb-1), HER2, HER3 and HER4. EGFR is expressed in many normal epithelial tissues (including skin and hair follicles) and in different malignant tumors. Through immunohistochemistry (IHC) techniques, approximately 72 82% of CRC express EGFR [6]. The interaction between EGFR and its ligands [epidermal growth factor (EGF), transforming growth factor alpha (TGF- ), amphiregulin and epiregulin] triggers a cascade of cell processes which are involved in cell growth, proliferation, transformation, angiogenesis, invasion, metastases and survival [7] (Fig. 1). The EGFR is a validated target in CRC, as cetuximab (a chimeric mouse-human MoAb targeted to the EGFR) obtained regulatory approval for the treatment of patients with EGFR-expressing, KRAS wild-type (WT) metastatic colorectal cancer in combination with chemotherapy or as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan [8]. Fig. 1. Activation of EGFR and tumor cell growth (adapted from Stephenson et al. [15]).

3 18 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Panitumumab (ABX-EGF, Vectibix ) is a fully human recombinant kappa immunoglobulin G (IgG)2 monoclonal antibody with a molecular weight of approximately 147 kilodaltons (kda), which binds specifically and with high affinity to the extracellular domain of EGFR in normal and tumor cells [9]. By competitively inhibiting the binding of ligands to EGFR, panitumumab prevents receptor dimerization, EGFR tyrosine kinase autophosphorylation and activation of molecular signals, resulting in the inhibition of tumor cell proliferation and favoring apoptosis induction [10,11] (Fig. 2). In vitro studies evaluating panitumumab demonstrated significant inhibition of tumor growth in a HT- 29 murine xenograft model of human colon cancer cell [12]. Panitumumab is approved as monotherapy for the treatment of patients with EGFR expressing metastatic colorectal carcinoma with WT KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [13]. This article reviews the efficacy and tolerance of panitumumab as a single agent and the clinical trials of panitumumab in combination with chemotherapy in mcrc patients. Potential predictive factors for response and survival are also discussed. 2. Panitumumab as single agent Several clinical trials have evaluated dosing, pharmacokinetics (PK), efficacy and safety profile of panitumumab as a single agent in mcrc patients (Table 1) Phase I clinical trials At least, two phase I studies were conducted in previously treated patients with mccr or other advanced solid tumors. In a phase I study [14], 96 patients with various types of tumors including CCR were treated at panitumumab doses of mg/kg every week, 6 mg/kg every 2 weeks (Q2W), or 9 mg/kg every 3 weeks (Q3W). Among the 39 included mcrc patients, there were 5 (12.8%) partial responses (PR) and 8 cases of stable disease (SD). Skin toxicity was dose-dependent. Maximum tolerated dose was not achieved. Neither human anti-human monoclonal antibody (HAHA) formation nor infusion-related reactions were observed. Another phase I trial included 84 patients with resistant tumors in two cohorts: Cohort 1: 6 mg/kg Q2W as either a 60-min infusion (cohort 1A; n = 20) or a 60-min initial infusion followed by 30-min infusions for subsequent cycles (cohort 1B; n = 43) and Cohort 2 (n = 21): 9 mg/kg Q3W as a 60-min infusion, until disease progression or drug intolerability [15]. There were 2 responses and 5 SD in 11 mcrc cases. Tolerance profile was similar among cohorts. Peak concentrations after 30- or 60-min infusions were similar. Panitumumab exhibited similar non-linear PK among different patient populations. Serum trough concentrations were Table 1 Clinical trials of panitumumab as single agent in colorectal cancer patients. Infusion reaction Author Phase n Tumor type Prior CT Dose (mg/kg) Efficacy mpfs mos Anti-Ab antibodies Weiner et al. [14] I 96 Several (CRC n = 39) Yes weekly RR 12.8% (mcrc only) No No 6 Q2W/9 Q3W SD 23% (mcrc only) Stephenson