Originally published Aug. 8.
By Turna Ray
Results of a Phase III trial conducted by Genentech suggest that HER2-positive metastatic breast cancer patients receiving Herceptin plus a new agent, pertuzumab, in combination with docetaxel experienced greater progression-free survival than those who received the Herceptin/docetaxel regimen.
"These results with pertuzumab combined with Herceptin and docetaxel are very encouraging and represent our commitment to developing potential new personalized options for people with this aggressive disease," Hal Barron, Genentech's chief medical officer and head of global product development, said in a statement last month.
Roche subsidiary Genentech is planning to file for regulatory approval of pertuzumab in combination with Herceptin (trastuzumab) and docetaxel as a new treatment for HER2-positive metastatic breast cancer. The Clinical Evaluation of Pertuzumab and Trastuzumab, or CLEOPATRA, study will be the pivotal trial supporting a filing with the US Food and Drug Administration and regulatory authorities in other countries, slated for later this year.
The first drug of its kind, the HER2 dimerization inhibitor pertuzumab prevents the HER2 receptor from joining with other HER receptors, such as EGFR/HER1, HER3, and HER4. Genentech believes that pertuzumab stops cancer growth by blocking cell signaling.
"The mechanisms of action of pertuzumab and Herceptin are believed to complement each other, as both bind to the HER2 receptor but on different regions," the company said in a statement. "The goal of combining pertuzumab with Herceptin and chemotherapy is to determine if the combination may provide a more comprehensive blockade of HER signaling pathways."
The Phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial is comparing the safety and efficacy of the pertuzumab/Herceptin/docetaxel regimen with Herceptin/docetaxel in 808 patients with HER2-positive metastatic breast cancer. The trial has been enrolled in 19 countries.
An independent review found that the study met its primary endpoint of progression-free survival, Genentech said. Secondary endpoints of the study are overall survival, safety profile, overall response rate, duration of remission, quality of life, and correlation of biomarkers with clinical outcomes. Genentech hasn't yet reported the full results of CLEOPATRA, which began enrolling patients in 2008.
Roche/Genentech initiated CLEOPATRA after a Phase II single-arm, open-label study in which 66 patients who received a pertuzumab/Herceptin regimen showed encouraging results. In that study, 8 percent saw their tumors disappear and 16 percent had a partial tumor response. Additionally, in this earlier study, reported at the American Society of Clinical Oncology's annual meeting in 2008, 25 percent of patients had stable disease for at least six months.
Genentech is also investigating pertuzumab in early-stage HER2-positive breast cancer. Last December, Genentech reported results from a Phase II neoadjuvant study looking at the pertuzumab/Herceptin/docetaxel regimen in early-stage, HER2-positive breast cancer patients.
In that trial, called the Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation, or NEOSPHERE, study, the pathologic complete response rate for patients on the trastuzumab/pertuzumab/docetaxel regimen was 48.5 percent, compared with 24 percent for patients receiving pertuzumab/docetaxel, 29 percent on trastuzumab/docetaxel, and 16.8 percent on trastuzumab/pertuzumab. The company is currently studying the trastuzumab/pertuzumab/docetaxel regimen in a Phase III study in early-stage HER2-positive breast cancer.
Expanding Markets and Price
Currently, Herceptin is approved in combination with docetaxel as a first-line treatment for HER2-postive metastatic breast cancer patients or as a single agent in patients with HER2-positive metastatic disease who have previously been treated with chemotherapy. Additionally, the drug is approved in combination with cisplatin/capecitabine or cisplatin/5-fluorouracil for patients with metastatic HER2-positive stomach cancer who haven't received prior treatment.
If Genentech is successful at gaining approval for pertuzumab in combination with Herceptin and docetaxel, it will not only provide a new option for advanced HER2-postive breast cancer patients, but also further expand the company's blockbuster Herceptin franchise.
