Retuximab receives positive opinion in Europe for first-line treatment of chronic lymphocytic leukemia (CLL)

The European Union’s Committee on Human Medicinal Products (CHMP), on January 22, 2009, issued a positive recommendation for the use of rituximab, (MabThera®, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland / Rituxan®, co-marked in the United Sates by Genentech, 1 DNA Way South San Francisco, CA 94080-4990 and Biogen Idec , 14 Cambridge Center, Cambridge, MA 02142), with any chemotherapy combination as a first-line treatment for chronic lymphocytic leukemia (CLL), the most common form of adult leukemia. This recommendation is considered an important step towards license extension for rituximab in combination with chemotherapy as initial treatment.

Rituximab is a chimeric monoclonal antibody (mAb) against the protein CD20+ B-cell antigen used to treat previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy, as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab, for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy and as monotherapy for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

Early predictions, great potential

The FDA approved rituximab in 1997 as the first antibody approved for the treatment of patients with non-Hodgkin's lymphoma (approval in Europe followed in 1998). The launch of rituximab as a therapeutic agent fulfilled predictions dating back to the early 1900s regarding the therapeutic effect of antibodies and their potential in medicine.

In 1895 Charles Robert Richet (1850 – 1935) and Jules Héricourt described the first attempts of a novel anti-cancer treatment. Their approach was a radical departure from the standard cancer treatments available at that time. Instead of surgery, Richet and Héricourt immunized dogs with a human sarcoma and then transferred the serum to patients with advanced cancer. The idea was to raise an antiserum for treating the patient.

These bold scientists believed that a mechanism to target diseases selectively, know today as ‘passive serotherapy’, which was realized only a few years earlier when scientists discovered that resistance to infectious disease (diphtheria) could be transferred from one animal to another through their serum, would also work in treating cancer. Their pioneering work was the forerunner of the ‘magic bullet’ concept, later developed by the German scientist Paul Ehrlich (1854-1915), believed that ‘toxins’ could be targeted to cancer and other diseases.

The results of these initial attempts seemed very promising. And while several patients with different types of advanced cancer were treated and showed significant improvements in their symptoms, none of them were actually cured. These trials were repeated during the early 1900s, but, again, did not yield the results hoped for. Problems were readily acknowledged. Inconsistent and contradictory results, lack of specificity and reproducibility, lack of purity and xenogeneic immune responses ultimately led to disappointing conclusion that ‘nothing may be hoped for at present in respect to a successful therapy from this direction’.

The science of the times was not yet ready for a proper understanding of idea of a ‘magic bullet’ proposed by Ehrlich in 1908. More than a half-century passed before antibodies were identified as the substance in serum responsible for the effects initially observed by Richet, et al. Ultimately, Ehrlich’s concept of a ‘magic bullet’ was fully realized with the development of monoclonal antibodies (mAbs) in the 1970s.

The great leap forward
In 1975 Georges Jean Franz Köhler (1946 -1995) César Milstein (1927 – 2002) and Niels Kaj Jerne ( 1911 – 1994), started major developments in the field of monoclonal antibodies (mAbs) for which they were awarded the 1984 Nobel Prize in Physiology for Medicine.

Köhler’s and Milstein’s development of the hybridoma technique, the first practical method for mass-producing monoclonal antibodies, is considered one of the most important advances in medicine during the 1970s. This technique has, in less than a decade, revolutionized the use of antibodies in health care and research.

During the following two decades, potential monoclonal antibodies as laboratory tools were rapidly exploited for biotechnology and biomedical applications. Today, mAbs represent over 30% of all biological proteins undergoing clinical trials and are the second largest class of biodrugs after vaccines. With the help of antibody engineering, mAbs have been reduced in size, rebuilt into multivalent molecules, and conjugated with drugs, toxins, or radioisotopes for the treatment of cancer, autoimmune disorders, graft rejection, and infectious diseases. Additionally, in the past few years, important advances have been made in the design, selection, and production of new types of engineered antibodies.

Impact
Since the introduction of rituximab, hundreds of thousands of patients have been treated with the drug. In 2002, rituximab became the number one anticancer drug worldwide. During its first decade of use (1993-2003), rituximab has had an important impact on treatment strategies for lymphoma and other hematologic malignancies. During the 5 years following approval, its applications expanded beyond non-Hodgkin's lymphoma to a variety of malignant and non-malignant B-cell disorders. Also, as a result of its early clinical trials, initiatives came about that eventually led to the development of the new international response criteria for non-Hodgkin's lymphoma. Rituximab has been characterized as the most important therapeutic development of the decade.