et al. [15] I 84 Several Yes 6 Q2W/9 Q3W RR 20% (mcrc only) 3 No SD 50% (mcrc only) Hecht et al. [18] II 148 Colorectal (EGFR+ and ) Yes 2.5 weekly (8 of 9 weeks) RR 9%; SD 29% 14 w 9 m No 1 pt Berlin et al. [19] (ongoing) II 91 (300) Colorectal (EGFR +) Yes 6 Q2W RR 8%; SD 21% 7.6 w No 1 pt Hecht et al. [20] II 71 CRC EGFR-/EGFR-weak Yes 6 Q2W RR 4%; SD 35% 8.1 w 10.1 m No 3% 79 RR 5%; SD 30% 8.1 w 8.7 m Yoshino et al. [21] II 52 Colorectal (EGFR 1%) Yes 6 Q2W RR 13.5%; SD 8 w 7.4 m No Van Cutsem et al. [22] III 231 Colorectal (EGFR + ) Yes 6 Q2W RR 10%; SD 27% 8 w* No 4% (1 pt g 3 4) 232 BSC RR 0%; SD 10% 7.3 w Van Cutsem et al. [23] Extension 176 Colorectal (EGFR +) Yes 6 Q2W RR 11.6%; SD 33% 9.4 w 6.3 m 4.2% No CT: chemotherapy; mpfs: median progression-free survival; mos: median overall survival; Anti-Ab: Anti-antibodies; EGFR: epidermal growth factor receptor; CRC: colorectal cancer; mcrc: metastatic colorectal cancer; Q2W: every 2 weeks; Q3W: every 3 weeks; RR: response rate; SD: stable disease; w: weeks; m: months; pt: patient; g: grade; BSC: best supportive care.

4 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Fig. 2. Mechanism of action of panitumumab (adapted from Stephenson et al. [15]). similar for 2.5 mg/kg/week (45 50 g/ml), 6 mg/kg Q2W (43 53 g/ml) and 9 mg/kg Q3W (37 53 g/ml) dosing. The half-life of panitumumab was also similar among the three doses: 6, 7 7.5, and 8.4 days, respectively [16]. Panitumumab is eliminated in two ways: by saturation of the receptor and by clearance produced by the reticuloendothelial system, as normally occurs with endogenous immunoglobulins. Potential effects of some covariables on the PK of panitumumab, such as age (21 88 years), gender, race, mild-moderate kidney or liver dysfunction, and intensity of EGFR stain on the membrane (1+, 2+, 3+) of tumor cells have no apparent impact on the PK of panitumumab [17]. PK studies of panitumumab have neither been conducted in patients with kidney or liver failure, nor has it been studied in pediatric patients. Considering these data, and for patient s convenience, the dose of 6 mg/kg every 2 weeks, in a 1-h intravenous (iv) infusion, was chosen for use as single agent and in combination with biweekly CRC chemotherapy regimens (FOLFOX or FOLFIRI) meanwhile the dose of 9 mg/kg every 3 weeks, that resulted in similar exposure, can be easily combined with 3-week chemotherapy schedules into clinical trials. Nowadays, the dose of 6 mg/kg every 2 weeks is approved as single agent for the treatment of patients with EGFR expressing mcrc with wild-type KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens Phase II clinical trials As some preliminary activity was observed in two phase I studies, the development of panitumumab in CRC continued into phase II trials. Hecht et al. [18], in a multicenter, nonrandomized study, treated 148 patients, who had failed prior treatment with fluoropyrimidines, oxaliplatin and/or irinotecan, with panitumumab (2.5 mg/kg/week for 8 weeks and 1 week s rest). Two strata were established depending on staining of EGFR: stratum A [high staining (n = 105)] and stratum B [low staining (n = 43)]. A RR of 9% (95% CI 5 15%) was observed, that was similar in both strata. Median PFS and overall survival (OS) were 14 weeks and 9 months, respectively, with no statistically significant differences between the two groups. In another phase II study, panitumumab (6 mg/kg Q2W) was investigated in EGFR-positive mcrc patients, progressing during or after 2 3 lines of chemotherapy [19]. In the intermediate analysis presented at ASCO 2006, response rate at week 16 (primary objective) was 8%, with stable disease in 21%, in 39 eligible patients. A third study also conducted by Hecht et al. [20], had a similar design except that EGFR expression had to be negative or low. Final efficacy results of 150 patients who had received 1 dose of panitumumab (6 mg/kg Q2W) were presented at 2008 ASCO Gastrointestinal