Phase III study in HER2-positive advanced breast cancer shows overall survival benefit when Tykerb is combined with paclitaxel

Issued: Friday 10 December 2010

In a blinded, randomised, Phase III study, women with previously untreated HER2-positive metastatic breast cancer achieved a statistically-significant improvement in overall survival when treated with an investigational combination of Tykerb® (lapatinib) plus paclitaxel, a widely used chemotherapy agent.[i] The results of the Phase III study in HER2-positve metastatic breast cancer were presented during the 33rd annual meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, held in San Antonio, Texas (8-12 December 2010).

The data showed women with previously untreated HER2-positive metastatic breast cancer (MBC) experienced a statistically significant improvement in overall survival when treated with lapatinib plus paclitaxel compared to those treated with paclitaxel plus placebo, (27.8 months vs 20.5 months, respectively; p =0.0124) equating to a 26 percent reduction in the risk of death.

The study also showed a statistically significant improvement in median progression-free survival for women treated with the lapatinib plus paclitaxel regimen (9.7 months lapatinib plus paclitaxel vs. 6.5 months for paclitaxel plus placebo p<0.0001). Response rates observed in the study were 69 percent in the lapatinib plus paclitaxel arm compared to 50 percent in the paclitaxel plus placebo arm (p<0.0001).

The study was primarily conducted within the Asia-Pacific region with 86 percent of patients in the study being of Asian genealogy.

“To see an overall survival result of this magnitude is definitely encouraging and positively affirms the clinical activity that a lapatinib-based therapy can demonstrate in first-line metastatic breast cancer” said Jeffrey Bloss, M.D., Vice President and Medicine Development Leader, GSK Oncology. “Importantly, the study builds on the growing volume of phase III data for Tykerb-based regimens in HER2-positive metastatic breast cancer.”

In the study, 444 patients with previously untreated HER2-positive metastatic breast cancer were randomised to receive once daily lapatinib plus weekly paclitaxel or weekly paclitaxel plus placebo. At the time of disease progression, patients receiving the paclitaxel plus placebo treatment had an option to be treated with lapatinib monotherapy until further disease progression.

The magnitude of the overall survival benefit observed on the lapatinib plus paclitaxel arm was achieved despite 67 percent of the paclitaxel plus placebo patients crossing over to monotherapy lapatinib. Typically studies that incorporate a cross-over design have a reduced chance of demonstrating a distinct survival advantage as patients on both arms are now receiving dosing of the active, investigational agent, i.e. lapatinib.[ii]

Safety analysis from the study showed the most common adverse events (incidence ≥15 percent) were diarrhoea, neutropenia, rash, leukopenia, alopecia, decreased appetite, nausea, anaemia, fatigue and vomiting. Of the Grade 3/4 adverse events observed (incidence ≥10 percent):

• Grade 3 diarrhoea was reported in 20 percent of patients on the lapatinib combination arm and less than 1 percent of patients on the paclitaxel plus placebo control arm. There were no incidents of Grade 4 diarrhoea on the lapatinib combination arm.
• Grade 3/4 leukopenia was reported on both arms (lapatinib plus paclitaxel Grade 3 = 23 percent and Grade 4 = 3 percent; compared to the paclitaxel plus placebo arm Grade 3 = 8 percent and Grade 4 < 1 percent)
• Grade 3 rash was reported in 20 percent of the patients on the lapatinib combination arm. Grade 4 rash was reported in 4 percent of patients on the lapatinib combination arm. No Grade 3 or Grade 4 rash was reported on the paclitaxel control arm.
• Neutropenia was higher in the investigational arm lapatinib combination Grade 3 = 35 percent and Grade 4 = 16 percent compared to the paclitaxel control arm, Grade 3 = 15 percent and Grade 4 = 5 percent. The adverse events profiles observed in this study were consistent with the known lapatinib and paclitaxel safety profiles.

No deaths due to any treatment related adverse events were reported in the lapatinib plus paclitaxel arm, compared with 8 deaths (4 percent) on the paclitaxel plus placebo arm. There were two fatal treatment-related SAEs in the monotherapy lapatinib open-label phase.

About EGF104535

EGF104535 is an international, randomised, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of lapatinib plus paclitaxel versus placebo plus paclitaxel. The study’s primary endpoint was overall survival. Secondary endpoints included progression-free survival, overall response rate, clinical benefit response rate, duration of response, time to response and safety.

Patients were randomised from the period of January 2006 to December 2008. Cut-off of events for survival analysis was in June 2010.

The study was conducted in China, Thailand, Hong Kong, Brazil, Peru, Pakistan, Ukraine and Russia.

About Tykerb (lapatinib)

In the United States, lapatinib is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that over-expresses the HER2 receptor for whom hormonal therapy is indicated. TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. Lapatinib is also FDA approved in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumours over-express HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

In Europe, lapatinib, in combination with an aromatase inhibitor (AI), is indicated for the treatment of post-menopausal women with hormone receptor (HR)-positive, HER2 (ErbB2) over-expressing metastatic breast cancer and for whom chemotherapy is currently not intended. In Europe, lapatinib is also approved in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumours over-express HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

Lapatinib is approved in 91 countries including the U.S., Europe, Australia, India, Brazil, Russia, Turkey, South Korea and other countries around the world. Registration dossiers have been filed in Canada, China, Japan, Mexico and a number of countries in Asia, Latin America and the Middle East.

US FDA boxed warning and important safety information for Tykerb

Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain.

Patients with known severe hypersensitivity to TYKERB or any of its components should not take TYKERB. Also, patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women. If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered. The most common adverse reactions (≥20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea (64%, 20%), rash (44%, 13%), nausea (31%, 21%), and fatigue (20%,17%). The most common adverse reactions (>20%) during therapy with TYKERB plus lapatinib versus lapatinib alone were diarrhea (65%, 40%), palmar-plantar erythrodysesthesia (53percent, 51%), nausea (44%, 43%), rash (28%,14%), vomiting (26%, 21%), and fatigue (23%, 25%).

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Notes to Editors:

TYKERB® and TYVERB® are registered trademarks of the GlaxoSmithKline group of companies.