FDA's approval on Oct. 20 of Herceptin (trastuzumab) in patients with HER2-positive, metastatic gastric and gastroesophageal junction cancers, is an important, albeit narrow new indication for one of Roche's best-selling oncology drugs and comes when the Swiss drug maker is under siege following a series of development setbacks.

Approval was based on results of ToGA, an international Phase III randomized study that enrolled 594 patients. It showed that people who received Herceptin along with chemotherapy had an overall survival of 13.5 months (based on a hazard ratio of 0.73), compared to 11 months for those receiving chemotherapy alone - giving the former group a 37% survival advantage. ToGA demonstrated a safety profile that was similar to that of Herceptin's use in various breast cancer studies, Roche said.

Herceptin, which had U.S. sales of $386 million in the third quarter and worldwide sales of $1.3 billion, is currently used in treatment of breast cancer patients who test positive for HER2 gene amplification (about 25% of breast cancer patients). Dosing and pricing will be the same for gastric cancer as for breast cancer ($4,200/month), although duration of therapy could be shorter, given the shorter life expectancy of patients.

Roche doesn't provide public forecasts of U.S. sales of its drugs, but Pharma COO Pascal Soriot said in a first-half 2010 earnings call that the new indication would "help us a bit" both in the U.S. and in Europe. That said, gastric cancer is the second most common form of cancer-related death worldwide, but it is an orphan disease in the U.S., with about 22,000 diagnosed cases a year.

A Companion Diagnostic Gets Approved Simultaneously

Only HER2-positive patients - about 22% of all stomach cancer patients - participated in Roche clinical trials for the new indication. And patients who had particularly high HER2 levels (about 16% of those enrolled, as measured by immunohistochemistry staining or fluorescent in situ hybridization) fared particularly well. These patients had a median overall survival of 16 months, compared to 11.8 months for patients receiving chemotherapy only.

Thus, as it did a decade ago in its breast cancer trials, Roche worked with Dako A/S, a Danish anatomic pathology company, to develop the companion diagnostic for Herceptin for use gastric cancer. Dako's tests for HER2 are already FDA approved and on the market for use in measuring HER2 levels in breast cancer patients, but the company received FDA approval for an expanded indication in gastric cancer patients also on Oct 21. Likewise, the Herceptin label for gastric cancer says patients have to be defined as HER2 positive based on an FDA approved test, and Dako is now the only manufacturer of such a test.

The test was a crucial part of the development program and led to a distinction between the U.S. and EU labeling. In the U.S., the label includes patients who score IHC3+ or who are FISH positive. A test result of ICH1+ or IHC2+ would be considered equivocal, and the patient would then have a FISH test performed.

Herceptin received EU marketing authorization for use in gastric and gastroesophageal junction cancers in January. The EU label is more restrictive, however, and includes only patients with metastatic stomach exhibiting high levels of HER2, defined as patients who score either IHC2+ or IHC3+ on immunohistochemistry staining tests and are confirmed as FISH positive ('NICE, In A Reversal, Endorses Use of Herceptin In A Subset Of Gastric Cancer Patients,' 'The Pink Sheet' DAILY, Sept. 29, 2009). That translates to about 16% of stomach cancer patients, compared to the 22% of patients who are eligible in the U.S.

Roche won't be selling the Dako test, but it will be educating oncologists and pathologists about the role of the diagnostic in determining eligibility for the drug, which it expects could be one of the biggest challenges to gaining traction with the drug's new indication. While the diagnostic may seem like a highly technical sticking point, it has pricing, reimbursement and procedural implications. More pharmaceutical companies are becoming involved in companion diagnostics, so Roche's experience is sure to be watched ('Companion Diagnostics Moves Toward Mainstream Drug Development,' IN VIVO, March 2010).

Oncologists aren't used to ordering HER2 tests for gastric cancer patients. Moreover, although it is widely used in triaging breast cancer patients who are eligible for Herceptin the test is handled somewhat differently in gastric cancer.

Gastric cancer biopsies, for example, have to include larger tissue samples because HER2 genes are spread out in breast cancer tumors, but they cluster in gastric cancers, and therefore could be missed if the tissue sample is too small. Also, pathologists have to learn a different way of reading the staining patterns on such samples.

Roche's core oncology business, which has driven its growth for most of the past two decades, is maturing, as U.S. and European sales growth slows of its five leading drugs (Avastin, Rituxan, Herceptin, Xeloda, and Tarceva). Regions outside of the U.S. and EU, where much of the opportunity for Herceptin in gastric cancer lies, saw stronger growth.

Aside from gastic cancer, however, Roche has no programs in mid or late stage development examining Herceptin's use in other cancers.

-Wendy Diller (w.diller@elsevier.com)

Roche's Challenge With Herceptin Gastric Cancer Claim Will Be Companion Dx Use

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