Mechanism of Action
Rituximab effectively eradicates CD20+ cells in lymphoma patients by several unique and distinct mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis. It binds to CD20 on the surface of normal and malignant B-cells and then recruits the body's natural defenses to attack and kill the marked B-cells. B-cell progenitors in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.

Label extension

The label extension which will be possible as a result of CHMPs positive recommendation for the use of rituximab, is based on the impressive, highly significant results of the international CLL-8 study which showed that the median time until patients progressed with their disease, experienced a relapse or died was 40 months if patients were given rituximab plus chemotherapy compared to just 32 months for those that received chemotherapy alone.

Pending the final approval by the EU authorities, physicians will soon be able to prescribe rituximab to CLL patients in combination with their preferred chemotherapy regimen.

‘Treatment with MabThera achieved significantly better outcomes for the patients than chemotherapy alone. This provides hope for the future treatment of a disease that remains life-threatening and incurable,’ said William M. Burns, CEO of the Pharmaceuticals Division of Roche.

Incidence of CLL
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, accounting for approximately 25-30% of all forms of leukemia. Overall incidence of CLL is around three per 100,000 and is twice as common in men compared to women. It mainly affects the elderly with up to 95% of patients diagnosed after the age of 55 and the median age for diagnosis believed to be approximately between 65 and 70 years of age. Despite the fact that the incidence has been reported to increase in younger patients, with about one-third of CLL patients younger than 55 years, the overall incidence of CLL has decreased during the past 15 years.

While CLL is generally considered a disease that is slow to progress, a significant proportion of patients have rapidly progressing forms of the disease.

Two pivotal trials

Significant new data from two pivotal phase III studies, presented at the 50th Annual Meeting of the American Society of Hematology in San Francisco (December 6 – 9, 2008), showed that patients with chronic lymphocytic leukemia (CLL) treated with rituximab in combination with chemotherapy live considerably longer without their disease progressing, compared to patients treated with chemotherapy alone.

The first trial, the CLL-8 study, an international study conducted by the German CLL Study Group and Professor Michael Hallek (Klinik I für Innere Medizin, Universitaet zu Koeln, Joseph-Stelzmann-Str. 9, Cologne, D-50924, Germany) in collaboration with F. Hofmann La Roche, included 817 patients with CLL receiving first-line treatment. The study was conducted at 191 study sites across 11 countries. In this randomized study, patients received either rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) or chemotherapy alone. The primary endpoint of the study was progression-free survival. No new or unexpected safety signals were observed.

Results from the CLL-8 study showed that at two years, more than three quarters (76.6%) of patients receiving rituximab plus chemotherapy lived without their disease progressing compared to 63.3 % of those treated with chemotherapy alone.

The second trial, the REACH study, a randomized international study that included 552 patients with relapsed or refractory CLL, was conducted at 88 study sites across 17 countries. The study was set up to investigate whether treatment of patients with relapsed or refractory CLL with rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) was more beneficial than treatment with chemotherapy alone. The primary endpoint of the study was to show an increase in terms of median progression-free survival.

After analyzing the data, the REACH study demonstrated that with rituximab, patients who had relapsed lived an average 10 months longer without their disease progressing compared to those receiving chemotherapy alone (30.6 months vs 20.6 months).

‘The positive results from both of these trials is very encouraging news for patients suffering from a disease that remains life-threatening and incurable ,’ noted Roche's Burns. ‘The outcome of these trials clearly demonstrates the important role MabThera will have in the treatment of this devastating disease.’

‘Rituximab has already revolutionized the treatment of people living with non-Hodgkin's lymphoma’, explained Professor Tadeusz Robak, Medical University of Lodz, Poland, and principle investigator for the REACH trial. ‘These results add to a growing body of evidence that underscores the important role MabThera has to play in the management of CLL, which currently remains a life-threatening and incurable disease.’

 

A new Standard of Care

Based on the results of both trials, the researchers involved feel that rituximab is set to change the face of chronic lymphocytic leukemia management. Commenting on the results of the CLL-8 trial, professor Hallek, who led the German CLL Study Group (GCLLSG) in conducting the study, said, ‘With new therapies emerging, the management of CLL is set to change markedly, with physicians having more options and greater treatment expectations for their patients. These data, which come from the largest randomized clinical trials ever reported in CLL, suggest that rituximab used in combination with chemotherapy has the potential to become the new standard of care for CLL patients.’