Cancers Symposium. Response rate (4% vs 5%), stable disease (35% vs 30%), and PFS (8.3 weeks vs 7.8 weeks) were similar for patients with EGFR-negative and low EGFR staining tumors, respectively. Finally, a Japanese trial reported a RR of 13% and a median PFS of 8 weeks in 52 mcrc patients previously treated with fluoropyrimidine, irinotecan and oxaliplatin. No correlation was found between EGFR tumor expression and clinical response [21]. In these trials, more than 95% of patients suffered at least one treatment-related adverse event (AE) (11 24% grade 3, 1% grade 4, 1% grade 5). The most frequent toxicities involved teguments and eyes (skin 92 96%, nails 28 30%, eyes 8 17%, hair 8%, and cheilitis 2 7%). The most common non-cutaneous AEs were diarrhea (23 27% any grade, 1 3% grade 3) and hypomagnesemia (8 12% any grade, 3%

5 20 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Table 2 Efficacy of panitumumab in combination with chemotherapy in colorectal cancer patients. Author/study Phase n EGFR status Line Regimen RR mpfs (m) mos (m) Berlin et al. [24] II 43 IHC 1+, 2+, 3+ 1 st Pmab 2.5 mg/kg/w + IFL 6-w 46% cycles Pmab 2.5 mg/kg/w + FOLFIRI 42% Q2W Siena et al. [25] III 1150 No required 1 st Pmab 6 mg/kg + FOLFOX4, Too early Too early Too early both Q2W PRIME FOLFOX4 Q2W Hecht et al. [26] III 1053 No required 1 st Pmab 6 mg/kg 46% Q2W + Oxa/bev-based CT PACCE Oxa/bev-based CT 48% Pmab 6 mg/kg Q2W+ 43% Iri/bev-based CT Iri/bev-based CT 40% Peeters et al. [28] III 700 (1100) No required 2 nd Pmab 6 mg/kg + FOLFIRI, both Too early Too early Too early Q2W FOLFIRI Q2W STEPP [30] Randomized 58 (100) NR 2 nd Pmab 6 mg/k + FOLFIRI, both 16% NR NR II Q2W Pmab 9 mg/kg + Irinotecan, 8% both Q3W Asmis et al. [31] Retrospective 34 NR 2 nd Pmab + irinotecan (72% of pts) 20% NR NR EGFR: epidermal growth factor receptor; RR: response rate; mpfs: median progression-free survival; mos: median overall survival; m: months; Pmab: panitumumab; IHC: immunochemistry; w: weeks; n = included patients (in parentheses, expected number for ongoing studies). NR: no reported; Q2W: every 2 weeks; Q3W: every 3 weeks; CT: chemotherapy; Pts: patients; Oxa: oxaliplatin; Iri: irinotecan; Bev: bevacizumab. grade 3 4), while grade 3 hypersensitivity reactions were rare ( 1%). In summary, phase II studies with panitumumab in monotherapy at a dose of 2.5 mg/kg/week or 6 mg/kg every 2 weeks in metastatic CRC patients previously treated with several lines of chemotherapy showed a response rate of 4 13% with an additional 21 35% stable disease rate. Patients with EGFR negative or low staining tumors also benefit from treatment with panitumumab. Main toxicity affects the skin, appearing in >95% of cases (any grade). Diarrhea and hypomagnesemia are the most common non-cutaneous toxicities. Infusion reactions are rare ( 1%) and HAHA formation has not been described Phase III clinical trials Approval of panitumumab in the United States and Europe was based on a multicenter, randomized, open-label, pivotal phase III study, that compared panitumumab plus BSC vs BSC alone in 463 patients with EGFR-positive mcrc resistant to fluoropyrimidines, oxaliplatin and irinotecan. Panitumumab was administered at a dose of 6 mg/kg Q2W, until progression, unacceptable toxicity or consent withdrawal. The primary endpoint was PFS and secondary endpoints were RR, OS and safety. With a follow-up of at least 12 months, response rate (10% vs 0%; p < 0.001), stable disease rate (27% vs 10%), and progression-free survival [8 weeks vs 7.3 weeks, hazard ratio (HR) 0.54 (95% CI ) p < ] were in favor of panitumumab [22]. However, 100% of patients treated with panitumumab presented at least an adverse event vs 86% of patients who received BSC alone. These adverse events were grade 3 in 33% and grade 4 in 2% in the panitumumab group vs 18% and 2%, respectively, for the BSC alone group. Skin-related toxicities occurred in 90% of patients in the panitumumab group vs 9% in