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The Lancet Oncology

Saturday, January 17, 2009

Tumor Mutation Predicts Effectiveness of Treatment for Colorectal Cancer

Routine screening of patients with metastatic colorectal cancer (mCRC) for mutations of KRAS, a gene that encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway, before initiating treatment with EGFr-inhibitors, will cut costs by providing treatment only to those patients who will benefit from the treatment and by helping those who will not benefit avoid unnecessary side effects.

This conclusion is based on an analysis of data presented during the sixth annual Gastrointestinal Cancers Symposium being held in San Francisco, California (January 15-17, 2009) by Dr.Veena Shankaran, MD, and his team from Northwestern University Feinberg School of Medicine, in Chicago, Illinois. These results demonstrate that savings can be realized by customizing therapy in any Gastrointestinal (GI) malignancy using a molecular tests.

European and US incidence
Gastrointestinal (GI) cancers include cancers of the esophagus, stomach, small intestine, colon, rectum, anus, pancreas and liver. More than 270,000 people are diagnosed with Gastrointestinal cancers in the United States every year and more than 135,000 people die from them annually.

In Europe, approximately 370,000 people develop colorectal cancer every year, accounting for 13% of the total cancer burden and an estimated 200,000 deaths. Around a quarter of CRC patients present with metastatic disease and for these patients survival rates areas low as 5%. Approximately 60-65% of mCRC patients have KRAS wild-type tumors.

The epidermal growth factor receptor plays an important role in carcinogenesis and tumor progression of colorectal cancer (CRC), a multi-step process involving the accumulation of molecular alterations in a number of genes and pathways of proliferative cells of the colon.
These molecular alterations lead to a loss of coordination between the processes of cellular proliferation and differentiation . Researchers have observed aberrations in the EGFR signaling pathway in a number of cancers including mCRC. Therefore, the EGFR has now evolved as a relevant target in the treatment of mCRC.

Monoclonal antibodies
Monoclonal antibodies
(MoAb), including cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), a human antibody against the epidermal growth factor receptor and panitumumab (Vectibix®, Amgen Inc, One Amgen Center Drive, Thousand Oaks, Ca 91320-1799), a fully human IgG2 monoclonal antibody that is highly selective for the epidermal growth factor receptor, inhibit EGFR activity. However, not all colorectal tumors respond, and not all patients benefit from these therapies. Recent discoveries have shown that the KRAS gene, when mutated, confers resistance to cetuximab and panitumumab by circumventing EGFR’s role in the signaling pathway.

In March 2008, the Journal of Clinical Oncology published results from an analysis of the first randomized, controlled clinical trial which showed that mCRC patients with mutated KRAS tumors do not respond to panitumumab monotherapy. Conversely, patients with wild-type KRAS tumors treated with panitumumab had a better response rate and a prolonged progression-free survival (PFS). Compared to best supportive care (BSC) alone, this therapy also had an impact on quality of life (QoL) and disease-related symptoms.

The Role of KRAS
Over twenty year of study has shown that the KRAS gene plays a central role in tumor development, regulating downstream proteins that are involved in proliferation, survival, metastasis and angiogenesis. It serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. Researcher identified the presence of activating KRAS mutations as a potent predictor of resistance to EGFR-directed monoclonal antibodies.

Anti-epidermal growth factor receptor (EGFr) therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to cancer cell signaling. However, in patients with tumors harboring a mutated or activated KRAS, the KRAS protein is always turned 'on' regardless of whether EGFr has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS, signaling continues despite anti-EGFr therapy. Mutated KRAS is detected in approximately 40% of CRC tumors.

Long term evidence
Although activating mutations in KRAS correlates with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker had not yet been established in randomized trials. A number of clinical trials have now demonstrated that patients can benefit from the addition of cetuximab to FOLFOX or FOLFIRI regime in the first-line treatment of metastatic CRC (mCRC). However, subsequent correlative analyses of these trials have also shown that this benefit is limited to patients whose tumors have wild type KRAS status by PCR-based testing.

A study by the Central European Cooperative Oncology Group (CECOG), the CECOG/CORE1.2.001 study, a randomized Phase II trial investigating the influence of KRAS status on the efficacy of cetuximab in combination with FOLFOX or FOLFIRI in the first-line treatment of 117 mCRC patients, provided a response rate (RR) of 53% in patients with KRAS wild-type tumors versus 36% in those with mutant tumors. The study also showed a trend towards improved overall survival (OS) in patients with KRAS wild-type tumors – 24.4 months for patients with KRAS wild-type tumors vs. 16.7 months for patients with KRAS mutant tumors (p=0.057).

‘It is really exciting to see such a consistent efficacy profile for cetuximab in patient populations defined by KRAS mutational status,' commented Prof. Thomas Brodowicz, MD from the University Hospital of Vienna, Austria, lead investigator of the CECOG/CORE1.2.001 study. 'This further highlights the absolute necessity to define mCRC according to the KRAS status of the tumor in order to determine the most effective treatment strategy and to provide patients with the best possible outcomes.’

