A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma

INTRODUCTION: Afatinib is an ErbB family receptor inhibitor with efficacy in head and neck squamous cell carcinoma (HNSCC). A phase I trial was conducted to determine the maximally tolerated dose (MTD) of afatinib in combination with carboplatin and paclitaxel as induction chemotherapy (IC). MATERIAL AND METHODS: Patients with newly diagnosed, locally advanced HPV-negative or HPV-positive HNSCC with a significant smoking history were enrolled. Afatinib alone was given daily for two weeks as lead-in and subsequently given with carboplatin AUC 6 mg/ml*min and paclitaxel 175 mg/m(2) every 21 days as IC. Afatinib was started at a dose of 20 mg daily and dose escalated using a modified Fibonacci design. After completion of IC, afatinib was discontinued and patients received concurrent cisplatin 40 mg/m(2) weekly and standard radiation. Toxicity was assessed using CTCAE version 4.0. RESULTS: Seven of nine patients completed afatinib lead-in and IC. Five patients had partial response and two patients had stable disease after IC. Dose level 1 (afatinib 20 mg) was well tolerated with one grade 3 (ALT elevation) and one grade 4 (neutropenia) toxicities. However, dose level 2 (afatinib 30 mg) was not well tolerated with nine grade 3 (pneumonia, abdominal pain, diarrhea, pancytopenia, and UTI), two grade 4 (sepsis) and one grade 5 (death) toxicities. CONCLUSIONS: The MTD of afatinib given with carboplatin AUC 6 mg/ml*min and paclitaxel 175 mg/m(2) is 20 mg daily. Combination of afatinib at doses higher than 20 mg with carboplatin and paclitaxel should be administered with caution due to the toxicities