Breast Cancer Drug Trastuzumab (Herceptin) Shows Unprecedented Survival In Aggressive Stomach Cancer

Main Category: Cancer / Oncology
Also Included In: GastroIntestinal / Gastroenterology;  Breast Cancer
Article Date: 03 Jun 2009 - 2:00 PDT

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Data from the ToGA study presented at the American Society for Clinical Oncology (ASCO) Annual Meeting in Orlando, Florida showed that adding trastuzumab to standard chemotherapy (capecitabine [Xeloda®] or intravenous 5-FU and cisplatin) prolongs the lives of patients with this aggressive cancer on average by nearly 2.7 months to 13.8 months, a 26% increase in survival. Advanced gastric (stomach) cancer is associated with a poor prognosis; the median survival time after diagnosis is approximately 10 months with currently available therapies.[i]

The international phase III study shows that trastuzumab given in combination with chemotherapy increases average survival by 26% in patients with HER2-positive advanced and inoperable stomach cancer compared to chemotherapy alone. This combination is also particularly beneficial to gastric cancer patients whose tumours express higher levels of HER2, increasing their median survival to 16 months.

Trastuzumab was the focus of intense media attention in 2005 when Patricia Hewitt, then Health Secretary, called for women with early stage HER2-positive breast cancer to be granted access to the treatment following data presented at ASCO showing that it offered unprecedented survival benefits.[ii]

"This is the first time that we have shown that adding a biological treatment to chemotherapy can improve survival in this patient group and represents a significant advance in how we treat patients with this type of advanced gastric cancer" said UK investigator Prof. Jeff Evans, CRUK Professor of Translational Cancer Research, University of Glasgow. "Trastuzumab's efficacy in these patients with gastric cancer demonstrates the important principle that targeting HER-2 positive tumours is not restricted to breast cancer."

Gastric cancer is the seventh most common cause of cancer-related death in the UK with over 8,000 new cases diagnosed each year.[iii] Early diagnosis is challenging because most patients do not show symptoms in the early stage. Approximately 22% of stomach tumours are HER2-positive[iv]. This rate is the same in Europe and in Asia, where stomach cancer is particularly frequent.

"Trastuzumab has brought significant benefit to women suffering from HER2-positive breast cancer. We are extremely pleased to see its impressive benefit extending to patients with stomach cancer" commented William M. Burns, CEO of Roche's Pharmaceuticals Division. "The targeted therapy trastuzumab will become the new standard of care and we can make an important contribution in helping these patients live longer."

Trastuzumab is already well established as the foundation of care for patients with HER2-positive breast cancer and now, based on the ToGA results, Roche will seek regulatory approvals for the use of trastuzumab in HER2-positive advanced stomach cancer.

In the ToGA study, no new or unexpected side effects were observed. The most common side effects were diarrhoea (4.8%) and febrile neutropenia (3.4%).

About the ToGA study

ToGA is the first randomised Phase III trial investigating the use of trastuzumab in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive gastric cancer. 3883 patients were tested for HER2-positive tumours 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. A targeted anti-cancer therapy is a type of medication that blocks the growth of cancer cells by interfering with specific molecules which cause a tumour to grow.

In the ToGA study, patients were randomised 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 (87%) 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

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. The most common side effects were diarrhoea (4.8%) and febrile neutropenia (3.4%). For overall survival, the Hazard Ratio was 0.74 (CI 0.6, 0.9) with a highly significant p-value of p=0.0046. Herceptin increased the median overall survival time by 2.7 months to 13.8 months. The response rate was increased with Herceptin from 34.5 % to 47.3%. Patients with tumours exhibiting high levels of HER2 experienced even greater benefit from the addition of trastuzumab.

About Herceptin (trastuzumab)

Trastuzumab is a humanised 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 tumour. Trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, trastuzumab has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2-positive breast cancer.

Trastuzumab received approval for use in the European Union for advanced (metastatic) HER2-positive breast cancer in 2000, and for early HER2-positive breast cancer in 2006. In the advanced setting, trastuzumab is now approved for use as a first-line therapy in combination with paclitaxel where anthracyclines are unsuitable, as first-line therapy in combination with docetaxel, and as a single agent in third-line therapy. It is also approved for use in combination with an aromatase inhibitor for the treatment of post-menopausal patients with HER2 and hormone receptor co-positive metastatic breast cancer. In the early setting, trastuzumab is approved for use following standard (adjuvant) chemotherapy. Trastuzumab is not approved for use in stomach cancer.

Trastuzumab is marketed in the United States by Genentech, in Japan by Chugai and internationally by Roche. Since 1998, trastuzumab has been used to treat nearly 600,000 patients with HER2-positive breast cancer worldwide.

About Xeloda (capecitabine)

-- Capecitabine is a targeted oral chemotherapy that uniquely activates the cancer-killing agent 5-FU (5-fluorouracil) directly inside the cancer cells[v]

-- As an oral tablet with equivalent efficacy to IV 5-FU/FA, patients can take capecitabine in their own home, reducing the number of hospital visits

-- Licensed in more than 100 countries worldwide, capecitabine has over ten years proven clinical experience providing an effective and flexible treatment option to over 1.5 million people with cancer. In the UK capecitabine is currently indicated for

-- Stage III (Dukes' stage C) colon cancer
- Monotherapy as adjuvant treatment following surgery
-- Metastatic (advanced) colorectal cancer
- Monotherapy
- In combination with any chemotherapy in all lines of treatment
-- Advanced gastric (stomach) cancer
- In combination with platinum-based chemotherapy first line
-- Locally advanced or metastatic breast cancer
- Monotherapy first line in patients after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom anthracycline therapy is not indicated
- In combination with docetaxel in patients after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline

References

[i] Hosokawa et al. Long-term outcomes of patients with metastatic gastric cancer after initial S-1 monotherapy. J Gastroenterol 2007; 42:533-538

[ii] Department of Health. Available at http://www.dh.gov.uk/en/News/Speeches/Speecheslist/DH_4121929. Accessed May 2009

[iii] Cancer Research UK. Stomach cancer statistics. Available at http://www.cancerresearchuk.org. Accessed May 2009

[iv] Bang YJ et al. ASCO 2008 (poster no. 4526)

[v] Maroun JA. Capecitabine in the management of colorectal cancer. Expert Rev Anticancer Ther 2001; 1:327-33

Source
Roche