Combination therapy improves overall survival in women with advanced breast cancer

In a clinical study, women with an aggressive form of breast cancer experienced a median survival of 14 months when treated with an investigational combination of TYKERB® (lapatinib) plus HERCEPTIN® (trastuzumab). The results of the Phase III study in HER2-positive metastatic breast cancer were presented during the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium, held in San Antonio, Texas (Dec. 9 - 13).

The study included 296 women with a type of breast cancer known as HER2-positive disease, characterized by an overexpression of the HER2 protein in the cancer cells. Patients enrolled in the study experienced recurrence of breast cancer despite a median of three prior trastuzumab-based therapies. The data presented at the San Antonio congress showed that patients overcame resistance to trastuzumab with the introduction of the lapatinib-trastuzumab combination.

"The clinical benefits brought forth by the lapatinib and trastuzumab combination are quite compelling and lead me to believe the agents may be acting together to form a sort of 'dual blockade' to obstruct the HER2 pathway necessary for the tumor to thrive," said primary investigator, Kimberly Blackwell, M.D., Duke University Medical Center.

Patients in the study were randomized to receive single agent lapatinib (1500 mg/daily) or a combination of lapatinib (1000 mg p.o. daily) plus trastuzumab (2 mg/kg). For those patients treated with monotherapy lapatinib, cross-over to the combination was allowed if the disease progressed after at least four weeks of therapy. Final analysis showed clinical activity for lapatinib in the control arm. Women treated with monotherapy lapatinib experienced a median overall survival of 9.5 months compared with 14 months when treated with the combination (median HR: 0.74,>

"It's possible that, by lapatinib working inside the cell and trastuzumab working outside the cell, the combination of agents is able to provide a more complete anti-tumor attack," said Blackwell. "To achieve a survival advantage of greater than one year for this aggressive form of breast cancer is very encouraging."

Final safety analysis showed the incidence of adverse events were similar among both treatment groups with the exception of the incidence of grade 1 and 2 diarrhea, which was significantly higher in the combination group (P = 0.03). The incidence of grade 3 or higher AEs was similar among treatment groups (7%).The most common adverse events (incidence greater than or equal to 10%) were diarrhea, nausea, rash, fatigue and vomiting. Of the Grade 3/4 adverse events observed, cardiac events were reported in three patients on the combination arm and in one patient on the monotherapy arm. One patient in the combination arm experienced cardiac failure and later died due to pulmonary thromboembolism that was caused by disease progression and/or study medication.

"Very few clinical studies have shown a survival benefit in metastatic breast cancer," said Steven Stein, M.D., Vice President, Medicine Development, GSK Oncology. "It's very encouraging to see the results gained by combining these two agents."

TYKERB is currently indicated in combination with Xeloda® (capecitabine) for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and Herceptin (trastuzumab). TYKERB alone or in combination with HERCEPTIN is not approved in this setting.