the BSC group. Non-cutaneous toxicities were fatigue (24% any grade; 4% grade 3), diarrhea (21% any grade; 1% grade 3), and hypomagnesemia (36% any grade; 3% grades 3 4) in the panitumumab group, and fatigue (15% any grade, 3% grade 3), diarrhea (11% any grade, 0% grades 3 4) and hypomagnesemia (1%) in the BSC alone group. A single patient had a grade 2 infusion reaction and no HAHAs were detected in the panitumumab group. There were no treatment-related deaths. Patients in BSC group could switch to receive treatment with panitumumab after progression, within an extension protocol. The endpoints of safety and efficacy were also evaluated in this cohort. 176 patients randomized to BSC in the phase III pivotal study received at least one dose of panitumumab (6 mg/kg Q2W). Response rate was 11% and 33% of patients achieved stable disease, with a median PFS of 9.4 weeks (95% CI ) and an OS of 6.3 months (95% CI ). Again, the most common side effect was skin toxicity. There were no infusion reactions. Anti-panitumumab antibodies were detected in 3 (4.2%) of the 71 patients from whom samples were taken, although there was no impact on efficacy or safety [23]. This crossover design could explain why a statistically significant difference was not detected in OS in the pivotal phase III trial. In summary, panitumumab increases PFS in patients with CRC resistant to chemotherapy in comparison with the BSC alone.

6 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Panitumumab in combination with chemotherapy The activity of panitumumab as a single agent in chemoresistant mcrc patients led to the investigation of its efficacy and tolerance in combination with classical chemotherapy regimens in the first and second line settings (Tables 2 and 3). Furthermore, a randomized phase III trial tested panitumumab associated with oxaliplatin/bevacizumab or irinotecan/bevacizumab-based CT in untreated patients First line setting A multicenter phase II study was initially designed to assess panitumumab 2.5 mg/kg/w with irinotecan, 5FU bolus and LV (IFL) (Part 1). As an unacceptable toxicity was observed with this combination, the protocol was amended to replace IFL with FOLFIRI (part 2) and the primary endpoint was changed to estimate the incidence of grade 3/4 diarrhea. Globally, 43 patients were included (part 1, n = 19; part 2, n = 24). The response rate was similar in both groups (46% and 42%). However, PFS and OS were in favor of panitumumab plus FOLFIRI and grades 3 4 diarrhea was less common with panitumumab plus FOLFIRI regimen than with panitumumab plus IFL (25% vs 58%) [24]. The PRIME study is the first phase III study to investigate panitumumab (6 mg/kg Q2W) plus FOLFOX4 as first-line treatment in mcrc patients. A total of 1150 untreated patients were randomized 1:1 to panitumumab plus FOL- FOX 4 or to FOLFOX4 alone. The primary endpoint is to evaluate the treatment effect on PFS among in patients with WT KRAS tumors and patients with mutant KRAS tumors. In a pooled safety analysis, with 903 patients treated, main grade 3/4 non-cutaneous AEs reported were neutropenia (28%) and diarrhea (11%). Ninety-three patients (10%) experienced a grade 3-skin reaction and only three patients (<1%) had a grade 4. There were four investigator-reported adverse events of infusion reaction (three grade 1; one grade 2) [25]. Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) approved for mcrc. Based on the knowledge of the important roles that both EGFR and VEGF pathways play in tumor development and progression, the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study was designed to evaluate the benefit of adding panitumumab (6 mg/kg Q2W) to either oxaliplatin/bevacizumab or irinotecan/bevacizumabbased CT (Table 2). The primary endpoint was PFS within the oxaliplatin cohort. A total of 823 and 230 patients were randomly assigned to the oxaliplatin and irinotecan cohorts, respectively. Panitumumab was discontinued after a