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Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.

Background

The efficacy of combined therapies of oxaliplatin-based chemotherapy and anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MAbs) remains controversial in colorectal cancer (CRC). The aim of this study is to estimate the efficacy and safety of adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first line treatment in KRAS wild type patients with metastatic colorectal cancer (mCRC) through meta-analysis.

Methods

Medline, EMBASE, and Cochrane library, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated oxaliplatin-based chemotherapy with or without anti-EGFR drugs (cetuximab or panitumumab) in untreated KRAS wild type patients with mCRC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. Hazard ratios (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals.

Results

This meta-analysis included four RCTs with 1270 patients, and all of the patients were administered oxaliplatin-based chemotherapy regimens with or without anti-EGFR MAbs. The result of heterogeneity of OS was not significant. Compared with chemotherapy alone, the addition of cetuximab or panitumumab didn’t result in significant improvement in OS (HR = 1.00, 95%CI [0.88, 1.13], P = 0.95) or PFS (HR = 0.86, 95%CI [0.71, 1.04], P = 0.13). The subgroup analysis of cetuximab also revealed no significant benefit in OS (HR = 1.02, 95%CI [0.89, 1.18], P = 0.75) or in PFS (HR = 0.87, 95%CI [0.65, 1.17], P = 0.36). Patients who received combined therapy didn’t have a higher ORR (Risk Ratio = 1.08, 95%CI [0.86, 1.36]). Toxicities slightly increased in anti-EGFR drugs group.

Conclusions

The addition of cetuximab or panitumumab to oxaliplatin-based chemotherapy in first-line treatment of mCRC in wild type KRAS population did not improve efficacy in survival benefit and response rate. More RCTs are warranted to evaluate the combination of chemotherapy and targeted therapy.

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.

Two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) have been approved in Canada for the treatment of metastatic colorectal cancer (mCRC) – cetuximab, a mouse-human chimeric MoAb, and panitumumab, a fully human MoAb. This paper reviews the efficacy of the anti-EGFR monoclonal antibodies cetuximab and panitumumab – both as monotherapy and in combination with cytotoxic chemotherapy – in the treatment of mCRC. Both cetuximab and panitumumab have demonstrated clinical efficacy in monotherapy in patients with mCRC, an advantage that has recently been found to be limited largely to those with wild-type KRAS tumors. Advantages of using these agents in monotherapy include reduced cost and toxicity. While the addition of cetuximab to irinotecan has shown superior progression-free survival and response compared with cetuximab monotherapy, there is currently no evidence for a benefit of panitumumab in combination with irinotecan.

Background:

Panitumumab is a fully human anti-epidermal growth factor receptor monoclonal antibody approved as monotherapy for patients with metastatic colorectal cancer. The 181 study was designed to evaluate the efficacy and safety of panitumumab with FOLFIRI vs. FOLFIRI alone as second-line treatment for metastatic colorectal cancer according to tumor KRAS mutational status.

Methods:

This was a randomized, multicenter, phase 3 study. Patients were randomized 1:1 to receive panitumumab 6.0 mg/kg Q2W+FOLFIRI vs. FOLFIRI alone. Patients had metastatic adenocarcinoma of the colon or rectum; only 1 previous chemotherapy regimen for mCRC; ECOG 0-2 and available tumor tissue for biomarker testing. Randomization was stratified by ECOG 0-1 vs. 2, previous oxaliplatin, and previous bevacizumab exposure. The co-primary end points were progression-free survival and overall survival and were independently tested. Originally designed to compare the treatment effect in the all-randomized population, the study was amended to focus on hypothesis testing in the wild-type KRAS subset. KRAS status was determined by a blinded central laboratory using allele-specific PCR prior to the first efficacy analysis.

Results:

From June 2006 to March 2008, a total of 1,186 patients were randomized, signed informed consent, and received treatment. Overall demographics included 61% men, median (range) age 61 years (28–86), 48% ECOG 0, 45% ECOG 1. 1083/1186 pts (91%) had available tumor sample results for KRAS: 597 (55%) wild-type, 486 (45%) mutant. Preliminarily, across both arms, the most common grade 3 or 4 adverse events were neutropenia (19%), diarrhea (12%), rash (8%), fatigue (6%), and dermatitis acneiform (4%).

Conclusions:

Efficacy and safety data will be presented by KRAS status and treatment arm.

Background:

Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without panitumumab in the two trials.

Methods:

Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.

Results:

In the first-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial.

