Tykerb/Herceptin Combination Will Go Before FDA Advisory Panel

[Hopeful]

The Pink Sheet Daily. 2012 May 30, S Haley

FDA’s Oncologic Drugs Advisory Committee will review an application July 24 for use of two targeted agents in combination against metastatic HER-2 positive breast cancer, an area of labeling regulators thus far have not had much chance to consider.At issue is GlaxoSmithKline PLC’s supplementary marketing application to use its breast cancer drug Tykerb (lapatinib) with Roche’s Herceptin (trastuzumab) in the treatment of patients with HER-2 positive metastatic breast cancer who have received prior Herceptin therapy. A similar combination application is under consideration in Europe, where lapatinib is marketed as Tyverb, seeking to treat women with metastatic HER-2 positive breast cancer whose disease has progressed on prior trastuzumab regimens.

The submissions are based on results of an open label Phase III trial comparing the combination against lapatinib monotherapy in women whose disease had progressed on a trastuzumab-containing regimen. The combination produced statistically significant improvement in progression-free survival compared to the monotherapy with only the side effect of diarrhea reported more often in the combination arm, relieving fears the combination might create synergies in side effects as well as efficacy.

In the study, the first to compare the two biologics in tandem, dual blockade of HER-2 by lapatinib and trastuzumab, was tested to assess the complementary mechanism of action of the two agents. Lapatinib is an oral inhibitor of the epidermal growth factor receptor and HER-2, and trastuzumab binds the HER-2/neu receptor. The data were highlighted in a briefing leading up to the 2008 annual meeting of the American Society of Clinical Oncology.
The randomized, multi-center trial included 296 heavily pretreated patients whose cancer had progressed on Herceptin alone. On the primary endpoint of progression-free survival, the combination conferred a 27% reduction in risk of disease progression and had a 10.3% response rate compared to 6.9% with lapatinib alone. PFS was 12.0 weeks versus 8.1 weeks for monotherapy.
At the ASCO meeting this year, June 1-5 in Chicago, related presentations on the schedule include a preview of a Phase III trial currently enrolling patients in the U.S. and Canada to test the efficacy of the combination as maintenance therapy.

Earlier European Application Withdrawn

At the time GSK announced the submissions in February, the company announced it had withdrawn an application in the EU for use of lapatinib in combination with paclitaxel for treatment of patients with metastatic breast cancer whose tumors over-express HER-2. The European Medicines Agency’s advisory body, the Committee for Medicinal Products for Human Use had concluded that the lack of a direct comparison to trastuzumab plus paclitaxel hampered the proper assessment of the risk/benefit to European patients, the company said.

“It is important to note that CHMP recognized the study was well designed, provided benefit to the population studied, and there were no safety issues,” the company said. The study supporting that application demonstrated a significant clinical benefit for patients with first-line HER-2 positive metastatic breast cancer, with a statistically significant increase in overall survival and a safety profile consistent with labeling for both lapatinib and paclitaxel, GSK said. “Regulatory review of the combination [is] ongoing in other regions.”

In the U.S., Tykerb is approved in combination with the aromatase inhibitor letrozole (Novartis AG’s Femara) for treatment of postmenopausal women with HER-2 positive hormone receptor positive metastatic breast cancer for whom hormone therapy is indicated and in combination with capecitabine (Roche’s Xeloda), a chemotherapy, for treatment of HER2 positive advanced or metastatic breast cancer in women who have received prior therapy, including an anthracycline, a taxane and trastuzumab.

Later that day ODAC will discuss the evaluation of radiographic review in randomized clinical trials using progression-free survival as a primary endpoint in non-hematologic malignancies. They also will consider the merits of an independent audit of investigator progression assessment in a pre-specified subgroup of patients instead of an independent review of all progression assessments. The next day, the panel is set to take up the role of imaging in development of products to treat clear cell renal carcinoma.

Hopeful