For the third year in a row, the American Society of Clinical Oncology (ASCO) has included cetuximab (Erbitux?, Merck Serono/Merk KGaA in its annual report , Clinical Cancer Advances 2010: ASCO?s Annual Report on Progress Against Cancer [1]
Cetuximab is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.
Clinical Cancer Advances was developed under the guidance of a 14-person editorial board made up of leading oncologists, including specialty editors for each of the disease- and issue-specific sections. Editors reviewed studies in peer-reviewed scientific journals and the results of research presented at major scientific meetings from October 2009 through September 2010. Only studies that significantly altered the way a cancer is understood or had an important impact on patient care were selected for the report.
This year?s report critically reviews the most significant clinical cancer research studies, highlights 12 major advances and 41 notable advances.
?This year?s Annual Report on Progress Against Cancer highlights those studies that have had the greatest impact on patient care,? said Mark G. Kris, MD, Executive Editor of the report. ?Yet much work is still needed to advance clinical cancer research and care. We?re on the verge of great discoveries, but we will not be able to speed the pace of progress without revitalizing the nation?s clinical trial system.?
Increased funding necessary
In the report, the report?s authors calls for a doubling of funds for the National Cancer Institute?s (NCI) Cooperative Group trials program over the next five years. The authors state that, in real terms, funding for the program has actually declined over the past decade, leading to a limiting of the number and speed of these important research studies. The report also urges the cancer community to collaborate on implementing the recommendations laid out in the recent Institute of Medicine (IoM) report, ?A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the National Cancer Institute (NCI) Cooperative Group Program.?
BRAF Status
In the report the editorial board recognized that BRAF mutation status is a prognostic, not predictive, marker for the efficacy of cetuximab in metastatic colorectal cancer (mCRC) as a notable advance.
The report states that two large, randomized trials, the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) and the OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) studies, showed that adding the targeted drug cetuximab to initial chemotherapy improved outcomes compared to chemotherapy alone for those patients with metastatic colon cancer tumors that do not have KRAS gene mutations.
In a follow-up analysis, researchers pooled data from both trial populations(which included 1,645 patients, though only 1,378 evaluable samples) and assessed outcomes based on both KRAS and BRAF gene mutation status. They found that adding cetuximab to chemotherapy improved outcomes for all patients with normal forms of KRAS, regardless of BRAF status, but that those with normal forms of both the KRAS and BRAF genes benefited most.
Median survival for patients with normal KRAS and BRAF treated with chemotherapy and cetuximab was 24.8 months, versus 21.1 months for chemotherapy alone. For patients with normal KRAS and BRAF mutations, adding cetuximab increased median survival from 9.9 months to 14.1 months. These data demonstrate that BRAF mutations are prognostic; patients whose tumors harbor BRAF mutations have significantly shorter progression-free and overall survival. However, patients with a normal KRAS gene and a BRAF mutation still seem to benefit from cetuximab, and treatment decisions regarding the use of cetuximab should not be made based on the presence of BRAF mutations.
Predicting Overall Survival
The ASCO report notes that researchers have previously evaluated the prognostic value of eight selected molecular markers on relapse-free survival in stage II and stage III colon cancer. A study by Roth A, et al, presented at the 46th Annual Meeting of the American Society of Clinical Oncology; June 2010; Chicago, IL, examined the prognostic value of the same eight markers on survival after relapse in 392 of 990 patients with relapse.
The researchers found that, while BRAF gene status and tumor site had no prognostic value in relapse-free survival, both, along with time to relapse, were strong determinants of overall survival in colon cancer after relapse. In their data set, patients with BRAF mutated tumors had a median survival of 7.5 months compared to 25.2 months for patients with BRAF wild-type tumors. The median survival after relapse of patients with right-sided tumors was 16.2 months compared to 28.4 for those patients with left sided tu?mors. Finally, patients with late relapse lived more than 2.5 years compared to 1.5 years for those who had early relapse. Researchers suggest that the markers evaluated in this study should be used in stratifying metastatic colon cancer patients for clinical trial. [3]
Commenting on the inclusion in the ASCO report, Dr. Oliver Kisker, Senior Vice-President, Global Clinical Development Unit for Oncology, Merck Serono, said: ?This is the result of our focused work on biomarker-guided research to improve cancer care. We are honored to have our Erbitux clinical development program recognized in three different cancers in three successive years by the oncology community.?
In 2009, cetuximab was included in the report as a major advance suggesting that it had the potential to lead to a reduction in mortality from cancer. Cetuximab was recognized as an advance in personalized medicine and targeted therapies in head and neck cancer. The results from the randomized EXTREMEc (ErbituX in 1st-line Treatment of REcurrent or MEtastatic head and neck cancer) trial presented during the ASCO 2009 meeting showed that cetuximab is the first treatment in more than 30 years to demonstrate an improvement in overall survival for advanced head and neck cancer patients.[4]
Earlier, in 2008, cetuximab was twice highlighted as a major advance in the treatment of both mCRC and non-small cell lung cancer (NSCLC). [5] In that year cetuximab was listed as the only significant advance in personalized medicine. The results of the CRYSTAL study validated KRAS mutation status as predictive of Erbitux efficacy in mCRC patients.
In hard-to-treat cancers, cetuximab was listed as the only treatment to advance lung cancer care. Results from the randomized FLEX (First-Line ErbituX in lung cancer) study showed that adding cetuximab to chemotherapy increased overall survival in patients with NSCLC that expressed the epidermal growth
factor receptor (EGFR).
?We continue to believe that using biomarkers to convert therapies targeted at specific pathways into personalized medicines will lead to greater progress in improving cancer care for patients,? said Dr. Kisker. ?We look forward to yet another year of advances in oncology.?
Other findings
Research advances made this past year focus on progress against cancer, hard-to-treat cancers, reducing cancer recurrence, targeted therapies and personalized medicine, quality of life and new drug approvals. Highlights of this year?s report also include:
- Reducing the risk of cancer recurrence: Researchers discovered that a three-week hypofractionated radiation therapy course was just as effective in preventing recurrence as the standard five-week course for women diagnosed with early-stage breast cancer.
- Enhancing quality of life: Patients with advanced lung cancer who received standard chemotherapy coupled with palliative care immediately after diagnosis lived significantly longer and had a better quality of life than those who were treated with chemotherapy alone.
- Advances in drug therapies: First-line treatment with FOLFIRINOX ? a combination of the chemotherapy drugs 5-fluorouracil, leucovorin, irinotecan and oxaliplatin ? resulted in better response rates, progression-free survival and overall survival for patients with advanced pancreatic cancer.
- Addressing side effects: Researchers have found that the majority of patients (80%) undergoing chemotherapy for cancer suffer from sleep difficulties ? a rate approximately two to three times higher than what is seen in the general population. This is a clear area where more awareness is needed so patients can get the additional help they need.
- Improving progression-free survival in hard-to-treat cancer: Studies found that administering chemotherapy and bevacizumab (Avastin?, Roche followed by longer-term treatment with bevacizumab, was the most effective strategy for extending progression-free survival in patients with ovarian cancer.
Additional significant developments discussed in the report include:
- The discovery that a monoclonal antibody, ipilimumab (Bristol-Myers Squibb), improves survival in patients diagnosed with advanced melanoma ? a major advance for a very difficult-to-treat cancer.
- A study showing that the targeted drug crizotinib (Pfizer) produces high response rates and shrinks tumors in many patients whose tumors harbor a specific gene mutation in the ALK gene.
- Findings from an early-stage trial of advanced melanoma showing that a novel gene-targeted therapy, PLX4032 (Plexxikon ), caused tumors to shrink in a majority of patients with a specific BRAF gene mutation.
- A chemotherapy combination that was found to increase survival in elderly patients with advanced lung cancer, and is well-tolerated by these patients.
- A report issued by leading U.S. health and cancer organizations showing continued declines in cancer incidence and death rates over recent years.
- The FDA approvals of cabazitaxel (Jevtana, Sanofi-Aventis) and sipuleucel-T (, Dendreon) ? a therapeutic vaccine ? for metastatic hormone-refractory prostate cancer.
References
[1] Kris MG, Benowitz SI, Adams S, Diller L, Ganz P, Kahlenberg MS, Le QT, Markman M, Masters GA, Newman L, Obel JC, Seidman AD, Smith SM, Vogelzang N, Petrelli NJ. A Clinical Cancer Advances 2010: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.
[2] Bokemeyer C, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. Presented at the 46th Annual Meeting of the American Society of Clinical Oncology; June 2010; Chicago, IL.
[3] Roth A, Klingbiel D, Yan P, Fiocca R, Delorenzi M, Labianca R, Cunningham D, Van Cutsem E, Bosman F, Tejpar S. Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC): Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. Presented at the 46th Annual Meeting of the American Society of Clinical Oncology; June 2010; Chicago, IL.
[4] Petrelli NJ, Winer EP, Brahmer J, Dubey S, Smith S, Thomas C, Vahdat LT, Obel J, Vogelzang N, Markman M, Sweetenham JW, Pfister D, Kris MG, Schuchter LM, Sawaya R, Raghavan D, Ganz PA, Kramer B. Clinical Cancer Advances 2009 : major research advances in cancer treatment, prevention, and screening–a report from the American Society of Clinical Oncology. J Clin Oncol. 2009 Dec 10;27(35):6052-69. Epub 2009 Nov 9. Review
[5] Winer E, Gralow J, Diller L, Karlan B, Loehrer P, Pierce L, Demetri G, Ganz P, Kramer B, Kris M, Markman M, Mayer R, Pfister D, Raghavan D, Ramsey S, Reaman G, Sandler H, Sawaya R, Schuchter L, Sweetenham J, Vahdat L, Schilsky RL; American Society of Clinical Oncology. Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening–a report from the American Society of Clinical Oncology. J Clin Oncol. 2009 Feb 10;27(5):812-26. Epub 2008 Dec 22. Erratum in: J Clin Oncol. 2009 Jun 20;27(18):3070-1.
More information
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