Conclusion:

The addition of panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.

The tumor biology targeted therapies have improved outcomes in colorectal cancer (CRC). The epidermal growth factor receptor (EGFR) inhibitors represent one of these successful strategies. EGFR is frequently overexpressed in CRCs and associated with a malignant phenotype. Two EGFR inhibitors have shown efficacy in metastatic CRC, cetuximab and panitumumab. Cetuximab is a human–mouse chimeric monoclonal antibody that binds to the extracellular domain of the EGF-receptor. Similarly, panitumumab is a fully humanized monoclonal IgG2 antibody, directed against EGFR. Being fully humanized, panitumumab does not contain mouse protein reducing the risk of hypersensitivity. In a pivotal clinical trial, panitumumab was well tolerated and effective, demonstrating an objective response rate of 10% vs best supportive care (ORR = 0%; P < 0.0001). Panitumumab was approved for the treatment of mCRC by the FDA in 2006. Studies combining panitumumab with cytotoxic chemotherapy and other targeted therapies have been completed while others are ongoing to further evaluate the clinical utility of this agent. Recently it has been demonstrated that mutations in KRAS predict the efficacy of panitumumab and cetuximab, limiting their use to CRC patients with wild-type KRAS, and moving the clinical field towards personalized cancer care.

Background:

Panitumumab (pmab) is a fully human anti-epidermal growth factor receptor monoclonal antibody approved as monotherapy for patients (pts) with mCRC. The PRIME trial was designed to evaluate the efficacy and safety of pmab with FOLFOX4 vs. FOLFOX4 alone as first-line treatment for mCRC according to tumor KRAS mutational status.

Methods:

This was a randomized, multicenter, phase 3 study. Pts were randomized 1:1 to receive pmab 6.0 mg/kg Q2W+FOLFOX (Arm 1) vs. FOLFOX alone (Arm 2). Pts had metastatic adenocarcinoma of the colon or rectum; no previous chemotherapy for mCRC; no previous oxaliplatin therapy; ECOG 0-2; and available tumor tissue for biomarker testing. Randomization was stratified by ECOG 0-1 vs. 2 and region (Western EU, Canada, and Australia vs. rest of world). The primary end point was progression-free survival (PFS). Originally designed to compare the tx effect in the all-randomized population, the study was formally amended to focus on hypothesis testing in the wild-type (WT) KRAS subset. KRAS status was determined by a blinded central laboratory using allele-specific PCR after the completion of accrual, but prior to the primary analysis.

Results:

From August 2006 to February 2008, a total of 1,183 pts were randomized, signed informed consent, and received tx: 593 Arm 1, 590 Arm 2. Overall demographics included 63% men, median age 62 years (range: 24–85); 55% ECOG 0; 40% ECOG 1; 5% ECOG 2. 1096/1183 pts (93%) had available tumor sample results for KRAS: 656 (60%) WT, 440 (40%) mutant. Preliminarily, across both arms, the most common grade 3 or 4 adverse events were: neutropenia (40%), diarrhea (14%), rash (8%), paresthesia (7%), and hypokalemia (7%).

Conclusions:

Efficacy and safety data will be presented by KRAS status and treatment arm.

Purpose

Panitumumab monotherapy is approved for chemotherapy-refractory wild-type KRAS metastatic colorectal cancer (mCRC). Patient-reported outcomes—although important in the palliative setting—have not been reported in this patient population.

Methods

In a phase 3 trial (n = 463), patients with chemotherapy-refractory mCRC were randomized 1:1 to panitumumab plus best supportive care (BSC) or BSC alone. Patient-reported outcomes were assessed using the NCCN/FACT CRC Symptom Index (FCSI) and EQ-5D Index. KRAS tumor status was analyzed in a prospectively defined, retrospective analysis. Average difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.

Results

KRAS tumor status and post-baseline patient-reported outcomes were available for 363 patients. Linear mixed models indicated significant differences in the FCSI score (difference in least-squares [LS] adjusted means [95% CI]; 5.62 [2.38, 8.86]) and the EQ-5D Index (difference in LS adjusted means [95% CI]; 0.22 [0.12, 0.32]) favoring panitumumab over BSC in patients with wild-type KRAS mCRC. By pattern-mixture analysis, the advantage of panitumumab over BSC was more pronounced in those patients with wild-type KRAS mCRC who did not drop out of the study early. In patients with mutant KRAS mCRC, no differences were observed between groups.

