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

Abstract

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.

• Authors: Nicolas Martin, Nicolas Isambert, Carlos Gomez-Roca, Rainer-Georg Goeldner, Sylvie Zanetta, Behbood Sadrolhefazi, Hélène de Mont-Serrat, Mario Campone, Jean-Pierre Delord
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 82 Issue 6 Pg. 979-986 (12 2018) ISSN: 1432-0843 [Electronic] Germany
• PMID: 30350178 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Afatinib
• Receptor, ErbB-2
• Trastuzumab

Topics

• Afatinib (administration & dosage, adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism)
• Diarrhea (chemically induced, prevention & control)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Receptor, ErbB-2 (metabolism)
• Salivary Gland Neoplasms (drug therapy, metabolism)
• Stomach Neoplasms (drug therapy, metabolism)
• Trastuzumab (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome