Panitumumab : leading to better overall survival in metastatic colorectal cancer?

Drug Evaluation

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Panitumumab: leading to better overall survival in metastatic colorectal cancer? 1.

Introduction

2.

Pharmacological data and tolerability

3.

Biomarkers of clinical efficacy

4.

Clinical trials

5.

Expert opinion

Ana Sebio, Sebastian Stintzing, Stefan Stremitzer, Wu Zhang & Heinz-Josef Lenz† †

University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA

Introduction: Survival of metastatic colorectal cancer (mCRC) patients has improved greatly over the past few years, essentially due to the appearance of new biological therapies. Among these new therapies, monoclonal antibodies targeting the EGFR are the leading contributors to the so-called personalized medicine. Biomarkers within the EGFR pathway, such as K-Ras mutation, have proved to help better select the patients benefiting from these treatments. Areas covered: Panitumumab is a fully human monoclonal antibody that targets the EGFR and is currently approved in combination with chemotherapy or in monotherapy for the treatment of mCRC patients. Following a description of the pharmacological and tolerability data, this review focuses on the clinical activity of panitumumab through the description of clinical trials and biomarker research. Expert opinion: Recent biomarker research with expanded Ras testing has led to an improvement in overall survival for all Ras wild-type patients treated with panitumumab. Furthermore, the thorough evaluation of markers within the EGFR pathway could potentially prevent detrimental effects for patients treated with panitumumab and avoid unnecessary toxicity and costs. Keywords: biomarker, metastatic colorectal cancer, panitumumab, survival Expert Opin. Biol. Ther. (2014) 14(4):535-548

1.

Introduction

Colorectal cancer represents the second cause of cancer death in the United States and the fourth worldwide [1]. Although most patients are diagnosed in a local or locally advanced stage, metastatic colorectal cancer (mCRC) represents approximately a quarter of the total cases. Furthermore, a non-negligible percentage of patients treated initially with a curative intent will relapse, increasing the number of patients with metastatic disease [2]. Overall survival (OS) of mCRC patients has significantly improved over the past decades due to surgical and therapeutic advances [3]. Improvements in the hepatic surgical techniques as well as a better selection of patients have made surgery a major contributor to the increased OS [4]. Regarding systemic therapy, in the late 1990s the addition of irinotecan and oxaliplatin to fluoropyrimidine treatment increased the median OS from 12 months to 18 -- 20 months [5,6]. In the 2000s, the advent of the targeted therapies boosted the median OS to > 2 years in several Phase III trials [7-10]. These biological therapies can be divided into those targeting the EGFR signaling (cetuximab and panitumumab) and those inhibiting angiogenic pathways (bevacizumab, aflibercept, and regorafenib). The increasing number of available drugs for mCRC highlighted the need for molecular markers and led to the discovery of predictive factors that allow a more 10.1517/14712598.2014.894502 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary.


Drug name Phase Indication Pharmacology description Route of administration Chemical structure Pivotal trial(s)

Panitumumab Launched Colorectal cancer EGFR 1 antagonist Injectable Human monoclonal antibody Panitumumab plus best supportive care versus best supportive care (NCT00113763) Folfiri plus panitumumab versus Folfiri alone (NCT00339183) Folfox plus panitumumab versus Folfix alone (NCT00364013)

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).

personalized approach to the treatment of mCRC. Mutations in the K-Ras gene, a downstream component of EGFR signaling, were found to be predictive of non-response to anti-EGFR monoclonal antibodies [11-13]. However, despite of the use of K-Ras mutations as negative predictive biomarkers, up to 30 -- 40% of the patients did not respond to anti-EGFR therapies. Very recently, further biomarker research has proven that mutations in N-Ras, another member of the Ras family, can also predict the lack of response to anti-EGFR targeted treatment [14]. Regarding the drugs targeting angiogenesis, despite of extensive research efforts, none of the found biomarkers has made it to the patient’s bedside. As a result of the increased number and more effective usage of the available drugs, the prognosis of mCRC has significantly improved. Following a summary of the pharmacological properties as well as the relevant molecular data in the EGFR pathway, this article focuses on the clinical evidence that supports the contribution of Panitumumab to the improvement in OS in mCRC patients (Box 1). 2.

Pharmacological data and tolerability

EGFR pathway and panitumumab activity The EGFR also known as HER1 belongs to the ErbB receptor tyrosine kinase family [15]. Upon ligand binding homo or heterodimerization of EGFR occurs, following autophosphorylation and the initiation of a signaling cascade that ultimately leads to cell proliferation, invasion, metastasis development, and apoptosis evasion [16]. Among the pathways activated by EGFR signaling two of the more relevant in colorectal cancer tumor development and progression are Ras/Raf/MAPK and PI3K/protein kinase B (AKT)/mTOR. The regulation of these pathways is extremely complex and comprises of multiple phosphorylations, dimerization, and interactions with other proteins. Briefly, after Ras proteins are activated by 2.1

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guanine nucleotide exchange factors they induce activation of Raf proteins, which in turn trigger phosphorylation of the MAPKs. MAPKs translocate to the nucleus where through the regulation of several transcription factors favor cell survival and proliferation [17,18]. In the PI3K/AKT/mTOR cascade when EGFR becomes activated, the PI3K catalytic subunit is able to phosphorylate phosphatidylinositol 4,5-bisphosphate into phosphatidylinositol 3,4,5-trisphosphate (PIP3). The PIP3 function is antagonized by tumor suppressor phosphatase and tensin homolog providing balance within the pathway. Activated PIP3 phosphorylates AKT that in turn will be able to phosphorylate many substrates. Activated AKT promotes cell proliferation by negatively regulating tumor suppressor p53 through the phosphorylation mouse double minute 2 [19]. In the same manner, AKT also activates the mTOR complex by negatively regulating tuberous sclerosis protein complex 1 (TSC1) and TSC2 (Figure 1) [20]. Additionally, these two main downstream branches of EGFR signaling have many crosstalk points that contribute to self-regulation of the pathway [21,22], but also favor the appearance of drug-resistance mechanisms. Panitumumab is a recombinant IgG2 fully humanized monoclonal antibody that targets EGFR by binding with high affinity (dissociation constant [KD] = 5 10 -- 11 mol/l) [23] to its extracellular domain. Panitumumab competes for the EGFR binding with its natural ligands, resulting in the EGFR internalization [24]. By blocking the ligand-induced phosphorylation of EGFR, panitumumab can inhibit proliferation in EGFR-expressing cell lines in vitro as well as impede tumor development and abolish tumor formation in mice models implanted with human epidermoid carcinoma [23,25]. Other mechanisms have been proposed besides EGFR binding and internalization to explain how panitumumab exerts its antitumor activity. EGFR has been found located in the nucleus after radiation therapy, leading to an increase in the DNA-dependent kinases involved in DNA repair, suggesting the implication of EGFR in the DNA repair mechanisms [26]. Moreover, panitumumab has been proposed to induce autophagy in cell lines [27] and also to inhibit angiogenesis by reducing in vitro the tumor production of inflammatory and proangiogenic factors, such as IL-8 or VEGF. Antibody-dependent cell-mediated cytotoxicity (ADCC), may also contribute to panitumumab activity. Despite of being an IgG2 mAb, panitumumab has been reported to induce ADCC via cells of myeloid origin [28]. The approved dose of panitumumab is 6 mg/kg administered intravenously every 2 weeks and the administration of higher drug doses has been shown to decrease the serum clearance [29]. The pharmacokinetic analyses on 1200 patients in 14 clinical trials in solid tumors treated with panitumumab were used to create a pharmacokinetic model of the drug. Data from these analyses showed that patients’ body mass is the baseline most important characteristic altering clearance and volume distribution of the drug. The pharmacokinetic properties of panitumumab were not altered with the addition

