First Targeted Biological Therapy to Show Survival Benefit in Stomach Cancer

The European Commission has approved trastuzumab (herceptin, Roche Pharmaceuticals) in combination with chemotherapy for use in patients with HER2-positive metastatic stomach (gastric) cancer.

Trastuzumab is a humanized antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumor. trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer.

The approval of trastuzumab in combination with chemotherapy for the treatment of metastatic stomic cancer is based on the impressive results from the international ToGA trial, which showed that treatment with trastuzumab significantly prolongs the lives of patients with this aggressive cancer. Overall survival for patients with high levels of HER2 in the ToGA study was 16 months versus 11.8 months (on average) for patients receiving chemotherapy alone [1]

“Herceptin is the first targeted biological therapy to show a survival benefit in advanced stomach cancer and represents a significant advance in the treatment of this devastating disease”, said Pascal Soriot, Chief Operating Officer of, Roche’s Pharmaceutical Division. “We believe that Herceptin will help patients with HER2-positive stomach cancer, as much as it has helped so many women with HER2-positive breast cancer.”

Based on the strong results from the phase III ToGA study, the submission for the label extension was reviewed in an accelerated process by the European Health Authorities, allowing patients to benefit sooner from this life-extending treatment. This marketing authorization is valid with immediate effect in all European Union (EU) and EEA-EFTA states (Iceland, Liechtenstein and Norway). Following approval in the European Union, approvals for a label extension for trastuzumab in other regions of the world are expected to follow soon.

“I am delighted that today’s approval will make Herceptin available to patients with HER-2 positive metastatic stomach cancer across Europe,” said Professor Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium, one of the lead investigators of the ToGA trial. “The approval of Herceptin for HER2-positive stomach cancer represents an important advance for the treatment of these patients. Clinicians will need to ensure that patients with metastatic stomach cancer are accurately tested for HER2 expression.”

Diagnosis and treatment
Stomach cancer is the second most common cause of cancer-related death in the world and is the fourth most commonly diagnosed cancer, with over 1,000,000 cases of stomach cancer diagnosed each year [2] Advanced stomach cancer is associated with a poor prognosis; the median survival time after diagnosis is approximately 10-11 months with currently available therapies. [3] Approximately 15 - 18% of stomach tumours show high levels of HER2 [4,5]. Early diagnosis of this disease is challenging because most patients do not show symptoms in the early stage.

ToGA is the first randomized Phase III trial investigating the use of trastuzumab in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive stomach cancer. Approximately 3,800 patients were tested for HER2-positive tumors and 594 patients with HER2-positive disease were enrolled into the study. The rationale for conducting this trial was based on the knowledge that the targeted therapy trastuzumab has demonstrated unprecedented efficacy in the treatment of HER2-positive breast cancer. In addition, the overexpression of HER2 was also observed in stomach cancer. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.

In the ToGA study, patients were randomized to receive one of the following regimens as their first line of treatment:

• A fluoropyrimidine (capecitabine (xeloda) or intravenous 5-FU (5-fluorouracil)) and cisplatin every 3 weeks for 6 cycles. Most patients were receiving capecitabine and cisplatin as chemotherapy
• Trastuzumab 6mg/kg every 3 weeks until progression in combination with a fluoropyrimidine and cisplatin for 6 cycles

Study results
The primary objective of the study was to demonstrate superiority in overall survival of the trastuzumab containing treatment arm compared to the chemotherapy alone arm. The pre-planned interim analysis was triggered by the occurrence of 347 events. Secondary endpoints for the study included progression-free survival, overall response rate, duration of response, safety and quality of life. In the ToGA study, no new or unexpected side effects were observed. For overall survival, the Hazard Ratio was 0.74 (CI 0.60, 0.91) with a highly significant p-value of p=0,0046.

Trastuzumab increased the median overall survival time by 2.7 months to 13.8 months (intent to treat patient group, defined as IHC3+ or FISH-positive, represented 22% of patients tested for HER2 in the ToGA study). The response rate was increased with trastuzumab from 34.5 % to 47.3%. Patients with tumors exhibiting high levels of HER2 (IHC3+ or IHC2+/FISH-positive, 16% of patients tested for HER2 in the ToGA study) experienced even greater benefit from the addition of trastuzumab. For these patients, overall survival in the study was 16 months on average versus 11.8 months for patients receiving chemotherapy alone. The EU label recommends trastuzumab for patients expressing high levels of HER2.

Personalized Healthcare: Fitting treatments to patients
Different people respond differently to medicines. The aim of aim of a personalized approach to healthcare is to target treatments to the patients most likely to benefit. This means tailoring treatments to specific patient sub-groups who share similar characteristics in their genetic makeup or in the molecular nature of their disease. This approach has enormous potential to make healthcare better, safer and more effective, with benefits for patients, physicians, payers, and society at large.

Trastuzumab treatment in breast cancer is a case in point: Measuring the levels of the protein HER2 in breast cancer cells with specific tests reliably identifies patients who are likely to respond to trastuzumab. The same approach can also be applied in the diagnosis and the treatment of HER2-positive metastatic gastric cancer with trastuzumab.

References
[1]Van Cutsem et al. Abstract #7BA ECCO/ESMO 2009
[2]American Cancer Society. Global Cancer Facts & Figures 2007
[3] Ohtsu A. J Gastroenterol 2008;43:256-264
[4] Hofmann M, Stoss O, Shi D, Buttner R, van d, V, Kim W et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008; 52(7):797-805.
[5] Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 2006; 51(8):1371-1379.

Also:

• Onco’Zine – The International Cancer Network

Trastuzumab plus Standard Chemotherapy Provides Unprecedented Survival Benefit for Patients with HER2-positive Advanced Gastric Cancer

A detailed analysis of the Phase III ToGA study, the first randomized Phase III clinical trial investigating the use of trastuzumab (Herceptin) in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive gastric cancer, revealed an unprecedented survival benefit for patients when trastuzumab, a humanized antibody designed to target and block the function of HER2, was added to standard chemotherapy regimen containing capecitabine (Xeloda) or intravenous 5-FU and cisplatin.

The analysis evaluated patient benefit according to the level of HER2 identified in their stomach tumour. Overall survival for patients with high levels of HER2 receiving Herceptin was 16 months on average versus 11.8 months for patients receiving chemotherapy alone.

These results were presented at the joint 15th Congress of the European CanCer Organisation (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO) in Berlin, Germany. They illustrate the importance of an individualized approach to patient care and the opportunity that a targeted medicine may offer.

The rationale for conducting this trial was based on the knowledge that the targeted therapy trastuzumab has demonstrated unprecedented efficacy in the treatment of HER2-positive breast cancer. In addition, the overexpression of HER2 was also observed in stomach cancer.

In the ToGA study, patients were randomized to receive one of the following regimens as their first line of treatment:

• A fluoropyrimidine (capecitabine or intravenous 5-FU) and cisplatin every 3 weeks for 6 cycles. Most patients were receiving Xeloda and cisplatin as chemotherapy
• Trastuzumab 6mg/kg every 3 weeks until disease progression in combination with a fluoropyrimidine and cisplatin which was stopped after a maximum of for 6 cycles

The primary objective of the study was to demonstrate superiority in overall survival of the trastuzumab containing treatment arm compared to the chemotherapy alone arm. The pre-planned interim analysis was triggered by the occurrence of 347 events. Secondary endpoints for the study included progression-free survival, overall response rate, duration of response, safety and quality of life. In the ToGA study, no new or unexpected side effects were observed.

For overall survival, the Hazard Ratio was 0.74 (CI 0.60, 0.91) with a highly significant p-value of p=0.0046 corresponding to a 26% reduction in the risk of death. All patients who were included the study to receive trastuzumab had a median overall survival increase by 2.7 months to 13.8 months. The response rate was increased with trastuzumab from 34.5 % to 47.3%. Patients with tumors exhibiting higher levels of HER2 experienced even greater benefit from the addition of trastuzumab.

“It is now clearly proven that Herceptin prolongs the lives of patients suffering from HER2-positive gastric cancer. As an investigator on this study and a treating physician, it is very rewarding to see a new effective treatment option emerging”, said principle investigator, Professor Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium. “The results of the ToGA study reinforce the need for early and accurate HER2 testing of all advanced gastric cancer patients.”

Based on the significant findings of the ToGA study, Roche has submitted a label extension application with the EU Health Authorities for use of trastuzumab in HER2-positive advanced gastric cancer. Applications for label extension in other regions of the world will follow as soon as possible.

“We are pleased to see the impressive benefit that the targeted therapy Herceptin provides for patients with HER2-positive stomach cancer. That this benefit is even greater in patients with higher levels of HER2demonstrates the significant advances through personalized medicine”, commented William M. Burns, CEO of Roche’s Pharmaceuticals Division, “Herceptin will become the new standard of care and will make an important contribution to helping these patients.”

Stomach cancer is the second most common cause of cancer-related death worldwide with over 1,000,000 new cases diagnosed each year. Stomach cancer is associated with poor prognosis and early diagnosis is challenging because most patients do not show symptoms until the later stages. Around 16% of stomach tumors express high levels of HER2 (IHC 3+ or IHC2+/FISH+).

A New and Advanced Imaging Technique Allows Researchers to Monitor Protein Changes in Mouse Tumors

A new imaging technique can monitor, in living mice, the HER2 protein found in above-normal amounts in many cases of breast cancer as well as some ovarian, prostate and lung cancers. This new approach, once validated in mice and pending further experiments, could provide a real-time noninvasive method for identifying tumors in women who express HER2 and who would be candidates for targeted therapy directed against this protein.

The new technique may also provide real-time information that will help clinicians optimize treatment for individual patients. The study by Kramer-Marek and colleagues, published in the July 2009 issue of The Journal of Nuclear Medicine, was conducted at the National Cancer Institute (NCI) and the National Institute of Biomedical Imaging and Bioengineering, both parts of the National Institutes of Health.

