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Multiple cellular pathways influence the growth and metastatic potentialof tumors, which is thought to be related to the ability of cancer cells todevelop primary or acquired resistance.(4) It is believed that targetedinhibition of several tumor cell signaling pathways may be more effective thaninhibition of a single pathway alone.(4)
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"Targeted therapies, either used in combination or as a single agent, arethe future of cancer treatment and may have the potential to treat patientsmore effectively," said Dr. Paolo Paoletti, Senior Vice President of theOncology Medicine Development Center at GSK. "GSK Oncology is committed tonumerous trials across a wide range of settings that not only reflect clinicalpractice today but also the possible treatment practices of the future. Themore we know about how and when to combine targeted therapies the closer weare to the ultimate goal -- personalized treatment regimens that better fitthe individual needs of patients."
Two key drivers of the growth and spread of tumors are the HER family oftyrosine kinase receptors and vascular endothelial growth factors (VEGF).(4)HER2 overexpression is associated with poor prognosis(5) and reduced overallsurvival,(6) while VEGF is linked to formation of new blood vessels(angiogenesis).(7)
Lapatinib and pazopanib in HER2-positive advanced or metastatic breastcancer: abstract 1016(1)
DATA PRESENTATION: SUNDAY, JUNE 1, 2008; 9:30 - 9:45 AM (CDT)
TYKERB and pazopanib separately target the HER2 and VEGF pathways. This isthe first Phase II trial to evaluate the combination of two oral, smallmolecule, targeted agents in first-line HER2-positive metastatic breastcancer. The primary endpoint was progressive disease rate (PDR) at week 12 asassessed by an independent review panel.(1) Progressive disease rate wasdefined as the percent of patients who had progressive disease by week 12 orhad missing evaluations at week 12. In the study of 141 patients, 36.2 percentof patients treated with TYKERB plus pazopanib experienced disease progressionversus 38.9 percent of patients who received TYKERB alone (p=0.37).
Additionally, response rate, a clinical term that is calculated bycomplete and partial disappearance of the tumor, was evaluated:
A retrospective analysis of response rate at any time up to 12 weeks wasalso performed:
"Data outcomes from this study are important because they demonstrate thatthese two targeted therapies can be combined and may provide a potential,future treatment option for HER2-positive breast cancer," said Dr. DennisSlamon, UCLA Jonsson Comprehensive Cancer Center. "In addition, both drugs aretaken orally once daily."
Treatment continued until tumor progression, patients withdrew due to anadverse event (AE) or withdrawal of consent.(1) Three patients in thecombination arm had an asymptomatic decrease (greater than or equal to 20percent) in left ventricular ejection fraction (LVEF) that was below the lowerlimit of normal. One patient had a smaller decline (< 20 percent) in LVEF thatwas symptomatic. The most common adverse events (AEs) in the combination armversus the monotherapy arm were diarrhea (67 percent vs. 58 percent), rash (28percent vs. 29 percent), AST increase (32 percent vs. 16 percent), ALTincrease (30 percent vs. 16 percent), nausea (29 percent vs. 16 percent),hypertension (26 percent vs. 4 percent), respectively (all grades).(1) Ther