Expert Opin. Biol. Ther. (2014) 14(4)

Panitumumab

ER

AR

Panitumumab

EGF

EGF EGF EGFR

Cell membrane P

P


PIP2 K-Ras

PI3K

PTEN

RAS

PIP3

N-Ras

AKT RAF MDM2

mTOR MAPKs

Nucleus

Proliferation Angiogenesis Migration Invasion

Figure 1. EGFR signaling pathway. AKT: Protein kinase B; AR: Amphiregulin; ER: Epiregulin; K-Ras: Kirsten rat sarcoma viral oncogene homolog; MDM2: Mouse double minute 2; mTOR: Mammalian target of rapamycin; N-Ras: Neuroblastoma ras sarcoma viral oncogene; PI3K: Phosphatidylinositide 3-kinase; PIP2: Phosphatidylinositol 4,5-bisphosphate; PIP3: Phosphatidylinositol 3,4,5-trisphosphate; PTEN: Tumor suppressor phosphatase and tensin homolog; Raf: Rapidly accelerated fibrosarcoma; Ras: Rat sarcoma.

of cytotoxic compounds or by different tumor EGFR expression. In the same manner, the presence of antibodies in a low percentage of the patients did not significantly influence the AUC [30]. Tolerability Panitumumab has a good overall tolerability profile, as most of the toxicity is usually grade 2 or less. The most characteristic side effects include skin rash, diarrhea, and hypomagnesemia. Skin rash despite of not being a life-threatening side effect is present in approximately 90% (17 -- 36% grade 3/4) of the patients and can reduce quality of life [31,32]. Moreover, skin rash can influence medical decisions and lead to treatment interruption. This acneiform rash develops within the first 2 -- 4 weeks of treatment and is usually presented in the face and thorax. The underlying molecular mechanism seems to correlate with the high dependence on the EGFR pathway of the skin and skin appendages. Keratinocytes are dependent on the EGFR pathway for normal proliferation. 2.2

Panitumumab blocking the EGFR signaling leads to increased keratinocyte apoptosis and disruption of normal keratinocyte maturation favoring the appearance of xerosis and pruritus. EGFR inhibition also favors inflammatory processes that promote cutaneous injuries such as papulopustules or periungual inflammation [33]. Other skin and nail toxicities include: xerosis, photosensitivity, fissures located on fingertips, paronychia, hyperpigmentation, and telangiectasias. Hair disorders, such as follicular necrosis and alopecia, are also present due to the retardation of hair growth [34]. Treatment options for skin and nail disorders consist of local therapy such as topical steroids and systemic therapy that includes antibiotics like tetracycline or isotretinoin at low doses [35]. Although there are not evidence-based guidelines, some authors recommend the use of tetracycline for skin rash prevention [36]. Diarrhea is the second most common side effect of panitumumab treatment after skin toxicity. Diarrhea grades 3 -- 4 rates vary from 1% when panitumumab is administered in monotherapy [37], to 14 -- 18% when administered concomitantly with chemotherapy [8,38]. There is no specific


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treatment for anti-EGFR mAb-induced diarrhea, although in most cases adequate hydration, correct diet, and the use of loperamide treatment are able to prevent severe cases [39]. Hypomagnesemia is also frequently found in patients treated with panitumumab with or without combination chemotherapy. The physiological mechanism behind this side effect relies on the fact that EGFR is essential for the regeneration of tubular epithelial cells [40] as well as for the activation of the transient receptor potential member 6 in charge of the Mg reabsorption in the distal tubule [41]. However, the exact mechanism by which panitumumab induces hypomagnesemia is not fully understood. In a meta-analysis of randomized studies that included panitumumab and cetuximab in several cancer types, the overall incidence of hypomagnesemia was 17% (13.8 and 20.9 % for panitumumab and cetuximab, respectively) [42]. However, in a prospective study, up to 97% of the patients experienced a decrease in the Mg levels, which seemed to be inversely correlated with the baseline Mg levels as well as the patient’s age [43]. The risk of hypomagnesemia has been associated with the drug administration period [42] and can be increased when anti-EGFR are combined with platinum derivates [44]. So far, no severe complications or toxic deaths have been reported due to hypomagnesemia caused by panitumumab. To this regard, the appropriate measures of prevention and treatment are not well established. 3.