For more information:

• 50th ASH Annual Meeting and Exposition, Online Abstracts: Chronic Lymphocytic Leukemia - Therapy, Excluding Transplantation (abstract 325 - 330).
• The official MabThera website (Roche).
• International Standard Randomised Controlled Trial Number (ISR CTN) Register: ISRCTN02757147
• National Cancer Institute rituximab
• The Nobel Prize in Physiology or Medicine 1984 laureates
• The Nobel Prize: Presentation Speech (1984)
• Click here for an overview of FDA approved antibodies for the parenteral use in the detection and treatment of cancer.
• Understanding Cancer Series (National Cancer Institute) Slide 36.
• Oldham RK, Dillman RO, Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress. Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1774-1777 (Full Text Aricle).

Also read PubMed abstracts:

• Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia. J Clin Oncol. 2008 Dec 15. [Epub ahead of print].
• Nissim A, Chernajovski Y. Historical development of monoclonal antibody therapeutics. Handb Exp Pharmacol. 2008;(181):3-18.
• Hallek M; German CLL Study Group. Prognostic factors in chronic lymphocytic leukemia. Ann Oncol. 2008 Jun;19 Suppl 4:iv51-3.
• Eichhorst B, Hallek M, Dreyling M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii60-2. Click here for Full Text Article.
• Keating MJ, O’Brien S, Albitar M, et al, Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14.
• Cartron G, Blasco H, Paintaud G, et al. Pharmacokinetics of rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol. 2007 Apr;62(1):43-52. Epub 2007 Feb 6.
• Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res. 2006 May;82(5):760-6. Epub 2005 Nov 11.
• Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin. 2006 Jul-Aug;56(4):226-43. Click here for Full Text Article. http://caonline.amcancersoc.org/cgi/content/full/56/4/226
• Olszewski AJ, Grossbard ML. Empowering targeted therapy: lessons from rituximab.
  Sci STKE. 2004 Jul 6;2004(241):pe30. Review.
• Grillo-López AJ, White CA, Varns C, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26: 66-73.
• Piro LD, White CA, Grillo-López AJ, et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999 Jun;10(6):655-61.
• Ritz J. Pesando JM, Sallan SE, et al. Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood. 1981 Jul;58(1):141-52.
• De StGroth SF, Scheidegger D. Production of monoclonal antibodies: strategy and tactics. J Immunol Methods. 1980;35(1-2):1-21
• Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7.
• Currie GA, Eighty years of immunotherapy: a review of immunological methods used for the treatment of human cancer. Br J Cancer. 1972 Jun;26(3):141-53.

Download:

• European Summary of Product Characteristics (only for healthcare professionals outside the Unites States of America). The ESPC provides comprehensive clinical, pharmacological and prescribing information about MabThera. Detailed information about the safety experience with MabThera can be found in the ESPC.

Additional references:

• Hericourt J, Richet CH. ‘Physologie pathologique’ - de la serotherapie dans la traitement du cancer. Comptes Rendus Hebd Seanc Acad Sci (Paris) 1895; 120: 567–569
• Himmelweit F. The Collected Papers of Paul Ehrlich. Vol. 3. London: Pergamon; 1960: 59.

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.

Carcinogenesis
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.

Cetuximab
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.

Panitumumab
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.’

For more information, read:

• Shankaran V, Bentrem DJ, Mulcahy MF, et al. Economic implications of Kras testing in metastatic colorectal cancer (mCRC).2009 Gastrointestinal Cancers Symposium (GICS). Abstract 298. Presented January 17, 2009. General Poster Session E (Poster Presentation).

Also read:

• F. Di Fiore, E. Van Cutsem, P. Laurent-Puig, et al.
  Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 4035
• E. Van Cutsem, I. Lang, G. D'haens, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC)treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 2
• Van Cutsem E, Peeters M, Siena S et al. Panitumumab significantly improves progression-free survival in patients with metastatic colorectal cancer. Ann Oncol 2006; 17 (Suppl 6): vi27 (Abstr O-027).
• Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol (Meeting Abstracts) 2007 25: 4000.

For more information read PubMed abstracts:

• Heinemann V, Stintzing S, Kirchner T, Boeck S, Jung A. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2008 Dec 29. [Epub ahead of print]
• Weber J, McCormack PL. Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs. 2008;22(6):403-11.
• Amado RG, Wolf M, Peeters M, et al.
  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1;26(10):1626-34. Epub 2008 Mar 3.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group.
  Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii29-30.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii33-4
• Van Cutsem E, Dicato M, Haustermans K, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2008 Jun;19 Suppl 6:vi1-8. Contact the author.
• Annemans L, Van Cutsem E, Humblet Y, et al.
  Cost-effectiveness of cetuximab in combination with irinotecan compared with current care in metastatic colorectal cancer after failure on irinotecan--a Belgian analysis. Acta Clin Belg. 2007 Nov-Dec;62(6):419-25
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Also read:

• Full prescribing information (USA) Vectibix®
• Vectibix® website.
• Full prescribing information cetuximab.