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For the six months ended June 30, Roche reported that Herceptin generated global revenues of CHF 2.7 billion ($3.5 billion) — a 10 percent increase over the first half of 2010. For the first half of 2011, Herceptin sales in the US were $952 million, representing a 5 percent increase from the year-ago period.
Herceptin, approved by the FDA in 1998 and considered the first pharmacogenomically targeted personalized medicine product, is only indicated for breast and stomach cancer patients whose tumors overexpress the HER2 protein.
The drug is estimated to cost between $42,000 and $65,000 per year for breast cancer patients. Some industry observers have estimated that the price of a regimen containing Herceptin and pertuzumab could easily top $100,000 a year.
During a July 21 call to announce Roche's half-year earnings for 2011, Pascal Soriot, chief operating officer of the pharmaceutical division, said that while the CLEOPATRA and NEOSPHERE trials have given the company a better sense of pertuzumab's value, the firm still hasn’t settled on how to price the drug when combined with Herceptin.
"Because the role of cost is kind of an issue even if the two products … will be cost effective, there is of course a limit to the ability [and] to the willingness of what payors are going to pay," Soriot said. "I know how to price pertuzumab in isolation relatively quickly. What I need to figure out now is the logistics and how do we practically implement the pricing of the combination," he said.
Soriot added that Roche will probably need to come up with a scheme to help patients manage costs associated with the combination treatment.
While there are currently no reported cost-effectiveness studies for the pertuzumab/Herceptin/docetaxel regimen, past studies have found Herceptin to be cost-effective as an adjuvant treatment with various chemotherapy combinations.
In 2007, two cost-effectiveness studies on Herceptin were published in the Journal of Clinical Oncology. Liberato et al. estimated that adjuvant Herceptin treatment in HER2-positive early stage breast cancer patients cost $19,000 per life-year saved, while Kurian et al. estimated a cost of under $40,000 per life-year saved. Researchers in both studies agreed that adjuvant Herceptin improved long-term survival by at least one year; that the cardiac toxicities associated with treatment didn't negatively impact long term patient outcomes; and that the cost-effectiveness ratios were comparable to or less than other standard treatments.
However, Bruce Hillner and Thomas Smith of Virginia Commonwealth University cautioned in an editorial accompanying the two studies in JCO that despite the fact that both studies found Herceptin to be cost-effective based on different calculations, "an acceptable cost-effectiveness ratio should not be viewed as justifying a new therapies price especially when the evidence supporting its use was predominantly done using public (National Cancer Institute) funds."
Although fluorescence in situ hybridization- and immunohistochemistry-based HER2 tests are already available, Roche has continued to improve the companion tests that can better pick put best responders to Herceptin in an effort to maintain its profitable HER2-positive cancer franchise.
In June, the FDA approved a new HER2 assay, called the HER2 Dual-ISH assay, manufactured by Roche subsidiary Ventana Medical Systems. According to Roche, the test is faster and more sensitive than existing FISH tests, requiring less tumor tissue.
During the half-year earnings call, Daniel O'Day, chief operating officer of Roche's diagnostics division, noted that the D-ISH assay enables doctors to have test results in one day as opposed to three days with current FISH tests.
Furthermore, "it can be done in a better workflow for pathologists. Pathologists don’t have to go into a dark room. They can use a bright-field-like microscopy and they can see these two DNA markers in the presence of morphology, which is different than what we have in our test today," O'Day said.
He highlighted that the D-ISH assay detects HER2-positive patients who would be missed by currently marketed tests. The D-ISH test "has 96 percent concordance to FISH, but what we’ve seen … by an independent group of pathologists" is that the D-ISH test was "able to identify HER2 in patients that were missed by the current standard" testing, O'Day said during the call.
The D-ISH test "allows us to make sure that no woman is missed with breast cancer for Herceptin treatment and for some of the other HER2 treatments that we have in our pipeline as we move forward," he noted.
The American Cancer Society estimates that approximately 230,000 women will be diagnosed with breast cancer in 2011. Between 15 percent and 25 percent of breast cancer patients have HER2-positive tumors.
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