GSK Study Showed Targeted Therapy Combination Achieved 14 Month Overall Survival in Patients with Advanced Breast Cancer

Saturday, December 12, 2009 Cancer News
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LONDON and PHILADELPHIA, Dec. 11 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, p=0.026).

"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.

GSK in Oncology

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About GlaxoSmithKline

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BOXED WARNING and Additional Important Safety Information

Hepatotoxicity - TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.

Decreased Left Ventricular Ejection Fraction - TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Patients with Severe Hepatic Impairment - If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.

Diarrhea - Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.

Interstitial Lung Disease/Pneumonitis - TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are greater than or equal to Grade 3 (NCI CTCAE), TYKERB should be discontinued.

QT Prolongation - TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.

Pregnancy: Pregnancy D - TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions - The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).

The most common grade 3 and 4 adverse reaction (NCICTC v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).

Please see full prescribing information, including BOXED WARNING.

Notes to Editors:

TYKERB® is a registered trademark of the GlaxoSmithKline group of companies in the United States.

TYVERB® is a registered trademark of the GlaxoSmithKline group of companies in Europe.

XELODA® is a registered trademark of Roche Laboratories Inc.

HERCEPTIN® is a registered trademark of Genentech, Inc.

Enquiries: Onsite Media Enquiries (US Media) Ken Inchausti (267) 809 7552 Onsite Media Enquiries (ex-US Media) Gregory Clarke (610) 405 0053 UK Media Enquiries: Philip Thomson (020) 8047 5502 David Outhwaite (020) 8047 5502 Stephen Rea (020) 8047 5502 US Media Enquiries: Nancy Pekarek (919) 483 2839 Mary Anne Rhyne (919) 483 2839 Kevin Colgan (919) 483 2839 Sarah Alspach (919) 483 2839 European Analyst/Investor Enquiries: David Mawdsley (020) 8047 5564 Sally Ferguson (020) 8047 5543 Gary Davies (020) 8047 5503 US Analyst/Investor Enquiries: Tom Curry (215) 751 5419 Jen Hill Baxter (215) 751 7002

SOURCE GlaxoSmithKline

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