Abstract
BackgroundTrastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer.Materials and methodsThis phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer.ResultsOf the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit.ConclusionsDespite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.
Highlights
Overexpression of HER2, a tyrosine kinase receptor member of the ErbB family, leads to increased activation of downstream signaling pathways associated with cell proliferation, differentiation, survival and angiogenesis [1]
The maximum tolerated dose (MTD) for daily oral afatinib when combined with 3-weekly trastuzumab was 20 mg
Diarrhea induced by afatinib is known to be primarily secretory and several mechanisms have been postulated: impaired regulation of chloride secretion [11], mucosal atrophy, altered gut motility, colonic crypt damage, changes in the intestinal microflora and altered colonic transport
Summary
Overexpression of HER2, a tyrosine kinase receptor member of the ErbB family, leads to increased activation of downstream signaling pathways associated with cell proliferation, differentiation, survival and angiogenesis [1]. Results of a phase II trial of afatinib in patients with heavily pre-treated metastatic breast cancer (mBC) resistant to trastuzumab showed promising results [4]. An irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer. Materials and methods This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer. Conclusions Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily
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