Biomarkers of clinical efficacy

Ras mutations As previously discussed, Ras proteins are critical members in the Ras/Braf-MAPK downstream cascade of EGFR signaling and they regulate cellular mechanisms, such as survival, proliferation, or vesicle trafficking in response to several stimuli including growth factors [45]. The discovery of activating somatic mutations within the K-Ras member of the Ras family has repeatedly proven to be a predictive factor of non-response to anti-EGFR therapies [12,13]. K-Ras mutations are present in approximately 35 -- 45% of the colorectal cancer tumors. These mutations are located in exon 2 (codons 12, 13), exon 3 (codons 59, 61), and exon 4 (codons 117, 146), however, the vast majority of the mutations are found within exon 2 (40%) [14,46]. Since the first report of the relationship of K-Ras mutations and the lack of response to anti-EGFR therapies in CRC [11], several retrospective analyses of Phase II and III trials have proved their predictive value [12,47-49]. Nonetheless, the value of the K-Ras mutations in codon 13 (G13D, glycine to aspartate) is controversial. In vitro and in vivo studies have suggested a reduced transforming activity for the codon13 mutation when compared to the codon 12 mutations [50,51], thereby these tumors could have a less aggressive behavior. Since the first study published by De Rook et al. demonstrating a better outcome of patients with codon 13 K-Ras mutations treated with cetuximab [52], several retrospective analyses in 3.1

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cetuximab-treated population have pointed in the same direction [53,54]. However, the available data regarding codon 13 mutations and panitumumab treatment so far does not support these findings. In a recent pooled analysis of three Phase IIII randomized panitumumab, the authors concluded that patients with both codon 12 or codon 13 mutations within the K-Ras gene do not benefit from panitumumab [55]. This topic has been discussed by Morelli et al. [56]. Of the three canonical Ras genes, N-Ras has recently gained relevance as a predictive marker of response to anti-EGFR therapies. Mutations in N-Ras are less frequent than in K-Ras [46], and they are typically mutually exclusive, their co-existence being exceptional [57]. N-Ras mutations have been evaluated as a predictive factor of response to panitumumab in various trials. The PRIME study [8] evaluated the mFOLFOX6 with or without panitumumab in first-line mCRC. Among the 639 K-Ras wild type (wt) exon 2 population, 108 patients were found to have other Ras mutations, which included KRas exons 3 and 4, N-Ras. A total of 48 patients (44%) harbored a N-Ras mutation. The updated analysis including all Ras mutations showed an improvement in the progressionfree survival (PFS) and the OS for wt patients for all the Ras mutations. Moreover, a detrimental effect of panitumumab was observed in patients harboring a Ras mutation [14]. In the Phase II randomized PEAK study evaluating mFOLFOX6 plus panitumumab or bevacizumab, no difference in PFS was reported between the two arms when only KRas exon 2 mutations were considered. A recent analysis excluding patients with any Ras mutation (K-Ras and N-Ras) revealed an improved PFS in the panitumumab arm for the wt patients. In this analysis, data has shown a median OS of 41.3 months for the Ras wt patients in the panitumumab arm [58]. In the same direction, the analysis of a randomized Phase III study of panitumumab plus best supportive care (BSC) versus BSC alone in chemorefractory patients revealed similar results: patients wt for both K-Ras and N-Ras mutations showed longer PFS than patients with only K-Ras exon 2 wt [59]. Other mutations in the EGFR pathway B-Raf mutation is present approximately in 8% of the colorectal cancers and is a prognostic marker associated with shorter survival regardless of the treatment [10]. B-Raf V600E mutation represents almost all of the mutations within B-Raf. The value of B-Raf mutation as a predictive marker of nonresponse to anti-EGFR therapies has been retrospectively studied in numerous works [10,14,52,60-62]. Nevertheless, due to the small sample representing this subgroup of patients, the predictive value of B-Raf mutation is not clearly established. Thus, to truly embrace B-Raf mutation as predictive factor, further prospective studies with a larger sample size are needed. In the EGFR ectodomain a mutation (S492R) has been described that impedes cetuximab binding conferring resistance. Interestingly, this mutation does not prevent panitumumab binding and, therefore, successful treatment with panitumumab after cetuximab failure has been reported [63]. 3.2


Panitumumab

Of increasing importance are the different methodologies used for the detection of mutations as their sensitivity varies significantly. The use of newer and more sensitive techniques might help to better classify the mutational status of CRC especially in those samples with low percentage of tumor cells [64,65]. Furthermore, newer approaches to molecular characterization of tumors like the detection of tumor-associated mutations in blood (liquid biopsy), could help identify resistance mechanisms and design novel clinical trials [66]. Beyond EGFR signaling, other predictive factors As discussed earlier, the development of skin toxicity is the most common adverse effect of panitumumab treatment. The grade of skin toxicity has been systematically correlated with the treatment efficacy. Data from all three Phase III trials in first-, second- and third-line settings have shown that patients developing skin toxicity grade 2 or greater have longer PFS and OS when compared to patients with only skin rash grade 1 or no skin rash [67-69]. Furthermore, in the PRIME and the FOLFIRI with or without panitumumab in second-line studies, this association occurred regardless of K-Ras mutational status. Patients with a K-Ras mutation and skin toxicity grade 2 or more benefited more from the treatment than patients with a lower grade skin rash. Results from these studies revealed that the majority of patients develop their worse skin rash grade within the first 28 days of treatment. This fact raises the question whether the absence of skin rash within the first two cycles could be used as a predictive value o no-response. However, this potential predictive value needs to be tested in a prospective clinical trial. The decrease in the serum Mg levels after anti-EGFR treatment has also been evaluated as a predictive factor. The available data come from cetuximab studies and has yielded conflicting results [44,70,71]. In the same manner, data from cetuximab studies also revealed the high expression of EGFR ligands amphiregulin and epiregulin as well as an increased copy number or an amplification of EGFR gene as potential predictive markers of response [72-75].


3.3

4.

Clinical trials

Phase I trials The first clinical trial to evaluate panitumumab monotherapy in advanced solid tumors expressing EGFR, reported equivalence and comparable safety profiles for three schedule administrations: 2.5 mg/kg weekly, 6 mg/kg biweekly, and 9 mg/kg every 3 weeks. In this study the majority of the responding patients were mCRC and the most frequent side effects included skin toxicity, fatigue, nausea, and diarrhea [76]. Later on, panitumumab monotherapy was evaluated in a Japanese population concluding no differences from other populations [77]. Further Phase I studies showed no drug interactions when combined with chemotherapy and other targeted therapies [78-82]. 4.1

Phase II trials Data from Phase II clinical trials have been summarized in Table 1. 4.2

First-line In the first-line setting the first study to evaluate panitumumab efficacy in combination with chemotherapy initially evaluated a total of 19 patients treated with IFL (irinotecan, 5-flourouracil bolus and leucovorin) plus panitumumab. The treatment protocol was amended due to an unacceptable toxicity profile attributed to the IFL scheme also found in other studies and was changed to FOLFIRI plus panitumumab [83,84]. Following this protocol change, a total of 24 more patients entered the trial in a second part. The first end point was tolerability measured by severe diarrhea (grade 3/4) which in the first part occurred in a high percentage of patients (58%) compared to only 25% of the patients treated in the second part of the trial. The most common adverse event was the development of skin rash. Regarding secondary end points, the response rate was higher in the IFL part one group than in the FOLFIRI part two (47 vs 33%, respectively) however, the median PFS and OS were longer in the group of patients treated with FOLFIRIpanitumumab. In this study, K-Ras status was not evaluated and inclusion criteria was restricted to only patients with EGFR expression measured by immunohistochemistry. The preplanned sample sized was not achieved due to early study closure based on the low accrual [85]. Later on the combination of FOLFIRI plus panitumumab in the first-line setting for mCRC was evaluated in an open label, multicenter single-arm trial that included 154 patients. Data were analyzed by K-Ras tumor status in a retrospective manner. The K-Ras wt population presented a higher percentage of objective responses (56 vs 38%), longer duration of response (13.0 vs 7.4 months) as well as a higher percentage of R0 resection (8 vs 5%) and longer PFS (8.9 vs 7.2 months). Tolerability evaluation revealed skin toxicity as the most frequent adverse effect and a similar percentage of diarrhea grade 3 -- 4 to the previously described study (24%). It is worth mentioning that an overall 8% of fatal adverse events were reported [86]. A recent trial (MetaPan) evaluated XELOX plus panitumumab in patients with unresectable liver-limited disease. A total of 49 patients were enrolled of whom 35 were K-Ras wt. The overall response rate (ORR) was 65.7% in the wt population, allowing 15 patients to undergo liver surgery. For the total of the patients regardless of K-Ras status, the median PFS was 8.4 months and the median OS was 21.9 months. Progression-free and OS were longer in the subgroup of patients who underwent surgery of liver metastasis (14.7 vs 7.3 months for PFS; median OS for resected patients not reached). The toxicity profile of the study was as expected and no toxic deaths were reported [87]. Recently, the Gruppo Oncologico Nord Ovest (GONO) has published the results of their Phase II study evaluating 4.2.1


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the efficacy of panitumumab in combination with FOLFOXIRI in unresectable mCRC patients with K-Ras, H-Ras, N-Ras and B-Raf wt. A total of 37 patients enrolled in the trial and an objective response of 89% was reported allowing 43% of the patients to undergo surgical resection of metastatic lesions. Median PFS was 11.3 months in this highly selected population. The most common grade 3/4 adverse events were neutropenia in 48%, asthenia (27%) and diarrhea (35%). The first two were comparable to FOLFOXIRI alone, but the grade 3/4 diarrhea was higher [88]. The latest data on a Phase II trial of panitumumab in a first-line setting for mCRC come from the multicenter randomized PEAK study. In this trial a total of 285 K-Ras exon 2 wt patients were randomized to receive mFOLFOX6 plus panitumumab or bevacizumab. In the first analysis, data was similar in both arms in terms of response rate and PFS. At that time the median OS in the panitumumab group was not reached and in the bevacizumab arm was 25.4 months. Longer follow-up analysis with 46% OS events showed a statistically significant difference favoring the panitumumab arm (24.3 vs 34.2 months; HR 0.62; 95% CI 0.44 -- 0.89; p = 0.009). Further biomarker analysis taking into account all Ras mutations (K-Ras and N-Ras exons 2,3,4) revealed a statistically significant advantage for patients Ras wt in the panitumumab group regarding the primary end point PFS (13.0 vs 10.1 months; HR 0.66; 95% CI 0.46 -- 0.95; p = 0.03). Additionally, a trend towards a greater benefit in OS (28.9 vs 41.3 months; HR 0.63; 95% CI 0.39 -- 1.02; p = 0.058) [58,89] was shown. These results are comparable to an extent with those of the FIRE-3 trial. FIRE-3 is the first randomized Phase III trial to compare FOLFIRI plus bevacizumab or cetuximab in first-line for K-Ras exon 2 wt mCRC patients. Although the primary end point of the study was not met as no differences were found in response rate, nor in PFS, this trial showed a clear advantage in OS for the cetuximab arm [90]. In an extended Ras analysis, patients with a Ras wt had longer OS when allocated to the cetuximab arm (33.1 vs 25.6 months; HR 0.70; 95% CI 0.53 -- 0.92; p = 0.011). No statistical differences were found in PFS or ORR in the Ras wt population [91]. Second-line In the second-line setting all the published studies include irinotecan-based as the backbone chemotherapy. The single arm PRECEPT trial enrolled a total of 116 patients of whom 59% were K-Ras wt and, evaluated panitumumab as second-line therapy with a prespecified analysis of K-Ras status. In the K-Ras wt subgroup of patients a numerical difference was found for the three outcome parameters evaluated compared to patients with K-Ras mt: response rate (23 vs 16%), PFS (26 vs 19 weeks) and OS (50 vs 31 weeks). The toxicity profile was comparable to previously published data with FOLFIRI combination [92]. The STEPP Phase II randomized trial evaluated the efficacy of preemptive rash treatment consisting of skin moisturizers, 4.2.2

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sunscreen, topical steroid, and doxycycline previous to rash appearance, compared to reactive skin treatment. This trial included a total of 95 patients treated either with FOLFIRI or irinotecan plus panitumumab. The main end point of the study was met as the incidence of skin rash grade >/= 2 was significantly lower in the preemptive treatment group compared to the reactive group (29 vs 62%) [93]. Later on, Mitchell et al. reported data by K-Ras status on an efficacy secondary analysis of the STEPP study. K-Ras wt status correlated numerically with better ORR (16 vs 8%; OR: 2.0; 95% CI 0.5 -- 8.2), better PFS (5.5 vs 3.3 months; HR 0.8; 95% CI 0.4 -- 1.3) and slightly better OS (13.7 vs 13.1 months; HR 0.8; 95% CI 0.4 -- 1.5) compared to patients harboring a K-Ras exon 2 mutation [49]. The SPIRITT randomized Phase II trial evaluated the combination of FOLFIRI plus bevacizumab or panitumumab in K-Ras exon 2 wt mCRC patients treated with first-line oxaliplatin-bevacizumab based chemotherapy. This estimation study enrolled 185 patients and no differences in PFS or OS were reported [94]. More recently, results from a Phase II study of panitumumab in combination with irinotecan every three weeks in K-Ras wt mCRC patients have been published. This trial included 53 patients and the primary end point was the ORR, reporting 23% of partial responses and 41% disease stabilizations. Secondary end points included evaluation of PFS (4.5 months) and OS (15.1 months). The authors reported a correlation with the presence of skin rash toxicity grade 2 or higher and the tumor response [95]. Third line In the third line a Phase II trial enrolling 148 chemorefractory patients evaluated the efficacy of panitumumab monotherapy. The primary end point was response rate according to EGFR expression measured by immunohistochemistry. The reported ORR was 9% and did not vary significantly among patients with high or low EGFR expression. Skin toxicity correlated with better survival as patients with grade 2 -- 4 had longer PFS and OS compared to those with grade 1-0 (HR; 0.67; 95% CI 0.50 -- 0.90 for PFS and HR 0.72; 95% CI 0.54 -- 0.97 for OS) [96]. In Asian population the efficacy of panitumumab administered in monotherapy in the third-line setting was evaluated in a Phase II trial that enrolled 52 patients with EGFR positive staining. The authors reported an ORR of 13.5%, a PFS of 8 weeks and a median OS of 9.3 months. No differences according to EGFR staining intensity were found. Pharmacokinetics and toxicity did not differ from the previously reported in western populations. Retrospective K-Ras analysis was performed in 16 of the total patients and was pooled with data of 8 patients of another Phase I trial. Of this subgroup the four patients who achieved a partial response (n = 4) were K-Ras wt [97]. The only third-line setting Phase II trial published to date to evaluate panitumumab in combination with chemotherapy 4.2.3


Panitumumab

Table 1. Phase II studies. Study name Author (year) First-line Berlin (2007) [85]


Kohne (2012) [86] MetaPan Leone (2013) [87] Fornaro (2013) [88] PEAK Schwartzberg (2013) [58,89] Second-line PRECEPT Cohn (2010) [92] STEPP Mitchell (2011) [49] Carrato (2013) [95] SPIRITT Hecht (2013) [94] Third-line Hecht (2007) [96] Muro (2009) [97] Andre (2012) [98]

Treatment schemes

Number of patients

Response rate%

PFS m‡ (95 % CI)

OS m‡ (95 % CI)

IFL + pmab FOLFIRI + pmab FOLFIRI + pmab

19* 24* K-Ras wt = 86 K-Ras mt = 59 K-Ras wt = 35 All patients = 49 Ras/B-Raf wt = 37 K-Ras wt = 142 K-RAs wt = 143 Ras wt = 88 Ras wt = 81

47 33 56 38 65.7 54 89 58 54 64 60

5.6 (4.4 -- 8.3) 10.9 (7.7 -- 22.5) 8.9 (7.6 -- 14.3) 7.2 (5.6 -- 7.8)

17 (13.7-NE) 22.5 (11.4-NE)

8.4 (6.8 -- 9.9) 11.3 (9.7 -- 12.9) 10.9 (9.7 -- 12.8) 10.1 (9.0 -- 12.0) 13.0 (10.9 -- 15.1) 10.1 (9.0 -- 12.7)

21.9 (13.3 -- 30.6) 34.2 24.3 41.3 28.9

K-Ras K-Ras K-Ras K-Ras K-Ras K-Ras

23 16 16 8 23 32 19

26 w (19 -- 33) 19 w (12 -- 25) 5.5 (4.0 -- 6.8) 3.3 (2.9 -- 5.2) 4.5 (2.1 -- 8.4) 7.7 (5.7 -- 11.8) 9.2 (7.8 -- 10.6)

50 w (39 -- 76) 31 w (23 -- 47) 13.7 (10.0-NE) 13.1 (9.2 -- 13.8) 15.1 (4.5 -- 22.5) 18.0 (13.5 -- 21.7) 21.4 (16.5 -- 24.6)

9 13.5 35.2 29.2 46.3

14 w (8 -- 16) 8 w (7.4 -- 11.4) 6.3 (3.7 -- 8.7) 5.5 (3.7 -- 7.6) 8.7 (5.5 -- 10.4)

8.6 (5.9 -- 9.8) 9.3 (7.1 -- 12.8) 11.9 (6.8 -- 18.2) 9.7 (6.6 -- 15.8) 15.8 (9.5 -- 25.1)

XELOX + pmab FOLFOXIRI + pmab FOLFOX + pmab FOLFOX + bevacizumab FOLFOX + pmab FOLFOX + bevacizumab FOLFIRI + pmab FOLFIRI/Iri vs FOLFIRI/Iri + pmab Irinotecan + pmab FOLFIIR + pmab vs FOLFIRI + bevacizumab Pmab monotherapy Pmab monotherapy Irinotecan + pmab

wt = 64 mt = 45 wt = 49 mt = 38 wt = 53 wt = 182

185* 52 K-Ras wt = 54 All patients = 65 Ras + B-Raf wt = 41

(26.6-NRE) (21.0 -- 29.2) (28.8 -- 41.3) (23.9 -- 31.3)

*K-Ras not evaluated. z m: Median months unless otherwise specified. FOLFIRI: 5-Fluoruracil continuous infusion, irinotecan, leucovorin; FOLFOXIRI: 5-Fluorouracil, oxaliplatin, irinotecan, leucovorin; IFL: Irinotecan bolus, 5-fluoruracil, leucovorin; Iri: Irinotecan; mt: Mutated; NE: Not estimable; NRE: Not reached; OS: Overall survival; PFS: Progression-free survival; pmab: Panitumumab; RR: Response rate; w: Weeks; wt: Wild type.

included 54 K-Ras wt previously treated with 5-fluorouracil, oxaliplatin and irinotecan with or without bevacizumab. For this group of patients the ORR was 35.2%, increasing to 46.3% when N-Ras and B-Raf mutations were also analyzed, compared to no tumor response found in the mutated group of patients. This trial proved the combination of panitumumab plus irinotecan as an active regime in a highly selected refractory population [98]. The efficacy of panitumumab monotherapy after progression to cetuximab in K-Ras wt patients was evaluated in a single arm Phase II study. Twenty patients were treated but no responses were reported and 45% of the patients presented stable disease, proving the minimal efficacy of panitumumab in this setting (data not shown in Table 1) [99]. Phase III trials Data from Phase III trials have been summarized in Table 2. 4.3

First-line To date, two Phase III trials have appraised the value of panitumumab in the first-line setting. The multicenter, randomized, two-arm PRIME study evaluated FOLFOX with 4.3.1

or without panitumumab combination in 1183 mCRC patients. Results were prospectively analyzed by K-Ras status. The study met its primary end point as in the K-Ras wt population the median PFS was improved in the panitumumab arm (9.6 vs 8.0 months; HR 0.80; 95% CI 0.66 -- 0.97; p = 0.02). As secondary end points, the OS was also superior in the panitumumab arm in patients with K-Ras wt tumors but this difference did not reach statistical significance (23.9 vs 19.7 months; HR, 0.83; 95% CI 0.67 -- 1.02; p = 0.072) [69]. Later on, an updated OS analysis with 82% of events showed a statistically significant survival benefit (23.8 vs 19.4 months; HR 0.83; 95%CI 0.70 -- 0.98; p = 0.03) [100]. In the same manner, response rate was higher in the K-Ras wt treated with panitumumab (55 vs 48%; p = 0.068), although resection rates did not vary. The toxicity profiles were similar in both arms except for the ones associated with the anti-EGFR treatment. Of notice in this study was the finding of a detrimental effect of panitumumab in the K-Ras mt subgroup of patients, who had a significantly shorter PFS (HR 1.29; 95% CI 1.04 -- 1.62; p = 0.02) and a tendency towards shorter OS (HR 1.24; 95% CI 0.98 -- 1.57; p = 0.068) compared to the control arm group.


541

542


BSC + pmab BSC BSC + pmab BSC BSC +pmab BSC Pmab Cmab

FOFIRI + pmab FOLFIRI FOLFIRI + pmab FOLFIRI Iri + pmab Iri Iri + pmab Iri

FOLFOX4 + pmab FOLFOX4 FOLFOX4 + pmab FOLFOX4 FOLFOX4 + pmab FOLFOX4 Oxa + Bev + pmab Oxa + Bev Oxa + Bev + pmab Oxa + Bev Iri + Bev + pmab Iri + Bev Iri + Bev + pmab Iri + Bev

Treatment schemes

17 0 0 0 15 22 19.8

K-Ras wt = 124 K-RAs wt = 119 K-Ras mt = 84 K-Ras mt = 100 Ras wt = 136 K-Ras wt = 499 K-Ras wt = 500

K-Ras wt = 303 K-RAs wt = 294 K-Ras mt = 238 K-Ras mt = 248 K-Ras wt = 230 K-Ras wt = 230 All wt*

35 10 13 14 34 12 43.8 12.3

50 56 47 44 54 48 30 38

K-Ras K-Ras K-Ras K-Ras K-Ras K-Ras K-Ras K-Ras

wt = 201 wt = 203 mt = 135 mt = 125 wt = 57 wt = 58 mt = 47 mt = 39

55 48 40 40

RR (%)

K-Ras wt = 322 K-Ras wt = 327 K-Ras mt = 217 K-Ras mt = 218 Ras wt = 512

Number of patients

< 0.0001

< 0.0001

< 0.0001

0.068

RR p value

4.1 4.4

12.3 w 7.3 w 7.4 w 7.3 w

5.9 3.9 5.0 4.9

9.6 8 7.3 8 10.1 7.9 9.8 11.5 10.4 11.0 10.0 12.5 8.3 11.9

PFS m

0.02 0.004

1.29 (1.04 -- 1.62) 0.72 (0.58 -- 0.90)

0.015

0.78 (0.64 -- 0.95)

1.00 (0.88 -- 1.14)

0.38 (0.27 -- 0.56)

0.99 (0.73 -- 1.36)

0.45 (0.34 -- 0.59)

0.0001

0.14

0.85 (0.68 -- 1.06)

0.68 (0.53 -- 0.86)

0.004

0.73 (0.59 -- 0.90)

1.19 (0.65 -- 2.21)

1.50 (0.82 -- 2.76)

1.25 (0.91 -- 1.71)

1.36 (1.04 -- 1.77)

0.02

p value*

0.80 (0.66 -- 0.97)

HR (95% CI)

10.4 10.0

14.5 12.5 11.8 11.1 10.4 10.5

23.9 19.7 15.5 19.3 26.0 20.2 20.7 24.5 19.3 19.3 NE 19.8 17.8 20.5

OS m

0.97 (0.84 -- 1.11)

10.1 (0.82 -- 1.22)

0.92 (0.73 -- 1.16)

1.01 (0.83 -- 1.23)

0.94 (0.76 -- 1.15)

0.85 (0.70 -- 1.04)

2.14 (0.82 -- 5.59)

1.28 (0.50 -- 3.25)

1.02 (0.67 -- 1.54)

1.89 (1.30 -- 2.75)

0.78 (0.62 -- 0.99)

1.24(0.98 -- 1.57)

0.83 (0.67 -- 1.02)

HR (95% CI)

0.0007z

0.81

0.91

0.12*

0.445

0.045

0.04

0.068

0.072

p value

*K-Ras, N-Ras, B-Raf, PI3K wild-type. z Non-inferiority. Bev: Bevacizumab; BSC: Best supportive care; Cmab: Cetuximab; FOLFIRI: Irinotecan, 5-fluoruracil continuous infusion, leucovorin; FOLFOX: Oxaliplatin, 5-fluoruracil continuous infusion, leucovorin; Iri: Irinotecan-based chemotherapy; m: Median months; mT: Mutant; NE: Not estimable; OS: Overall survival; Oxa: Oxaliplatin-based chemotherapy; PFS: Progression-free survival; RR: Response rate; w: Weeks; wt: wild type.

ASPECCT Price (2013) [91]

Third-line Van Custsem (2007) [10,37,59]

PICCOLO Seymour (2013) [57]

Second-line Peeters (2010) [38]

PACCE Hecht (2009) [101]

First-line PRIME Douillard (2010) [8,14]

Study/author

Table 2. Phase III studies.


