Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial

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art_HEGG_Subcutaneous_versus_intravenous_administration_of_(neo)adjuvant_trastuzumab_in_2012.PDF (245.4 KB)
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294
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article
Data de publicação
2012
DOI
Scopus
Web of Science
PubMed
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Título do Volume
Editora
ELSEVIER SCIENCE INC
Autores
ISMAEL, Gustavo
MUEHLBAUER, Susanne
HEINZMANN, Dominik
LUM, Bert
KIM, Sung-Bae
PIENKOWSKI, Tadeusz
LICHINITSER, Mikhail
SEMIGLAZOV, Vladimir
MELICHAR, Bohuslav
Citação
LANCET ONCOLOGY, v.13, n.9, p.869-878, 2012
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Resumo
Background A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. Methods The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1: 1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C-trough) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0.80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12.5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. Findings 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C-trough was 51.8 mu g/mL (coefficient of variation 52.5%) in the intravenous group and 69.0 mu g/mL (55.8%) in the subcutaneous group. The geometric mean ratio of C-trough subcutaneous to C-trough intravenous was 1.33 (90% CI 1.24-1.44). 107 (40.7%) of 263 patients in the intravenous group and 118 (45.4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4.7% (95% CI -4.0 to 13.4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33.2%] of 298 patients in the intravenous group vs 86 [29.0%] of 297 in the subcutaneous group), leucopenia (17 [5.7%] vs 12 [4.0%]), and febrile neutropenia (10 [3.4%] vs 17 [5.7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8.1%] in the subcutaneous group vs 13 [4.4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two-both in the subcutaneous group-were deemed to be treatment related. Interpretation Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.
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https://observatorio.fm.usp.br/handle/OPI/2557
Referências
  1. Aebi S, 2011, ANN ONCOL S, V22, pvi12, DOI 10.1093/ANN0NC/MDR371
  2. Bookbinder LH, 2006, J CONTROL RELEASE, V114, P230, DOI 10.1016/j.jconrel.2006.05.027
  3. Buzdar AU, 2007, CLIN CANCER RES, V13, P228, DOI 10.1158/1078-0432.CCR-06-1345
  4. Cardoso F, 2011, ANN ONCOL S, V22, pvi25, DOI 10.1093/ANNONC/MDR372
  5. Carlson RW, 2006, J NATL COMPR CANC S3, V4, P1
  6. Dawood S, 2007, CANCER, V110, P1195, DOI 10.1002/cncr.22895
  7. European Medicines Agency, EMEACPMPEWP215899
  8. European Medicines Agency, HERC SUMM PROD CHAR
  9. European Medicines Agency, CPMPEWPQWP140198 EUR
  10. Gianni L, 2010, LANCET, V375, P377, DOI 10.1016/S0140-6736(09)61964-4
  11. Goldhirsch A, 2011, ANN ONCOL, V22, P1736, DOI 10.1093/annonc/mdr304
  12. Haller MF, 2007, PHARM TECH, V10, P861
  13. Halozyme Therapeutics, HYLENEX REC HYAL HUM
  14. Pegram M, 1999, ONCOGENE, V18, P2241, DOI 10.1038/sj.onc.1202526
  15. Pivot X, 2012, 8 EUR BREAST CANC C
  16. Untch M, 2012, LANCET ONCOL, V13, P135, DOI [10.1016/S1470-2045(11)70397-7, 10.1016/S0140-6736(12)60068-3]
  17. Untch M, 2010, J CLIN ONCOL, V28, P2024, DOI 10.1200/JCO.2009.23.8451
  18. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, STAT APPR EST BIOEQ
  19. van der Hage JA, 2007, BREAST CANCER RES, V9, P70
  20. Wynne C, 2013, J CLIN PHARMACOL, V53, P192, DOI 10.1177/0091270012436560
  21. Zandvliet AS, 2008, CLIN PHARMACOKINET, V47, P487, DOI 10.2165/00003088-200847080-00001
  22. [Anonymous], CANC THER EV PROGR C
  23. [Anonymous], 2011, NCCN CLIN PRACT GUID

Coleções
Artigos e Materiais de Revistas Científicas - FM/MOG
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/58