planned interim analysis of 812 oxaliplatin patients showed worse efficacy in the panitumumab arm. In the final analysis, median PFS was 10.0 and 11.4 months [HR 1.27; 95% CI, ], and median survival was 19.4 and 24.5 months for the panitumumab and the control arms, respectively. Table 3 Pooled safety data of FOLFOX or FOLFIRI ± panitumumab (grade 3 4 toxicities). Author/study n Regimen G3 Skin (G4) Neutropenia Diarrhea Fatigue Nausea Hypomagnesemia Dehydration PE DVT Infusion reaction Siena et al. [25] PRIME 903 (1150) FOLFOX ± Panitumumab 10% (<1%) 28% 11% 4% 3% 2% 3% 2% 2% 0 Peeters et al. [28] (1100) FOLFIRI ± Panitumumab 12% 15% 9% 4% 2% 1% 2% PE: pulmonary embolism; DVT: deep venous thrombosis; G: grade; Pmab: panitumumab.

7 22 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Table 4 Grades 3 4 toxicity of panitumumab + CT/bevacizumab versus CT/bevacizumab. Pmab + bev/oxa-ct (n = 407) G3 (G4) Bev/oxa-CT (n = 397) G3 (G4) Pmab + bev/iri-ct (n = 111) G3 (G4) Bev/iri-CT (n = 113) G3 (G4) Neutropenia 14% (10%) 17% (7%) 14% (3%) 17% (4%) Skin 35% (1%) 1% (0%) 38% (0%) 0% (0%) Diarrhea 22% (2%) 12% (1%) 27% (1%) 9% (0%) Infection 16% (2%) 8% (2%) 12% (2%) 9% (0%) Dehydration 15% (2%) 5% (<1%) 14% (0%) 6% (0%) Nausea/vomiting 13% (0%) 6% (1%) 11% (2%) 8% (0%) Deep venous thrombosis 7% (0%) 8% (0%) 13% (0%) 6% (0%) Pulmonary embolism 0% (6%) 0% (4%) 0% (11%) 0% (5%) Hypomagnesemia 3% (1%) 0% (0%) 3% (2%) 0% (1%) Paronychia 1% (0%) 0% (0%) 4% (0%) 0% (0%) Neuropathy 3% (<1%) 7% (0%) Hypertension 4% (0%) 5% (0%) 2% (0%) 3% (0%) Pmab: panitumumab; Bev: bevacizumab; Oxa: oxaliplatin; Iri: Irinotecan; CT: chemotherapy. Grade 3/4 AEs in the oxaliplatin cohort were skin toxicity (36% vs 1%), diarrhea (24% vs 13%), infections (19% vs 10%) and pulmonary embolism (6% vs 4%) for panitumumab and control arms, respectively (Table 4). In the irinotecan cohort, increased toxicity without evidence of improved efficacy was observed in the panitumumab arm. KRAS analyses showed adverse outcomes for the panitumumab arm in both WT and mutant groups [26]. Similar results were seen in the CAIRO 2 study which combined cetuximab with bevacizumab and chemotherapy [27], suggesting that this is a class effect Second line setting The multicenter phase III study ( protocol) is ongoing to investigate the benefit of adding panitumumab to FOLFIRI as a second-line treatment patients previously treated with only one fluoropyrimidine-based CT regimen for mcrc were planned to be randomized 1:1 to either panitumumab (6 mg/kg Q2W) plus FOLFIRI or to FOLFIRI alone. Preliminary safety results, presented at 2008 ASCO Meeting reported that grades 3 4 neutropenia (15%) and grades 3 4 diarrhea (9%) were the main non-cutaneus toxicities. Grade 3 and 4 skin toxicities were 12% and <1%, respectively [28]. STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) is the first open-label, randomized phase II trial to evaluate prophylactic vs reactive skin treatment for skin toxicities due to panitumumab therapy. Patients with mcrc received either FOLFIRI plus panitumumab (6 mg/kg Q2W) or irinotecan plus panitumumab (9 mg/kg Q3W) in secondline setting, after failure to a previous fluoropyrimidine and oxaliplatin-based CT, with or without bevacizumab. Within each stratum, patients were randomized to pre-emptive therapy (24-h prior to first panitumumab dose and daily through week 6) or reactive skin therapy (given after developing skin toxicities). Pre-emptive skin treatment included administration of a skin moisturizer, sunscreen, 1% hydrocortisone cream, and doxycycline twice daily. The incidence of specific grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the prophylactic skin treatment group (29%) compared with the reactive skin treatment group (62%) [29]. Pooled analysis of the two groups of treatment showed skin toxicity (22%), neutropenia (16%), diarrhea (14%), dehydration (12%), hypokalemia (10%) and hypomagnesemia (5%) as main grade 3 4 AEs [30]. Preliminary efficacy data reported a RR of 16% and 8% for panitumumab plus FOLFIRI and panitumumab plus irinotecan, respectively [30]. In a retrospective series, 34 patients [24 (70%) previously treated with cetuximab] received panitumumab plus irinotecan [31]. Reasons for stopping cetuximab included hypersensitivity (n = 7), progression or rising CEA (n = 9), toxicity (n = 2), convenience of every other week schedule (n = 3) and others (n = 3). Seven patients (20%) achieved partial response, all in combination with irinotecan, and patients who received panitumumab due to cetuximab hypersensitivity did not have subsequent infusion reaction. In summary, available data on the use of panitumumab in combination with chemotherapy in first-line setting are limited to results from one phase II study and one randomized phase III trial. In the phase II study, panitumumab plus FOLFIRI had similar efficacy and better tolerance than panitumumab plus IFL. Combination of panitumumab with oxaliplatin-based CT did not present abnormal safety problems in an interim analysis in the phase III trial. Preliminary results of panitumumab in combination with irinotecanbased CT in second-line setting showed 8 16% of RR with 44 50% of stable disease and an acceptable safety profile. Finally, combination of four drugs (panitumumab, bevacizumab, oxaliplatin or irinotecan, and 5FU) did not have a higher activity and was more toxic than the same regimens without panitumumab, especially in patients over 65 years of age or/and with an ECOG of 2. This appears to be a class effect as similar results were seen with cetuximab in the similarly designed CAIRO2 trial. There are also data suggesting that some patients not responding to or with hypersensitivity to cetuximab may benefit from panitumumab. However, more studies are needed to confirm these results.

8 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Tolerance profile Typical adverse events associated with anti-egfr monoclonal antibodies, cetuximab and panitumumab, include skin toxicity, diarrhea, hypomagnesemia and infusion reaction. However, infusion reactions are less common with panitumumab, which is likely due to its fully human structure. In phase II clinical trials, most frequent adverse events of panitumumab involved teguments and eyes (skin 92 96%, nails 28 30%, eyes 8 17%, hair 8%, and cheilitis 2 7%) [20,21]. Acneiform rash, a phenomenon which occurs when the EGFR is blocked, usually appears at the start of treatment. When the treatment is suspended, rash spontaneously disappears. In a summary of pooled clinical safety data of 920 patients with mcrc included in 10 studies (phases I through III) of panitumumab monotherapy, skin toxicity was grades 1 2 in most patients and rarely caused discontinuation of the therapy [32]. Only 15% patients had grade 3 rash and <1% a grade 4. Other skin toxicities such as dry skin, fissures, pruritus and paronychia are also due to EGFR inhibition. Severe diarrhea is uncommon with anti-egfr antibodies. In the pooled safety study of panitumumab monotherapy, 13% of patients had diarrhea (any grade), but it was only grade 3 in 1%[32]. A combination of panitumumab with CT can increase the incidence and severity of diarrhea, which should be treated with hydration, astringent diet, loperamide and antibiotics, if necessary. EGFR blockage is associated to hypomagnesemia, which is suggested to be due to EGFR inhibition in the kidney, where 70% of filtered magnesium is reabsorbed. Incidence of hypomagnesemia was low (5% any grade; 2% grade 3) [32]. Generally, it is grades 1 2 and easy to correct with oral magnesium supplements. Very few patients require intravenous magnesium infusions and/or withdrawal of panitumumab. As panitumumab is a fully human MAb, incidence of infusion reactions is very low. In the pooled analysis study, 1.1% and 0.4% patients treated with panitumumab had an infusion reaction of any grade and grade 3, respectively. The number of infusions associated with an infusion reaction were 0.14% and 0.05% for any grade and 3 grade, respectively [32]. So far, no fatal reactions have been reported. Infusion should be stopped and permanent panitumumab withdrawal should be evaluated if a severe reaction is observed. It needs to be highlighted that a trial that attempted to combine anti-egfr and anti-vegf strategies with chemotherapy (panitumumab and bevacizumab, respectively) showed an unacceptable level of toxicity and was discontinued. Similar results were reported in the CAIRO2 trial with cetuximab. 5. Predictive factors Several potential predictive factors are being investigated for selecting patients who will most benefit from panitumumab. To date, most relevant factors predicting response to anti-egfr MoAb are the KRAS mutation status, BRAF mutation status, number of copies of EGFR gene and intensity of skin rash. Epiregulin and amphiregulin (EGFR-ligands) levels and other predictive markers need to be confirmed in subsequent trials KRAS mutation Approximately 40% of all cases of CRC expressing the KRAS mutation. Association of KRAS mutation and clinical outcome of patients treated with panitumumab in monotherapy was investigated in the pivotal randomized phase III study of panitumumab vs BSC. Response rate in wild-type KRAS (n = 124) was 17% vs 0% in mutated KRAS tumors (n = 84), and stable disease was reported for 34% vs 12%, respectively [33]. Patients with wild-type KRAS receiving panitumumab had better PFS compared with those treated with BSC alone and patients with mutated KRAS had a similar PFS whether or not they received panitumumab. On the other hand, the relative effect of panitumumab versus BSC alone on PFS was significantly greater in patients with wild-type KRAS mcrc [HR = 0.45 (95% CI: )]. An exploratory analysis of panitumumab as a single agent in patients with tumors expressing low or negative levels of EGFR examined the effect of tumor KRAS gene status on safety and efficacy. Seventy-five wild-type KRAS and 59 mutated KRAS patients were included in this analysis [34]. RR was 9% and 0%, and SD was reported for 47% vs 9%, respectively. Significantly longer median PFS and OS were observed in wild-type KRAS patients than in mutated KRAS patients (15 and 54 weeks, vs 7 and 29 weeks, respectively). These data confirm the utility of KRAS testing in identifying patients likely to benefit from panitumumab monotherapy. Similar results have been obtained in patients with mcrc treated with cetuximab (as monotherapy or in combination with CT) [35 39], which suggests that the KRAS marker is valid for both anti-egfr targeted therapies. On the basis of these results, the European Medicines Agency (EMEA) has approved panitumumab only for patients with wild-type KRAS metastatic colorectal cancer. This is the first indication of an agent based on the presence/absence of a gene mutation, and opens a new era in biomarker-driven oncology BRAF mutation The serine threonine kinase BRAF is the principal effector of KRAS. In a retrospective study, BRAF wild-type was required for response to cetuximab or panitumumab in mcrc patients with KRAS wild-type tumors [40] Number of copies of the EGFR gene Several authors have investigated the number of copies of the EGFR gene as a response-predicting factor. An Italian group [41] observed that an increased number of copies

