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+).

Growing Attendance for International GI Cancer Congress Demonstrates Importance and Increased Impact.

The 11th World Congress on Gastrointestinal Cancer, organized by ESMO, the European Society for Medical Oncology, opens today in Barcelona, Spain, with a substantial increase in registered attendees over previous years.

The conference is expected to provide important practice updates and promising new research into the numerous types of cancers that affect the gastrointestinal tract.

“Ongoing study and changing standards in the treatment of gastrointestinal cancers have made it mandatory for clinicians to continually update their knowledge to keep up with advances in the field,” says Congress co-chair Dr. Eric Van Cutsem. “The World Congress on Gastrointestinal Cancer addresses the immediate practice implications of these changes.”

Researchers will present studies indicating prolonged progression-free survival and focusing on the importance of personalized cancer care.

Gastrointestinal cancers include anal cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, liver cancer (hepatoma), pancreatic cancer, and small intestine cancers. The most prevalent of these is colorectal cancer in the Western world and gastric cancer in Eastern World.

Colorectal cancer is a major public health problem in Western countries, with the highest incidence rates in North America, Western Europe, Australia and New Zealand. It is the third most common cancer in both men and women, and the third most common cause of cancer death in both sexes. About 630,000 deaths from colorectal cancer are expected this year worldwide, accounting for 8% of all cancer deaths. Gastric is the second most frequent cause of cancer related mortality, accounting for nearly 800,000 deaths each year worldwide.

Over 400 studies will be presented at the world’s largest GI cancer conference and published in the Annals of Oncology, the official journal of the European Society for Medical Oncology (ESMO), outlining research taking place across the globe. Some of the most important work in the field outlines improved patient outcomes through novel drug therapies including combination therapies and new applications of existing therapies.

Six abstracts have been selected by the congress chairs as “top abstracts”. A common thread of these recognized papers is prolonged progression-free survival, enabling patients to live longer with the disease and with a better quality of life. Moreover, the experts will discuss the changing paradigm in gastrointestinal cancer toward a more personalized treatment approach for patients with gastrointestinal cancers.

Also being recognized at the congress are researchers from developing nations who received grants based on the scientific merit of their submitted work.

The ESMO Conference: 11th World Congress on Gastrointestinal Cancer, developed and managed by Imedex, will be held from 24-27 June at the CCIB convention center in Barcelona. The internationally recognized faculty will include 72 experts, chaired by Mario Dicato, MD of the Luxembourg Medical Center in Luxembourg and Eric Van Cutsem, MD, PhD of the University Hospital Gasthuisberg in Leuven, Belgium. 3,500 people from nearly 100 countries are expected to attend.

Designed to promote a multidisciplinary approach to treatment, the scientific agenda offers targeted sessions for oncology surgeons and nurses as well as a comprehensive range of topics for researchers, gastroenterologists, as well as medical and radiation oncologists.

The conference has received endorsements from leading professional societies and organizations, solidifying the reputation of the Congress as the premier platform for specialists in cancer research, leading oncologists and practicing clinicians to review the state-of-the-art advances in gastrointestinal cancer and share the latest information on its multidisciplinary management. Specialized sessions for nurses, surgeons and young medical oncologists provide enhanced educational opportunities.

The 11th World Congress on Gastrointestinal Cancer Congress is endorsed by:

• The Cholangiocarcinoma Foundation
• ENETS (European Neuroendocrine Tumor Society)
• EONS (European Oncology Nursing Society)
• EORTC (European Organisation for Research and Treatment of Cancer) – GI Tumor Group
• ESO (European School of Oncology)
• ESSO (European Society of Surgical Oncology)
• Europacolon

For more information:

• 11th World Congress on Gastrointestinal Cancer.
• ESMO: The European Society for Medical Oncology

For more information, read these PubMed abstract:

• ESMO Conference: 11th World Congress on Gastrointestinal Cancer, 24-27 June, 2009, Barcelona, Spain. Abstracts. Ann Oncol. 2009 Jun;20 Suppl 7:vii7-127 (Annals of Oncology Online)
• Abstracts of the ESMO International Symposium: 10th World Congress on Gastrointestinal Cancer. June 25-28, 2008. Barcelona, Spain. Ann Oncol. 2008 Jun;19 Suppl 6:vi9-105 (Annals of Oncology Online)
• Koh HC, Page B, Black C, Brown I, Ballantyne S, Galloway DJ. Ectopic pancreatic-type malignancy presenting in a Meckel's diverticulum: a case report and review of the literature. World J Surg Oncol. 2009 Jun 22;7(1):54. [Epub ahead of print]
• Beswick EJ, Reyes VE. CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World J Gastroenterol. 2009 Jun 21;15(23):2855-61.
• Caracino V, Maggi G, Altobelli S, Lambiase C, Danza C, D'Amico G. Voluminous bleeding stomach GIST: reflections on aetiopathogenesis, diagnosis and therapy. Chir Ital. 2009 Mar-Apr;61(2):255-9.
• Schulze-Bergkamen H, Weinmann A, Moehler M, Siebler J, Galle PR. Novel ways to sensitise gastrointestinal cancer to apoptosis. Gut. 2009 Jul;58(7):1010-24.

Photos courtesy of the American Society of Clinical Oncology