A. Sebio et al.


Panitumumab

Recently, further biomarker analyses of this trial examined K-Ras mutations in exons 3 and 4, N-Ras mutations in exons 2,3 and 4 and B-Raf mutations in the subgroup of patients with K-Ras wt exon 2 (n = 639). Patients wt for all Ras mutations (n = 512) and treated in the panitumumab arm achieved longer PFS (10.1 vs 7.9 months; HR 0.72; 95% CI 0.58 -- 0.90: p = 0.004) and OS (26.0 vs 20.2 months; HR 0.78; 95% CI 0.62 -- 0.99; p = 0.04). Furthermore, a detrimental effect for patients with any Ras mutation was found when treated in the panitumumab arm (7.3 vs 8.7 months; HR 1.31; 95% CI 1.07 -- 1.60; p > 0.001 for PFS and 15.5 vs 18.7 months; HR 1.21; 95% CI 1.01 -- 1.45; p = 0.001 for OS) The analysis of B-Raf mutation revealed a poor prognosis for these patients with a reduced OS regardless of treatment (10.5 months in the combination arm and 9.2 months in the FOLFOX4 alone arm; HR 0.90; 95% CI 0.46 -- 1.76; p = 0.76) [14]. Additionally, the analysis of the tumor shrinkage at week 8 demonstrated that in the panitumumab arm patients with a native Ras mutational profile who achieved early tumor shrinkage had a median OS of 33.1 (29.8- not reached) [100]. The PACCE trial was a multicenter randomized four-arm study evaluating the addition of panitumumab to oxaliplatin or irinotecan-based chemotherapy plus bevacizumab. A total of 823 and 230 patients were assigned to the oxaliplatin and irinotecan cohorts, respectively. The end point of the study was PFS in the oxaliplatin-treated cohort. The preplanned interim analysis of 813 patients in the oxaliplatin arm lead to the premature closure of the study as the panitumumb treated arm revealed a significantly worse PFS compared to the control arm (10.0 vs 11.4 months; HR 1.27; 95% CI 1.06 -- 1.52). Median OS also favored the control arm with 24.5 months compared to 19.4 months (HR 1.43; 95% CI 1.11 -- 1.83). In the irinotecan arm, PFS also favored the control group although these differences did not reach statistical significance (HR 1.19; 95% CI 0.79 -- 1.79). K-Ras status was evaluated retrospectively showing that the response rate did not vary depending on the presence of K-Ras mutation in neither chemotherapy group. Furthermore, in the oxaliplatin treated K-Ras wt population a difference was found favoring the control arm (Table 2). Regarding the safety analyses, the addition of panitumumab was also detrimental as more grade 3 -- 4 adverse effects were reported in the panitumumab arms compared to the control in both chemotherapy cohorts. Thereby, 19% of all the patients treated in the panitumumab arms experienced serious adverse effects. Several explanations for these results were postulated, mainly focusing in how the increased toxicity in the experimental arms influenced dose delays and intensity. The authors hypothesized that dual inhibition of tissue repair and the VEGF pathway could account for the high toxicity rate especially diarrhea and pulmonary embolism. Additionally, pharmacodynamics interactions between the two monoclonal antibodies as well as methodological factors such as the four-arm design were also mentioned as possible contributors to the results of the trial [101].

Similar results were also found in the CAIRO2 Phase III trial evaluating capecitabine plus oxaliplatin plus bevacizumab with or without cetuximab. The addition of cetuximab had a detrimental effect on PFS [102]. Second-line The two Phase III studies of panitumumab in the second-line setting had irinotecan as their backbone chemotherapy. The first trial was a multicenter, randomized two-arm evaluating FOLFIRI versus FOLFIRI plus panitumumab that included 1083 patients of whom 597 were K-Ras wt. In the K-Ras wt population, PFS was improved in the panitumumab arm with a median of 5.9 months compared to 3.9 months in the control arm (HR 0.73; 95% CI 0.59 -- 0.90; p = 0.04). The OS, the other coprimary end point, showed a nonsignificant difference toward increased OS with a median of 14.5 months in the panitumumab arm compared to 12.5 months in the chemotherapy alone arm (HR 0.85; 95% CI 0.70 -- 1.04; p = 0.12). The addition of panitumumab improved the response rate from 10 to 35% also in the K-Ras wt population. No unexpected adverse events were reported [38]. The recently published multicenter, randomized two-arm PICCOLO study evaluated the addition of panitumumab to irinotecan in a K-Ras wt population fluorouracil-resistant that included 460 patients. The study did not meet its primary end point, as the differences in OS did not favor the panitumumab arm: 10.4 versus 10.5 months in the control arm (HR 0.92; 95% CI 0.73 -- 1.04). Nonetheless longer PFS (HR 0.78; 95% CI 0.64 -- 0.95; p = 0.015) and higher response rate (34 vs 12%; p < 0.0001) were reported for the panitumumab arm. Additional biomarker analysis was performed to evaluate less frequent K-Ras mutations (c146), as well as N-Ras, PI3K, and B-Raf mutations. When analyzed as predictive markers, patients wt for all the tested mutations had better PFS (HR 0.68; 95% CI 0.53 -- 0.86) but no differences were found in OS (HR 0.92; 95% CI 0.73 -- 1.16). On the contrary, patients with any mutation experienced a detrimental effect in OS when allocated to the panitumumab arm (HR 1.64; 95% CI 1.1 -- 2.3; p = 0.028). Furthermore, in a post-progression analysis patients in the panitumumab group had a reduced survival, which was more pronounced in the any-mutation group. When these mutations were evaluated as prognostic markers in the irinotecan alone treated population, patients bearing tumors with any mutation had worse OS compared to all wt patients (p = 0.049) [57]. 4.3.2

Third-line The multicenter, randomized two-arm trial which lead to the first approval of panitumumab in the third-line setting included 463 patients with at least 1% EGFR cell membrane staining. In this study patients were randomized to receive BSC or BSC plus panitumumab. Median PFS was statistically better in the panitumumab arm: 8 weeks compared to 7.3 weeks (HR 0.54; 95% CI 0.44 -- 0.66; p < 0.0001). Responses were 10% in the experimental arm and 0% in the 4.3.3


543


A. Sebio et al.

BSC arm. No difference was reported for OS (HR 1.00; 95% CI 0.82 -- 1.22), however, a 76% cross-over between arms was reported [37]. K-Ras status was retrospectively evaluated showing a stronger benefit for the panitumumab arm in the wt population with a median PFS of 12.3 weeks compared to 7.3 weeks in the K-Ras mt (HR 0.45; 95% CI 0.34 -- 0.59; p < 0.0001) [12]. Additional biomarker analysis including K-Ras exon 4 and N-Ras decreased the HR to 0.38 (95% CI 0.27 -- 0.56) [103]. Cetuximab is also approved in the same third-line setting [104]. The ASPECCT trial was designed to prove panitumumab non-inferior to cetuximab in the chemorefractory K-Ras wt population. Recently known results have shown that at a median follow-up of > 9 months, median OS was 10.4 months with panitumumab and 10.0 months with cetuximab (HR 0.97; 95% CI 0.84 -- 1.11; p = 0.0007). Median PFS was also similar: 4.1 months for panitumumab and 4.4 months for cetuximab (HR 1.00; 95% CI 0.88 -- 1.14). The objective response rates were 22.0 and 19.8%, respectively. Regarding toxicity, in the panitumumab arm skin toxicity grade 3 or 4 was more common (12.5 vs 9.5%), as well as hypomagnesemia (7.2 vs 2.6%). Infusion reactions were more frequent in the arm cetuximab (1.8 vs 0.2%) [105]. 5.

