targeted therapy combos promising for breast cancer

Inpharma 1640 - 31 May 2008

lapatinib alone was conducted in women with HER2Targeted therapy combosadvanced or metastatic breast cancer.2 In a prespecifiedpromising for breast cancer interim analysis, data were evaluated from 62 patientswho were randomised to receive pazopanib 400 mg/dayCombining targeted therapies in patients with humanplus lapatinib 1000 mg/day (n = 32) or lapatinibepidermal growth factor receptor-2 (HER2)-positive1500 mg/day, for 12 weeks. Eligibility required thatadvanced breast cancer appears to have potential, basedpatients had received no previous chemotherapy oron the results from two studies that are to be presentedHER2-directed treatment.at the 44th Annual Meeting of the American Society of

Efficacy data was evaluable in 69% of pazopanib/Clinical Oncology (ASCO).1,2

lapatinib recipients and 77% of lapatinib recipients. TheTrastuzumab teams up with lapatinib progressive disease rate (PDR) at week 12 (the primary

In a randomised phase III trial involving 296 patients endpoint), the RR and the reduction in target lesions allwith metastatic breast cancer, the efficacy of the oral favoured treatment with pazopanib/lapatinib overtyrosine kinase inhibitor lapatinib was evaluated as a lapatinib monotherapy [see table 2].monotherapy and in combination with the anti-HER2monoclonal antibody trastuzumab.1 The heavily Table 2. Clinical outcomes: lapatinib + pazopanibpretreated participants, who had already progressed on vs lapatinib monotherapytrastuzumab, were assigned to lapatinib 1500 mg/day

Lapatinib Lapatinib +alone or lapatinib 1000 mg/day plus trastuzumabmonotherapy pazopanib2 mg/kg/week (after a 4 mg/kg loading dose).*

Outcome (% of patients):The combination of lapatinib plus trastuzumab wasassociated with significant benefits, compared with PDR 27 19lapatinib monotherapy, in terms of progression-free RR 30 44survival (PFS) and clinical benefit rate (CBR), but Target lesion reduction 43 73response rate (RR) and overall survival (OS), althoughgreater in the combination group, were not significantly Common adverse events in the pazopanib/lapatinibdifferent [see table 1]. group and in the lapatinib monotherapy group included

diarrhoea (63% vs 57%, respectively), rash (22% vs 20%,Table 1. Clinical outcomes: lapatinib + respectively) and nausea (22% vs 17%, respectively);trastuzumab vs lapatinib monotherapy AST and bilirubin elevation were more likely with

pazopanib/lapatinib than with lapatinib aloneLapatinib Lapatinib +monotherapy trastuzumab (63% vs 33% and 39% vs 21%, respectively). Pazopanib/

lapatinib was discontinued in one recipient after anEndpoint:asymptomatic decline in LVEF.PFS (median, weeks) 8.4 12.0** If patients progressed on lapatinib monotherapy they couldCBR (% of patients) 13.2 25.2*crossover to the combination treatment.RR (% of patients) 6.9 10.3** GlaxoSmithKline; phase III (in combination with lapatinib) forOS (median, weeks) 39 51.6inflammatory breast cancer in the US, Germany and several other

* p < 0.05 vs lapatinib monotherapy countries, and phase II (in combination with lapatinib) for metastaticbreast cancer in the US, the UK, India and several other countries.

1. O’Shaughnessy J, et al. A randomized study of lapatinib alone or in combinationBoth regimens were consider to be well tolerated.with trastuzumab in heavily pretreated HER2+ metastatic breast cancerHowever, rates of grade 1/2 diarrhoea, acneiform rashprogressing on trastuzumab therapy. 44th Annual Meeting of the American

and asymptomatic decline in left ventricular ejection Society of Clinical Oncology : abstr. 1015, 30 May 2008. Available from: URL:http://www.asco.org.fraction (LVEF) were all higher with lapatinib/

2. Slamon D, et al. Randomized study of pazopanib + lapatinib vs. lapatinib alonetrastuzumab than with lapatinib monotherapy; there in patients with HER2--positive advanced or metastatic breast cancer. 44thwas one death due to cardiac toxicity in the combination Annual Meeting of the American Society of Clinical Oncology : abstr. 1016

(plus oral presentation), 30 May 2008. Available from: URL: http://group.www.asco.org.Lead investigator Dr Joyce O’Shaughnessy from 801099655

Baylor-Sammons Cancer Center, Dallas Texas, US,» Editorial comment: These summaries were based onnoted that "many women with HER2 positive breastabstracts released early online. It is probable that updatedcancer are still very active and living full lives, yet whenresults will be presented at the ASCO meeting.their disease progresses after trastuzumab and

chemotherapy, we have limited treatment options". Sheadded that "effectively attacking HER2 from multipleangles is an exciting and innovative approach, anddemonstrates the significant advances being achieved intreating this complex form of breast cancer".

Pazopanib plus lapatinib positivePreclinical studies have shown a direct molecular link

between HER2 amplification and upregulation ofvascular endothelial growth factor (VEGF) in patientswith HER2-positive breast cancer, with simultaneousoverexpression of HER2 and VEGF being associated witha worse prognosis than overexpression of either alone.

To examine this further, a phase II trial assessing theefficacy of dual pathway inhibition with the oralangiogenesis inhibitor pazopanib** plus lapatinib versus

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Inpharma 31 May 2008 No. 16401173-8324/10/1640-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved