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+).

Valrubicin May Fill Unmet Need In Aggressive Form of Bladder Cancer

Specialty pharmaceutical company Endo Pharmaceuticals (100 Endo Boulevard, Chadds Ford, PA 19317, (610)558-9800) engaged in the research, development, sale and marketing of branded and generic prescription pharmaceuticals used to treat and manage pain, overactive bladder, prostate cancer and the early onset of puberty in children, or central precocious puberty (CPP), today announced the availability of valrubicin (Valstar™) for the treatment of a distinct form of bladder cancer.

Valrubicin is the only FDA-approved intravesical therapy for patients with Bacille Calmette-Guerin (BCG)-refractory carcinoma in situ (CIS) of the urinary bladder for whom immediate removal of the bladder would be associated with unacceptable medical risks. Valrubicin represents a new treatment option for these patients who may otherwise have exhausted all other FDA-approved treatment alternatives, including BCG.

Bladder cancer is the fourth most common cancer among men and the 11th most common among women in the United States, and approximately 70,000 Americans are newly diagnosed with bladder cancer each year. CIS bladder cancer is a rare and aggressive form of cancer with a 50 to 90 percent probability of recurrence in five years.

Standard treatment of CIS of the urinary bladder is transurethral resection of the bladder tumor (TURBT) followed by one or two courses of BCG. Although the initial response rate to BCG is high, recurrence occurs in up to 34 percent of patients.


Patients who don't respond to BCG therapy have few FDA-approved treatment options. The most conservative treatment option for BCG-refractory patients is surgical bladder removal. However, some patients are not candidates for radical surgery due to comorbid disease, and others refuse to consider the change in their lifestyle resulting from surgical bladder removal even when counseled on the risk of cancer progression.

"Bladder cancer is an under recognized disease, and it's important to increase public awareness of bladder cancer and research directed at the diagnosis, treatment and cure of the disease," said Diane Zipursky Quale, co-founder and president of the Bladder Cancer Advocacy Network (BCAN). "We are very encouraged by Endo's commitment to improving outcomes for bladder cancer patients."

"Patients with recurrent carcinoma in situ bladder tumors who fail traditional therapy have been significantly underserved due to the lack of available approved treatment alternatives, and valstar™ will provide a well-tolerated treatment option for these patients," said Dave Holveck, president and chief executive officer of Endo Pharmaceuticals. "Our launch of valstar™ also represents our initial offering in a long-term plan by Endo to deliver multiple therapies to improve and extend the lives of patients with different types of bladder cancer, as evidenced by our recent agreement with Bioniche."


Valrubicin, a sterile solution for intravesical instillation of valrubicin, is placed directly into the bladder through a catheter and is administered once a week for six weeks under the supervision of a physician experienced in the use of intravesical cancer chemotherapeutic agents.
In the pivotal clinical trial, valrubicin was shown to induce a complete response in about one in five patients at six months following initiation of therapy, and 29 percent of patients derived a clinical benefit from valrubicin treatment. It is important to note that if after valrubicin treatment a patient does not have a complete response of CIS after three months, or if CIS recurs, surgical bladder removal must be reconsidered.

Valrubicin was approved by the FDA for this indication in 1998 and marketed by Anthra Pharmaceuticals, Inc. In 2002, Anthra voluntarily withdrew valrubicin from the U.S. market because of a formulation issue with an inactive component. Since market removal, valrubicin has been on the FDA Drug Shortages List, which was established to address and alleviate shortages primarily of medically necessary drug products, since these can have significant public health consequences. On Feb. 27, 2009, Indevus Pharmaceuticals, Inc., the previous owner of valrubicin, received FDA approval to re-introduce valrubicin after modifying the formulation. On March 23, 2009, Endo acquired Indevus Pharmaceuticals and began preparing to re-launch valrubicin. The drug represents the first product launch by Endo Pharmaceuticals in the urology and oncology therapy markets.