Conclusions

Panitumumab-treated patients with wild-type KRAS mCRC maintained better control of CRC symptoms and quality of life compared with BSC alone, extending our understanding of the benefits of panitumumab treatment beyond improvements in progression-free survival.

Survival of patients with metastatic CRC (mCRC) has improved steadily over the past several decades, due largely to the development of new combinations of standard chemotherapy, as well as to the introduction of new targeted therapies. Among the available targeted therapies are two monoclonal antibodies that target the epidermal growth factor receptor (EGFR) – cetuximab and panitumumab – which have demonstrated efficacy in the treatment of mCRC. These therapies are associated with a unique set of toxicities and costs, prompting the need for tools to select patients who are most likely to derive a benefit from them. Mutations in the KRAS oncogene have consistently been shown to predict non-response to cetuximab and panitumumab. The role of KRAS as a marker of efficacy of anti-EGFR therapies is reviewed.

In January 2010, a panel of Canadian oncologists with particular expertise in colorectal cancer (crc) gathered to develop a consensus guideline on the use of therapies against the epidermal growth factor receptor (egfr) in the management of metastatic crc (mcrc). This paper uses a case-based approach to summarize the consensus recommendations developed during that meeting.

These are the consensus recommendations:

Testing for the KRAS status of the tumour should be performed as soon as an egfr inhibitor is being considered as an option for treatment.Anti-egfr therapies are not recommended for the treatment of patients with tumours showing mutated KRAS status.For a patient with wild-type KRAS and an Eastern Cooperative Oncology Group status of 0–2, whose mcrc has previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatin, switching to an egfr inhibitor is a recommended strategy.Cetuximab, cetuximab plus irinotecan, and panitumumab are all options for third-line therapy in patients with wild-type KRAS, provided that tolerability is acceptable.

The article examines the role of molecular markers pertaining to the appropriate use of targeted biologic agents in the treatment of metastatic colorectal cancer and discusses cost-effectiveness issues related to these agents.

Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab-naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan-naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA-approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild-type K-RAS tumors. The interpretation of the B-RAF mutation and other molecular markers may further define the appropriateness of anti-EGFR therapy. Recent literature revealed that the first-line use of combined anti-EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve.

The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.

EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.

Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.

Introduction:

Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.

Aims:

The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.

Evidence review:

The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.

Clinical potential:

To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined.

Purpose

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.

Patients and Methods

We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies.

Results

We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies.

Conclusions

Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab.

Discussion

Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

The treatment options currently available in the medical therapy of advanced colorectal cancer (CRC) appear to be an abundance of riches. The integration of oxaliplatin and irinotecan as conventional cytotoxic agents as well as bevacizumab and the epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, as novel targeted agents into standard medical therapy have improved median overall survival in metastatic CRC beyond 2 years. It cannot be overemphasized that these significant improvements in outcome of patients with CRC are closely linked to the number of active drugs available to treat this disease. The abundance of treatment options, however, comes with specific challenges for the practical management of palliative medical therapy in advanced CRC, in particular with regard to the utilization of targeted agents. In this context, bevacizumab has established itself as the standard component of first-line chemotherapy. It is of interest for clinical practice that so far no predictive marker for the activity of bevacizumab in metastatic CRC has been identified. The key questions surrounding the use of bevacizumab in the palliative setting are whether its continuation beyond tumor progression provides clinical benefit, and which patient group is at higher risk for bevacizumab-related toxicities. Cetuximab and panitumumab have demonstrated efficacy both in combination with chemotherapy or – in contrast to bevacizumab – as single agent. In unselected patients, the effect of both EGFR antibodies on time-related parameters, progression free survival and overall survival, is moderate at best with emphasis more on the induction of tumor responses in a select group of patients. Therefore, until recently, EGFR antibodies were mainly regarded as salvage therapy options, in particular, since there did not appear to be a loss of activity when used in later lines of therapy. The finding that CRC harboring KRAS (and BRAF) mutations are resistant to EGFR antibodies, has allowed us to enrich the patient population with CRC that have a chance to benefit from cetuximab or panitumumab therapy. Biomarker-based treatment decisions are therefore now an integral part of clinical practice and trial design in CRC. In conclusion, targeted agents have become an integral part of medical therapy for advanced CRC. The challenge for current oncologic practice is to develop a rationale and biomarker-based treatment algorithm utilizing all potentially active agents as individualized therapy.

Panitumumab is a fully humanized monoclonal antibody with a high degree of affinity for the extracellular domain of the epidermal growth factor receptor. Phase II clinical evaluation of this drug, when administered as a single agent, in patients with metastatic colorectal cancer refractory to chemotherapy, demonstrated a modest objective radiographic response rate with acceptable toxicity; the most frequently observed side effect is rash. A randomized phase III study in subjects with chemotherapy-refractory metastatic colorectal cancer documented a progression-free survival advantage in subjects treated with panitumumab plus best supportive care versus best supportive care alone; a difference in survival was not observed, likely due to the high cross over rate. Primary tumor KRAS mutation analysis performed in this study indicated that the benefit was confined to those patients whose tumors did not contain a KRAS mutation. Further studies with panitumumab will be required to develop biomarkers of response and to determine if panitumumab has a role in combination with cytotoxic chemotherapy. This article summarizes the current state-of-the-science knowledge on panitumumab therapy in the treatment of advanced colorectal cancer.

Background

Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial.

Methods

Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity.

Results

154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity.

Conclusions

First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity.

Trial registration

ClinicalTrials.gov NCT00508404

The results of a phase II study of bevacizumab and everolimus in patients with metastatic colorectal cancer are presented. Modest activity was observed.

Purpose.

For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC.

Methods.

Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily.

Results.

Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty-seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab-based therapy. Forty-nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression-free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for ≥6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1–2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade ≥3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%).

Conclusions.

Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients.

Background:

Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS.

Methods:

For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.

Results:

There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P<0.0001) and quality-adjusted OS (P=0.0303).

Conclusion:

In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone.

The human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, panitumumab, represents a significant advance in the treatment of colorectal cancer. The strategy to target this receptor is based on sound cancer biology demonstrating its essential role in colorectal carcinogenesis. Panitumumab, unlike its predecessor, cetuximab, is fully human and thus reduces the incidence of hypersensitivity reactions. But, in several clinical trials, unexpected toxicities have become more apparent, raising concerns of how readily panitumumab can succeed cetuximab. This paper reviews the development of this agent and the pivotal clinical trials that help our understanding of its optimal use in colorectal cancer treatment.

The biological agents approved for the treatment of patients with metastatic colorectal cancer – bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor A, along with cetuximab and panitumumab, two monoclonal antibodies that target the epidermal growth factor receptor – are associated with a number of adverse events that range in severity from relatively mild to potentially life threatening. Hypertension, thromboembolic events, proteinuria, bleeding, and gastrointestinal perforation have all been associated with bevacizumab, while dermatologic toxicities are common with cetuximab and panitumumab. Hypersensitivity reactions and hypomagnesemia are also a concern with cetuximab and panitumumab. The frequency of these adverse events in randomized clinical trials is reviewed, and recommendations for managing these events in patients undergoing treatment for metastatic colorectal cancer are provided.

AIM: To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients.

METHODS: Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and “high-grade” tumor budding was defined as 15 buds/high-power field.

RESULTS: Tumor buds and K-RAS mutation both correctly classified 68% of patients. All patients with K-RAS mutation (n = 7) or high-grade tumor budding (n = 11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P = 0.008)].

CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

In a randomised phase 3 trial, panitumumab significantly improved progression-free survival (PFS) in patients with refractory metastatic colorectal cancer (mCRC). This analysis characterises the association of PFS with CRC symptoms, health-related quality of life (HRQoL), and overall survival (OS). CRC symptoms (NCCN/FACT CRC symptom index, FCSI) and HRQoL (EQ-5D) were assessed for 207 panitumumab patients and 184 best supportive care (BSC) patients who had at least one post-baseline patient-reported outcome (PRO) assessment. Patients alive at week 8 were included in the PRO and OS analyses and categorised by their week 8 progression status as follows: no progressive disease (no PD; best response of at least stable disease) vs progressive disease (PD). Standard imputation methods were used to assign missing values. Significantly more patients were progression free at weeks 8–24 with panitumumab vs BSC. After excluding responders, a significant difference in PFS remained favouring panitumumab (HR=0.63, 95% CI=0.52–0.77; P<0.0001). At week 8, lack of disease progression was associated with significantly and clinically meaningful lower CRC symptomatology for both treatment groups and higher HRQoL for panitumumab patients only. Overall survival favoured no PD patients vs PD patients alive at week 8. Lack of disease progression was associated with better symptom control, HRQoL, and OS.