9 24 C. Gravalos et al. / Critical Reviews in Oncology/Hematology 74 (2010) Table 5 Comparison between panitumumab and cetuximab. IgG Type of MoAb Route Loading dose Schedule Duration of infusion Grade 3 4 infusion reactions Panitumumab IgG2 Human iv No 6 mg/kg every 2 w min 0.04% No Cetuximab IgG1 Chimeric iv Yes (400 mg/m 2 ) (2 h) 250 mg/m 2 weekly 60 min 3.2% Yes iv: intravenous; w: week; min: minutes Premedication Table 6 Efficacy of panitumumab or cetuximab versus best supportive care in phase III trials. Author Arms n RR SD PFS OS Crossover Van Cutsem et al. [22] Panitumumab % 27% 1.9 m ns Allowed BSC 232 0% 10% 1.8 m Jonker Cetuximab 287 8% 31.4% 1.9 m 6.1 m Not allowed BSC 285 0% 11% 1.8 m 4.6 m RR: response rate; SD: stable disease; PFS: progresión free survival; OS: overall survival; ns: no statistically significative; BSC: best supportive care; m: month. of the EGFR gene by fluorescent in situ hybridation (FISH) can predict response to anti-egfr monoclonal antibodies, suggesting that patients could be selected for these therapeutic agents based on the number of copies of the gene. Sartore-Bianchi et al. [42] analyzed the number of copies of the EGFR gene or chromosome 7 polysomia in 92 patients in the randomized study of panitumumab plus BSC (n = 58) vs BSC alone (n = 34). Patients whose tumors had 2.5/nucleus of copies of the gene or <40% of cells with chromosome 7 polysomia had a shorter PFS and OS. These exploratory data need to be validated in prospective studies Skin rash Rash is considered to be a response-predicting factor for all anti-egfr agents, both tyrosine kinase inhibitors (erlotinib, gefitinib) and MoAb. In the pivotal phase III study of panitumumab vs BSC, severity of rash was correlated to greater response rate and better overall survival [43]. A pooled analysis of the predictive value of skin toxicity with panitumumab confirmed these results, as a longer PFS and OS were observed in patients with grades 2 4 toxicity vs grades 0 1 (2.6 and 8.4 months vs 1.8 and 5.4 months, respectively) [44]. 6. Comparison between panitumumab and cetuximab The main difference between panitumumab and cetuximab lies on to the human or chimeric nature of these antibodies. This fact impacts on the duration of infusion, the incidence of hypersensitivity reactions and the premedications to be used (Table 5). Efficacy data of panitumumab or cetuximab versus best supportive care in chemotherapy-refractory mcrc patients are similar [22,45] (Table 6). In first line setting, the benefit of adding cetuximab to FOLFIRI or FOLFOX in KRAS wildtype mcrc patients has been established by the CRYSTAL trial [46] and the OPUS trial [47], respectively, while the role of panitumumab combined with FOLFIRI or FOLFOX is still being investigated in randomized trials. 7. Conclusions Panitumumab (ABX-EGF) is a fully human IgG2 MoAb directed against the EGFR. Panitumumab adds benefit to patients as a single agent in KRAS wild-type metastatic colorectal cancer versus BSC alone. Efficacy and tolerance of Panitumumab in combination with conventional chemotherapy is been investigated in clinical trials in first and second line settings. If the results of these clinical trials confirm the benefit of adding panitumumab to chemotherapy in KRAS wild-type tumors, panitumumab will be a new standard anti- EGFR therapy with less hypersensitivity reactions and an easier schedule than cetuximab. The toxicity profile is consistent with other anti-egfr agents, with skin toxicity, diarrhea and hypomagnesemia as main events. When combined with chemotherapy, the toxicity profiles are largely non-overlapping. However, when anti- EGFR and anti-vegf strategies (panitumumab or cetuximab and bevacizumab, respectively) were combined, an unacceptable level of toxicity was documented. This is a reminder that we need to learn more about the biology of targeted therapies and their potential interactions in order to more efficiently translate biologically sound combinatorial approaches to the clinic safely. Panitumumab has been approved in the European Union only for patients with wild-type KRAS in a un-precedented regulatory decision that opens a new era in biomarker-driven oncology. However, not all patients who have WT KRAS tumors respond to therapy, so other factors determining panitumumab efficacy in CRC must be involved. The elucidation of those biological features should now be the first point in the agenda to further improve the management and care of patients with CRC.

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