Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer

• Published in: Cancer chemotherapy and pharmacology 2018-12, Vol.82 (6), p.979-986
• Main Authors: Martin, Nicolas, Isambert, Nicolas, Gomez-Roca, Carlos, Goeldner, Rainer-Georg, Zanetta, Sylvie, Sadrolhefazi, Behbood, de Mont-Serrat, Hélène, Campone, Mario, Delord, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Afatinib - administration & dosage; Afatinib - adverse effects; Afatinib - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Asthenia; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer; Cancer Research; Diarrhea; Diarrhea - chemically induced; Diarrhea - prevention & control; Dose-Response Relationship, Drug; Drug Administration Schedule; ErbB protein; ErbB-2 protein; Female; Gastric cancer; Humans; Immunotherapy; Intravenous administration; Life Sciences; Lysis; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Monoclonal antibodies; Oncology; Original; Original Article; Patients; Pharmacology; Pharmacology/Toxicology; Receptor, ErbB-2 - metabolism; Salivary Gland Neoplasms - drug therapy; Salivary Gland Neoplasms - metabolism; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Targeted cancer therapy; Toxicity; Trastuzumab; Trastuzumab - administration & dosage; Trastuzumab - adverse effects; Trastuzumab - therapeutic use; Treatment Outcome
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-018-3689-2

Background Trastuzumab 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 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. Results Of 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. 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.