"Patients who have failed multiple courses of BCG have few to no remaining treatment alternatives, in part because many patients cannot undergo surgical bladder removal due to comorbid medical conditions, and the procedure may be associated with significant risk of complications and alteration of lifestyle and body image," said Gary Steinberg, M.D., FACS, Professor and Vice Chairman of Urology, Director of Urologic Oncology at the University of Chicago Medical Center. "Although valrubicin was previously available, it has never been an option for the thousands of people suffering today from this disease, and this reintroduction may bring new hope to many patients."


For more information:

• Valrubicin (Valstar™)
• Endo Pharmaceuticals
• Full Prescribing Information
• Expert Video (Endo Pharmaceuticals; Dr. Crawford, a Clinical Assitant Professor of Surgery at Florida State University College of Medicine

Standard of Care for Anal Cancer Should Not Be Changed

Findings from the largest trial ever conducted for anal cancer have shown that the current standard of care, using a novel, continuous radiation therapy delivery program combined with 5-fluorouracil (5-FU) , (a drug commonly used to treat many types of cancer including, breast, head and neck, anal, stomach, colon and some skin cancers), and mitomycin-C (a chemotherapy drug mainly used to treat bladder and rectal cancers, but also sometimes pancreatic, lung and breast cancers), results in the best outcomes so far reported for patients with anal cancer, and that cisplatin chemotherapy (a drug approved to be used together with other drugs to treat many different cancers), is not superior to mitomycin-C.

The study, presented on Saturday, May 30, 2009 by Roger James, MD, Maidstone Hospital, Kent, UK, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida, also showed no evidence of a benefit of adding maintenance chemotherapy to the standard of care.

Anal cancer is rare, with about 5,000 patients diagnosed in the United States each year. In the United Kingdom about 850 people are diagnosed with this disease each year. It is slightly more common in women than men, with rates increasing in women over the past 10 years.

Unlike colorectal cancer, the majority of patients with anal cancer do not need surgery, largely because the tumors are the squamous cell type, which are very responsive to chemotherapy and radiation. Cisplatin is commonly used for other squamous cell cancers, but it is less convenient to deliver and is known to have different toxicities from mitomycin-C, such as neurological and renal side effects and hearing loss.

The current study, called ACT II, conducted by the National Cancer Research Institute in the United Kingdom, and funded by Cancer Research UK, randomized 940 patients to receive radiation therapy given at the same time as 5-FU with either mitomycin-C or cisplatin. Patients were also randomized to receive follow-up maintenance therapy with cisplatin and 5-FU after chemoradiation or no maintenance therapy.

After a median follow-up of three years, the investigators found no significant difference in outcome in the two randomized comparisons:

• The complete response rate at 6 months (the number of patients who had all signs of their cancer disappear) was 94 percent in the mitomycin-C group compared with 95 percent in the cisplatin group.
• Recurrence-free survival at 3 years (the number of patients whose tumors did not return) was 75 percent both in patients who got maintenance therapy and in those who did not.
• Overall survival at 3 years was 85 percent in patients who received maintenance therapy and 84 percent in those who did not.

“These findings are good news in spite of the lack of evidence for an improvement in giving either cisplatin or maintenance therapy, since the standard chemoradiation schedule given in this trial was highly effective,” said Roger James, MD, FRCP, FRCR, a radiation oncologist from Maidstone Hospital, Kent, United Kingdom, and the study’s lead author. “Although this trial did not show an improvement from adding maintenance therapy, some form of additional treatment will be the subject of future studies, to determine whether some subset of patients might benefit from it.”

For more information:

• The National Cancer Research Institute (NCRI)
• Cancer Research UK
• Anal Cancer trials (UK)
• Glynne-Jones R, Mawdsley S, Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy? Journal of Clinical Oncology (JCO), Vol 26, No 22 (August 1), 2008: pp. 3669-3671

2009 ASCO Annual Meeting Abstracts:

• James R, Wan S, Glynne-Jones R, Sebag-Montefiore D, Kadalayil L, Northover J, Cunningham D, Meadows M, Ledermann J, National Cancer Research Institute (NCRI) ACT II Trial Management Group. A randomised trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II) LBA4009

Illustration courtesy of the American Society of Clinical Oncology.