Lapatinib or Trastuzumab in Combination with Aromatase Inhibitors for Hormone Receptor Positive/ErbB2-Positive Breast Cancer

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; LOPEZ, A.; ALCARAZ, A.; BARDACH, A.; CIAPONI, A; GONZALEZ, L

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Breast cancer is the most common neoplasm worldwide and the main cause of cancer death inwomen. Five to ten percent of the cases are already at advanced stages when diagnosed, whileapproximately 30% will recur despite having received an adjuvant therapy with curative intent. Inthose patients not eligible for treatment, survival averages 12 months. Approximately 20-30% ofthe subjects with metastatic breast cancer have ErbB2+/RH+ tumors. Overexpression of the ErbB2gene is associated with poor prognosis, decreasing survival by 50%. For postmenopausal patientswith RH-positive (RH+) tumors, first-line treatment with aromatase inhibitors (AI) is recommendedexcept in those patients with large rapid-growing tumors o requiring a faster antitumor response.Patients with expression of both receptors will obtain fewer benefits with hormone therapy thanErbB2-negative women; therefore dual Erb2/RH inhibition is proposed by combining lapatinib ortrastuzumab with an aromatase inhibitor in postmenopausal women with ErbB2+/RH+ metastaticbreast cancer.TechnologyTrastuzumab is a humanized monoclonal antibody selectively targeted against the ErbB2extracellular domain. It is intravenously administered in multiple regimes according to the primaryorigin of the tumor and the treatment goal. Lapatinib is an oral agent that inhibits the ErbB1-B2intracellular tyrosine kinase.PurposeTo assess the evidence available on the efficacy, safety and coverage policy related aspects onthe use of Lapatinib or Trastuzumab in combination with Aromatase Inhibitors in postmenopausalpatients with ErbB2+/RH+ metastatic breast cancer.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internetgeneral search engines, in health technology evaluation agencies and health sponsors. Prioritywas given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs);health technology assessments and economic evaluations; clinical practice guidelines andcoverage policies of other health systems.ResultsOne systematic review, three RCTs, two health technology assessments, three clinical practiceguidelines and ten coverage policies were selected for this report.Three RCTs assessed the ErbB2 blockage combined with an AI in postmenopausal women withErbB2+/RH+ metastatic breast cancer. None of them showed a significant increase in overallsurvival in the combination therapy groups. The TAnDEM study compared anastrozole withIECS ? INSTITUTO DE EFECTIVIDAD CLÍNICA Y SANITARIA - WWW.IECS.ORG.ARDocumentos de Evaluación de Tecnologías Sanitarias ? pág. 8trastuzumab versus anastrozole (n=207) and evidenced a significant increase of 1.8 months in theprogression-free period (PFP) favoring the combination therapy group in patients with confirmedRH. The EGF30008 study randomized subjects to treatment with letrozole associated withlapatinib or not (n= 219). There was a significant increase of 5.2 months in the PFP favoring thecombination therapy group. The eLEcTRA study (n=57) that assessed the use of trastuzumab plusletrozole was closed due to poor enrolment not evidencing a significant difference in time toprogression. In all the studies, the number of adverse effects was higher in the combinationtherapy groups. A paper published later did not show quality of life impairment in patients undercombination therapy with lapatinib.One 2012 meta-analysis of indirect comparisons assessed the overall survival and did not findstatistically significant differences between the use of exemestane, tamoxifen, anastrazole or thecombined use of trastuzumab and anastrazole or lapatinib and letrozole.The National Cancer Comprehensive Network (NCCN) recommends initial treatment with justhormone therapy for patients with ErbB2+/RH+ metastatic cancer. The United KingdomTechnology Assessment Agency (NICE) does not recommend the combination of lapatinib ortrastuzumab with an AI. In contrast, the First International Consensus for the Management ofAdvanced Breast Cancer (ABC1) and the European Clinical Oncology Society recommend thecombination of hormone therapy with anti-ErbB2 therapies. However, both documents state thatthey only improve disease-free progression period with no benefit on overall survival.The monthly cost of this therapy is approximately AR$29,300 (US$6,100 - December 2012) ifusing combined trastuzumab+anastrazole and AR$20,800 (US$4,400) for combinedlapatinib+letrozole. Both costs remarkably differ when compared with the cost of using hormonetherapy only: AR$1,300 (US$270). Two economic evaluations carried out in the United Kingdomconsider that any of the combination therapies are not cost-effective when compared withmonotherapy.There is consensus among different health sponsors surveyed on covering the combination use oflapatinib with an AI, but not with trastuzumab.ConclusionsThe methodological quality of the evidence found is moderate. In the reviewed RCTs, the use oflapatinib or trastuzumab in combination with an AI in postmenopausal women with metastaticbreast cancer has proved to be efficacious in slightly increasing the progression-free period andthe rates of response. However, it did not show superiority when assessing overall survival whencompared with the use of AI, thus resulting a higher number of adverse effects and a considerableincrease in costs.