Expert opinion

Until very recently, the benefit of panitumumab had been limited to an increase in the response rate as well as in the PFS, in the wt K-Ras stratum in first-, second-, and thirdline settings. Nonetheless, an updated analysis of the Phase III PRIME study with 82% OS events showed a marginal benefit in OS for the K-Ras exon 2 wt patients in the panitumumab group [100]. Further biomarker analyses have revealed the value of N-Ras mutations as predictors of response to anti-EGFR treatment. In the PRIME study, additional analyses of K-Ras exons 3 and 4 and N-Ras mutations have helped to further delineate the population that would benefit the most from the panitumumab addition to FOLFOX4 chemotherapy. In the all-wt population the OS reached 26 months compared to 20.2 months in the anymutation population. Despite of representing a relatively small percentage of patients, the additional biomarker analysis significantly improved the OS (HR = 0.78, p = 0.04). In the same manner, recent data from the FIRE-3 study (FOLFIRI plus cetuximab or bevacizumab, first-line in K-Ras wt) have paralleled these results by reporting an improvement in OS in the patients bearing wt Ras tumors in the cetuximab arm [90,91]. Of notice in the PRIME study was the finding of a detrimental effect of panitumumab in the patients bearing a tumor with any Ras mutation. These patients presented shorter PFS and OS when allocated to the panitumumab--FOLFOX4 combination compared to the FOLFOX4-alone group. This fact had already been reported in the first publication of the study [8] and, remained consistent when all Ras mutations were analyzed [14]. Interestingly, 544

similar findings were reported in a Phase II trial of FOLFOX plus cetuximab [7]. Moreover, data from the PICCOLO study, which had irinotecan as the backbone chemotherapy, have shown similar results as a detrimental effect in OS was found for the patients with any mutation allocated to the panitumumab arm [57]. Recently updated results from the PEAK study have also shown an improvement in OS in the K-Ras wt population. Additionally, these results are also in keeping with the importance of Ras testing for optimizing the use of anti-EGFR therapies as the evaluation of these markers revealed a significant improvement in the PFS and OS [58]. These results are comparable to an extent with results from the FIRE-3 study in which the extended analysis of Ras has also improved OS for Ras wt patients treated with FOLFIRI plus cetuximab first-line, although no statistical differences in PFS were found [91]. In the second-line setting the evaluation of other Ras mutations beside K-Ras exon 2 has not yielded the same results as in the first-line as none of the two published studies resulted in increased OS. Regarding the study of FOLFIRI with or without panitumumab in the second-line, for the K-Ras wt population a numerical difference toward an increased OS was found in the panitumumab arm, but this difference did not reach statistical significance. To date no N-Ras analysis has been performed in this study. In the PICCOLO study the primary end point was not met as no differences in survival were found, however, an imbalance in the use of EGFR inhibitor in subsequent lines of therapy was reported (6 vs < 0.5%). The additional biomarker analysis performed did not improve OS when patients with K-Ras mutations, N-Ras, PI3K, and B-Raf mutations were excluded. Nonetheless, patients with any mutation presented shorter OS when treated with panitumumab as previously mentioned. Overall, recent data on panitumumab trials clearly state an improvement in OS in the first-line setting. Deeper biomarker analysis beyond the established K-Ras mutation has proven useful to improve the selection of patients whom are more likely to benefit from panitumumab. Furthermore, there is growing evidence that a comprehensive Ras analysis can help prevent a detrimental effect and unnecessary toxicity derived from panitumumab. The extended Ras analysis data come from retrospective analyses. The fact that the data have been reproduced in various trials, and the unlikeliness that prospective trials will be designed to confirm these results, makes us believe that extended Ras analysis will be soon introduced into clinical practice. The data discussed in this review underscore the importance of retrospective analysis and currently other promising biomarkers like other mutations in EGFR pathway components are being tested. However, more efforts should be made to include prospectively designed biomarker analysis in all clinical trials. The design of future clinical trials should also take into consideration the molecular differences in CRC depending on tumor location and gender.


Panitumumab

Declaration of interest A Sebio is the recipient of Rio Hortega contract by Instituto de Salud Carlos III. S Stintzing is a postdoctoral fellow of Bibliography


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Affiliation Ana Sebio1, Sebastian Stintzing1, Stefan Stremitzer1, Wu Zhang1 & Heinz-Josef Lenz†1,2 MD † Author for correspondence 1 University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Division of Medical Oncology, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA Tel: +1 323 865 3967; Fax: +1 323 865 0061; E-mail: [email protected] 2 University of Southern California, Keck School of Medicine, Department of Preventive Medicine, Los Angeles, CA, USA

Patient considerations in metastatic colorectal cancer - role of panitumumab.

Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival.

Primary Tumor Resection and Overall Survival in Patients With Metastatic Colorectal Cancer Treated With Palliative Intent.

Modified two-dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer.

Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer.

Panitumumab in Metastatic Colorectal Cancer: The Importance of Tumour RAS Status.

Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report.

Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer.

Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

ASPECCT: panitumumab versus cetuximab for colorectal cancer.

ASPECCT: panitumumab versus cetuximab for colorectal cancer.

Does KRAS testing in metastatic colorectal cancer impact overall survival? A comparative effectiveness study in a population-based sample.

Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer.

Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer.

Surrogate markers of overall survival in metastatic colorectal cancer: an evolving challenge still more complex with repeat surgery.

Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer.

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.

Prolonged survival in metastatic colorectal cancer following chemotherapy.

Chromothripsis and progression-free survival in metastatic colorectal cancer.

Baseline hemoglobin and liver function predict tolerability and overall survival of patients receiving radioembolization for chemotherapy-refractory metastatic colorectal cancer.

A prognostic classifier consisting of 17 circulating cytokines is a novel predictor of overall survival for metastatic colorectal cancer patients.

Visceral Obesity Predicts Fewer Lymph Node Metastases and Better Overall Survival in Colon Cancer.

Methodologic diligence is needed to define and validate tumor-size response metrics to predict overall survival in first-line metastatic colorectal cancer.

II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer.