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

Bevacizumab Data Gives Hope to Colorectal Cancer Patients with Liver Metastases

New data from several studies presented at the joint multidisciplinary meeting of ECCO 15 (European CanCer Organisation) and ESMO 34 (European Society for Medical Oncology) in Berlin, Germany, confirm unique benefits of bevacizumab (Avastin®, Roche, Basel, Switzerland), an antibody that specifically binds and blocks VEGF (vascular endothelial growth factor), and capecitabine (Xeloda®, Roche, Basel, Swizerland), a highly effective targeted oral chemotherapy offering patients a survival advantage when taken on its own or in combination with other anticancer drugs, in treatment of colon cancer.

Colorectal cancer is the second most common cause of death from cancer across all tumor types in Europe and is the third most commonly reported cancer in the world.

Bevacizumab in combination with chemotherapy led to shrinkage or disappearance (overall response rate) of liver metastases (disease that has spread to the liver) in 78% of patients with advanced colorectal cancer. As a result, one third (33%) of patients who were initially unable to undergo surgery were eligible to undergo a potentially lifesaving surgery. Complete surgical removal of the metastases was achieved in 56% of all bevacizumab-treated patients.

II BOXER study
The multicentre phase II BOXER study, a single arm phase II study, investigated the efficacy and safety of bevacizumab in combination with oral capecitabine and intravenous oxaliplatin (NO16968 XELOX trial, an open-label, randomised, phase III study of oral capecitabine in combination with intravenous oxaliplatin versus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for patients with stage III colon cancer who have undergone surgery) in patients considered unsuitable for upfront resection (surgical removal) of their liver metastases.

Response rates in this trial were measured by RECIST criteria. Secondary objectives of BOXER trial included complete resection rate, safety and feasibility of the regimen, PFS and overall survival.

“The data from BOXER shows that bevacizumab in combination with standard chemotherapy has the ability to shrink metastatic lesions which might allow surgical removal and therefore offer a potential for cure for patients with advanced disease,” explained Professor David Cunningham, Head of the Gastrointestinal Unit at the Royal Marsden Hospital, UK.

First BEAT
Data from the large, observational First BEAT phase IV trial assessing the safety and efficacy of bevacizumab in almost 2,000 previously untreated patients with mCRC in combination with a variety of standard chemotherapies, showed that bevacizumab -based treatment delivers the same benefits to all patients including those aged above 65 years who represent the majority of people with advanced colorectal cancer. This is an important finding as older patients are often under-represented in clinical trials. The study results showed that the time patients lived without their disease advancing (PFS) was similar across age groups – 10.8 months for those below 65 years, 11.2 months for those between 65 and 74 years and 10 months for those 75 years and older.

The most common chemotherapy regimens combined with bevacizumab in First BEAT were FOLFOX, XELOX, FOLFIRI (oxaliplatin, fluorouracil and irinotecan) and capecitabine. The primary endpoint of First BEAT was safety and secondary objectives were PFS and overall survival.

NO16968 (XELOXA) study
Patients taking capecitabine with oxaliplatin immediately after surgery live disease free for longer compared to those treated with commonly used chemotherapy regimen. New results for capecitabine in early colon cancer were also presented at the ECCO 15 - ESMO 34 meeting. The pivotal NO16968 (XELOXA) study, the largest-ever study of patients with stage III colon cancer, showed that the three year disease-free survival (DFS) for patients receiving XELOX was 70.9%, superior to the 5-FU/LV arm (66.5%) (HR=0.80 (95% CI: 0.69-0.93), p=0.0045). The DFS result obtained with XELOX is similar to that shown in trials evaluating the use of FOLFOX in patients with stage III colon cancer.

"We know that XELOX helps keep patients free from recurrence of their cancer longer,’’ said Dr Dan Haller, Professor of Medicine, University of Pennsylvania. "These results now confirm that patients have an additional option for the treatment of stage III colon cancer. In these potentially curable patients, XELOX offers the additional benefit of an oral medication, Xeloda."

"Colorectal cancer sadly claims more than 600,000 lives each year, despite the treatment advances made in the last decade” said William M. Burns, CEO of Roche’s Pharmaceuticals. “Today’s announcements about Avastin and Xeloda are therefore very welcome news for patients and their families as they offer more options for fighting this disease and hope that some patients may even have the potential to be cured” he added.

Images courtesy American Society of Clinical oncology (ASCO) and Roche Pharmaceuticals.

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+).