The results of the CECOG/CORE1.2.001 study support the pivotal cetuximab trials – the randomized Phase III study CRYSTAL, also presented at this meeting, and OPUS recently published in the Journal of Clinical Oncology. Patients receiving cetuximab in the CRYSTAL and OPUS trials who had KRAS wild-type tumors showed similar response rates to those in the CECOG/CORE1.2.001 study, at 59%2 and 61%,3 respectively.

To further independently evaluate the association of KRAS status seen in a biomarker analysis of a Phase III, randomized, controlled clinical trial (the so-called ‘408’ study) that investigated the treatment effect of panitumumab monotherapy plus Best Supportive Care (BSC) versus BSC alone in patients with mCRC, additional retrospective analyses of all other studies of panitumumab monotherapy in mCRC were performed.

These data are consistent with 30 years of biology which indicate that KRAS is a clinically relevant oncogene,’ said Dr Sean Harper, MD., chief medical officer and head of Global Development at Amgen. ‘We believe the data from our panitumumab monotherapy trial indicates that the benefit-risk profile of panitumumab is improved by restricting use to those patients with mCRC whose tumors have wild-type KRAS genes.’

The data showed the relative effect of panitumumab versus best supportive care (BSC) was significantly greater in patients with non-mutated versus mutated KRAS (HR = 0.45 vs. HR = 0.99). Median PFS in patients without the mutation treated with panitumumab plus BSC was 12.3 weeks versus 7.3 weeks, respectively. When the analysis standardized the time to tumor assessment, the median PFS was 16 weeks versus 8 weeks, respectively (HR= 0.49 vs. 1.07). Some of these data were presented for the first time at the European Cancer Conference (ECCO) in September 2007, but a pooled analysis from data including more than 700 patients was presented at the European Society of Medical Oncology (ESMO) in 2008.

Additional endpoints of this analysis examined overall survival by KRAS status and treatment. When the treatment arms were combined (non-mutated vs. mutated) overall survival was longer in patients with non-mutated compared with mutated KRAS (HR = 0.67). No differences in overall survival were observed between panitumumab and BSC in either KRAS subgroup, potentially due to a high rate of crossover from BSC to panitumumab after progression, and similar efficacy of panitumumab in these patients.

In exploratory analyses, colorectal cancer symptoms and
health-related quality of life
(HRQoL) outcomes were compared between panitumumab and BSC treated patients using a validated instrument such as the Functional Assessment of Cancer Therapy-colorectal symptom index and HRQoL using the EQ-5D index, and the EORTC-QLQ-C30 Global Health Status. In patients with tumors carrying non-mutated KRAS genes, the analysis demonstrated that in panitumumab treated patients clinically meaningful inferior symptom control and QoL scores could be excluded compared to BSC, and that in fact, a clinically meaningful difference in favor of

Panitumumab was observed at most time points. In contrast, a clinically significant worsening of symptom control and QoL scores could not be excluded in patients with mutated KRAS tumors treated with panitumumab compared to best supportive care (BSC). The United States (U.S.) prescribing information states that the effectiveness of panitumumab as a single agent is based on progression-free survival. However, there is no currently data available that demonstrates an improvement in disease-related symptoms or increased survival with panitumumab.

In the panitumumab-treated group, patients with non-mutated KRAS had on average double the number of panitumumab infusions as patients with mutated KRAS (10.0 vs. 4.9). Additionally, 20 percent of the KRAS evaluable patients had a treatment-related grade 3 adverse event (12 percent mutated vs. 25 percent non-mutated).

New recommendations and opinions
In November 2008 the National Comprehensive Cancer Network (NCCN) announced, updates to their Guidelines on Colon and Rectal Cancers that included the recommendation that a determination of the KRAS gene status of either the primary tumor or a site of metastasis should be part of the pre-treatment work-up for patients diagnosed with metastatic colorectal cancer. Further, the guidelines recommended that EGFr inhibitors, including panitumumab, should only be used in patients with tumors characterized by the wild-type KRAS gene. These updates were prompted by a systematic review of the relevant literature.

Based on similar evidence, the American Society of Clinical Oncology (ASCO), last week released its first Provisional Clinical Opinion (PCO), reflecting the expert consensus based on clinical evidence on the use of KRAS gene mutation testing in patients with metastatic colorectal cancer. Provisional Clinical Opinions are intended to assist physicians in clinical decision-making and identify questions and settings for further research.

To help guide treatment with the anti-EFGR monoclonal antibodies (MoAb), such as cetuximab and panitumumab, the authors of this Provisional Clinical Opinion recommend that all patients with metastatic colorectal cancer who are candidates for anti-EFGR therapy have their tumors tested for KRAS gene mutations. If a patient has a mutated form of the KRAS gene, it recommends against the use of anti-EFGR antibody therapy, based on recent studies indicating this treatment is only effective in patients with the normal (wild-type) form of the KRAS gene. It is estimated that 40 percent of colon cancer patients have the KRAS mutation.

Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with MoAbs directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy.

Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status.

Researchers analyzed tumors from 587 patients with metastatic colorectal cancer for a mutated KRAS gene to determine which patients will benefit the most from treatment with a combination of chemotherapy and cetuximab. The KRAS gene is involved in the growth of cancer cells. About 30% to 45% of colorectal cancers have a KRAS mutation, which has been shown in previous studies to predict whether patients will benefit from treatment with drugs that block the epidermal growth factor receptor (EGFR), such as cetuximab.

Testing results in considerable savings
Shankaran and his team calculated the cost savings by creating an economic model derived from publicly available lab and drug-cost information and the 2008 estimated incidence of mCRC from the American Cancer Society. Clinical data were drawn from a recent, 2007, study by Van Cutsem and colleagues published in the
Journal of Clinical Oncology
investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing mCRC. The model used by Shankaran did not include the necessary additional costs associated with clinic appointments, infusion visits, and managing toxicity.

Based on the available data, there are an estimated 29,762 new cases of mCRC annually. The costs for screening is estimated to cost $13 million ($452.00/patient). Using the average wholesale price of cetuximab ($4,032.00/loading dose and $2,880.00/weekly dose for a patient of average height/weight) and assuming an average of 24 doses per patient, as seen in the analysis of the CRYSTAL trial, the first study to compare chemotherapy alone with chemotherapy plus cetuximab as the primary treatment for patients with metastatic colorectal cancer, drug cost per patient were estimated to cost $71,120.00.

According to Shankaran, data from studies indicate that the prevalence of KRAS mutations ranges from 35.6% to 42.3% in all patients with metastatic colorectal cancer. An even higher percentage has been recorded in several trials, suggestion KRAS mutations in up to 46% of all patients. Approximately 59% of patients whose tumors did not have a KRAS mutation and who received cetuximab and chemotherapy had a reduction in tumor size, compared with 43% of patients who received only chemotherapy. Patients with tumors with a mutated KRAS gene did not receive any benefit when cetuximab was added to chemotherapy.

With the assumption that patients with mutated KRAS (35.6% of all patients) would not receive cetuximab, theoretical drug cost savings would be $753 million; considering the cost of KRAS testing, net savings would be $740 million.

Benefit for patients
Commenting on the importance of these studies, Jennifer C. Obel, M.D., a gastrointestinal cancers specialist and attending physician at NorthShore University HealthSystem in Illinois, said ‘These studies address a pressing question in cancer care – how can we identify those patients who will benefit from treatment and differentiate them from those who will not?’

Because patients with colorectal cancer who carry KRAS mutations have been shown not to respond to treatment with EGFr-inhibitors, upfront KRAS testing to limit cetuximab therapy to patients with wild-type KRAS tumors can result in drug cost savings if patients with metastatic colorectal cancer undergoes first-line therapy with a cetuximab-containing regimen.

Dr Obel also said ‘In an era when the cost of cancer care continues to increase, the ability to tailor treatment to each patient’s disease could lead to improved outcomes and fewer side effects for patients, and significant cost savings.

Personalized medicine
This study helps us to identify which patients are most likely to benefit from adding cetuximab to treatment,’ said lead author Eric Van Cutsem, MD, PhD, Professor at the University Hospital Gasthuisberg in Leuven, Belgium. ‘KRAS testing in all people with colorectal cancer immediately after diagnosis could help doctors find the best treatment strategies for the individual patient.’

‘Based on available data, we believe that focusing panitumumab treatment on patients with wild-type KRAS tumors will avoid unnecessary adverse events in patients who are unlikely to benefit, maximize response rates and PFS in patients with wild-type KRAS genes, and redirect patients with a mutated KRAS gene to alternative therapies,' Sean Harper explained. 'We are thrilled to be taking a step forward in advancing the field of personalized medicine by being one of the first to realize the clinical potential of the KRAS gene in guiding treatment of advanced colorectal cancer patients.’

‘Personalized medicine is the next frontier in cancer care. Basing cancer treatment on the unique genetic characteristics of the tumor or the individual with cancer will improve patient outcomes and help avoid unnecessary costs and side effects for patients who are unlikely to benefit,’ said Richard L. Schilsky, MD, ASCO president and Professor of Medicine at the University of Chicago Medical Center. ‘Using KRAS testing to guide colorectal cancer treatment is a prime example of where cancer care is heading.’

Emphasizing the importance and the benefits for individual patients, Dr. Wolfgang Wein, MD Executive Vice President, Oncology, Merck Serono, concluded ‘This can help physicians help in the treatment decision-making process. Tailoring treatment for mCRC is now a reality. Through a simple diagnostic test, patients can be provided with a treatment that is most likely to succeed in their tumor type.’

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