Overexpression of HER2
The HER2 protein is overexpressed in approximately 20 percent to 25 percent of breast cancers. Numerous studies have shown that HER2 is associated with shorter disease-free and overall survival. In breast cancer, HER2 gene amplification was significantly associated with pathologic stage at diagnosis, axillary node involvement, and histologic subtype. In ovarian cancer HER2 has been associated with decreased overall survival and with an increase in relative risk of death.

Tumors that overexpress HER2 are more aggressive and more likely to recur than tumors that do not overexpress the protein. Targeted therapies directed against HER2 can slow or stop the growth of tumors that overexpress it.

Determining HER2
HER2 expression can be determined by any of several methods. The most commonly used methods include Fluorescence in situ hybridization or FISH, which detects gene amplification by measuring the number of copies of the HER2 gene in the nuclei of tumor cells and Immunohistochemistry or IHC, which measures the number of HER2 receptors on the cell surface and therefore detects receptor overexpression.

Chromogenic in situ hybridization or CISH, which measures gene amplification using a light microscope rather than a fluorescent microscope required for FISH and reverse-transcriptase polymerase chain reaction or RT-PCR, which detects HER2 gene amplification are among some other methods of HER2 testing whicj have been used increasingly in clinical studies and may eventually be incorporated into routine practice.

Not Perfect
In 2007, Wolff et al showed that Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) test results can be affected by testing conditions including the use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific instructions, and failure to include appropriate controls. Therefore, in order to increase the accuracy of HER2 testing results, testing should be performed by laboratories with demonstrated aptitude in the specific test requested. Even if tested in these high-end laboratories, expression of HER2 in test samples may still not accurately represent HER2 expression in the tumor as a whole. Moreover, follow-up biopsies are not always routinely performed after the initial diagnosis, and there are no means to evaluate how long a targeted therapy takes to reach its target, how effective it is, and how long its effects last.

In this study, the researchers used an imaging compound that consists of a radioactive atom (fluorine-18) attached to an Affibody molecule, a small protein that binds strongly and specifically to HER2. Affibody molecules are developed by Affibody AB, (Bromma, Sweden), a Swedish biotech company focused on developing next generation products for therapy, diagnostic imaging, and other applications based on its unique proprietary Affibody® molecules and albumin binding technology platforms. The Affibody molecules are much smaller than antibodies and can reach the surface of tumors more easily. The radioactive atom allows the distribution of the Affibody molecules in the body to be analyzed by positron emission tomography (PET) imaging.

The researchers first used the radiolabeled Affibody molecule to visualize tumors that expressed HER2 in mice. The mice were injected under the skin with human breast cancer cells that varied in their levels of HER2 expression, from no expression to very high expression. After three to five weeks, when tumors had formed, the mice were injected with the Affibody molecule and PET images were recorded. The levels of HER2 expression as determined by PET were consistent with the levels measured in surgically removed samples of the same tumors using established laboratory techniques.

To determine whether their method could be used to monitor possible changes in HER2 expression in response to treatment, the team next injected the Affibody molecule into mice with tumors that expressed very high or high levels of HER2 and then treated them with the drug 17-DMAG, which is known to decrease HER2 expression. PET scans were performed before and after 17-DMAG treatment. The researchers found that HER2 levels were reduced by 71 percent in mice with tumors that expressed very high levels of HER2 and by 33 percent in mice with tumors that expressed high levels of HER2 in comparison with mice that did not receive 17-DMAG. The researchers confirmed these reductions by using established laboratory techniques to determine the concentrations of HER2 in the tumors after they were removed from the mice.

"Our work shows that PET imaging using Affibody molecules was sufficiently sensitive to detect a twofold to threefold decrease in HER2 expression," said senior author Jacek Capala, Ph.D., of NCI’s Center for Cancer Research. "Therefore, PET imaging may provide a considerable advantage over current methods. Our technique would allow a better selection of patients for HER2-targeted therapies and also early detection of tumors that either do not respond to or acquire resistance to these therapies."

"This approach might easily be extended to forms of cancer other than breast cancer," Capala continued. "Because Affibody molecules may be selected to target specific cell proteins, similar compounds can be developed to target proteins that are unique to other types of tumors."

For more information:

• Kramer-Marek G, Kiesewetter DO, Capala J. Changes in HER2 Expression in Breast Cancer Xenografts After Therapy Can Be Quantified Using PET and 18F-Labeled Affibody Molecules. J. Nucl Med. 2009 Jun 12. [Epub ahead of print].
• Wållberg H, Ahlgren S, Widström C, Orlova A. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys(61)]-Z (HER2:2395)-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors. Mol Imaging Biol. 2009 Jun 26. [Epub ahead of print]

Also read PubMed Abstracts:

• Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707-12
• Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000 Feb;182(2):150-62. Review
• Sergina NV, Rausch M, Wang D, Blair J, Hann B, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007 Jan 25;445(7126):437-41. Epub 2007 Jan 7
• Konecny GE, Meng YG, Untch M, Wang HJ. et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 2004 Mar 1;10(5):1706-16
• Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18-43.

More information:

• View an animation of how Affibody® molecules will enable cancer specialists to locate and treat tumors and metastases!

Images courtesy of Affibody AB.