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
Head and neck squamous cell carcinoma (HNSCC) causes a significant morbidity worldwide with the incidence of approximately 550,000 cases per year [1]. The most common risk factors are tobacco use and human papillomavirus (HPV) infection [2], [3]. At diagnosis, a majority of patients present with locally advanced disease, but patients with HPV-positive HNSCC have a more favorable survival compared to patients with HPV-negative HNSCC [4], [5], [6]. However, there is a clear interaction between tobacco use and HPV-related carcinogenesis reflected by the worse survival of patients with HPV-positive HNSCC and smoking history compared to non-smokers [6], [7]. While overall survival (OS) is 80–90% for HPV-positive non-smokers given concurrent chemoradiation (CRT), HPV-negative or HPV-positive smokers have a significantly lower OS ranging from 40% to 70% [6], [8], [9]. For these patients, various strategies have been explored to improve the survival such as induction chemotherapy (IC) followed by CRT [10], [11], [12]. However, these IC regimens have proven to be relatively toxic, and there is a clear need for an effective regimen that is less toxic with the potential for improved efficacy in an intermediate to high risk population.
Epidermal growth factor receptor (EGFR) has been well established as a biomarker of poor prognosis and a therapeutic target [13], [14], [15], [16]. The most studied EGFR inhibitor in HNSCC is cetuximab which is a monoclonal antibody against EGFR and approved by Food and Drug Administration for use as a monotherapy or a combination with radiation or chemotherapy in HNSCC [17]. When cetuximab was combined with chemotherapy as a part of IC regimens, the efficacy and safety were favorable with a high response rate [18], [19]. However, cetuximab may induce infusion reaction, and its weekly and intravenous administration is inconvenient for some patients [20]. Afatinib is an irreversible inhibitor of the ErbB-family tyrosine kinase receptors, EGFR (erbB1/HER1), HER2 (erbB2), and HER4 (erbB4) and administered orally with daily dosing [21], [22]. In a randomized phase II trial of cetuximab or afatinib in 124 patients with recurrent and/or metastatic HNSCC, the disease control rate of afatinib was comparable to cetuximab (afatinib 50% and cetuximab 56.5%) [21]. In a randomized phase III trial, afatinib demonstrated a statistically significant improvement in progression-free survival (PFS) over methotrexate monotherapy in 483 patients with recurrent and/or metastatic HNSCC (median 2.6 months versus 1.7 months, respectively; p = 0.030) [23]. In addition, current data suggest that afatinib may be more effective than methotrexate in patients with recurrent and/or metastatic p16-negative compared to p16-positive HNSCC (Median PFS p16-negative: afatinib 2.7 months vs. methotrexate 1.6 months; p16-positive: afatinib 2.0 months vs. methotrexate 2.3 months) [24].
However, the objective response rate of afatinib as a monotherapy is modest at 10% in patients with recurrent and/or metastatic HNSCC [23]. Therefore, afatinib has been evaluated in combinations with commonly used chemotherapeutic agents including platinums, 5-FU, and taxanes [25]. In the phase Ib study, a treatment-related grade 5 toxicity was observed in the afatinib, cisplatin, and paclitaxel arm, but none in the afatinib, cisplatin, and 5-FU arm, suggesting the severe toxicity may be related to paclitaxel. Afatinib is known to modulate ABC transporters, ABCB1 (a.k.a. P-glycoprotein) and ABCG2 (a.k.a. BCRP), in several cancer cell lines by competitively blocking substrate transport and downregulating mRNA and protein expression of the transporters [26], [27]. Paclitaxel is an ABCB1 and ABCG2 substrate, and platinum is an ABCG2 substrate [28], [29], [30]. Because our hypothesis is that patients with the ABCB1 variants who are already at risk of increased chance of paclitaxel-related toxicities may have had an even greater risk of toxicities given the combination of afatinib and paclitaxel, we evaluated the ABCB1 rs1045642 (C3435T) and rs2032582 (G2677T) and not ABCG2 variants for their association with paclitaxel-related toxicities as the literature supports this association [30].
The current study was to select newly diagnosed, locally advanced HNSCC patients with poor prognosis according to HPV status and smoking habits, in whom the need for additional therapeutic options is pressing, and demonstrate the safety of adding afatinib to the established IC regimen of carboplatin and paclitaxel.
Section snippets
Patient selection
Eligible patients had histologically confirmed diagnosis of squamous cell carcinoma, operable or inoperable tumors, stage III (T3N0-1) and IVA-B (T1-4 N2-3M0 or T4N0-1M0) of oral cavity, oropharynx, hypopharynx and larynx. For patients with oropharynx primary, either HPV negative or HPV positive with a > 10 pack year tobacco history or current smokers were eligible. HPV status was determined before the enrollment in only non-smokers with oropharynx primary by HPV in-situ hybridization and/or p16
Patient characteristics
From April, 2013 to July, 2014, ten patients were consented, and nine patients were enrolled on the trial from two participating institutions, Johns Hopkins University and Vanderbilt University. One patient failed the screening. Characteristics of the patients are listed in Table 1. Of nine enrolled patients, eight were male, and one was female. Median age was 58. ECOG performance status was 0 for six patients and 1 for three patients. Primary sites were one oral cavity, six oropharynx and two
Discussion
The combination of afatinib with carboplatin and paclitaxel as an IC regimen was well tolerated at the dose level of 1 (20 mg) in patients with newly diagnosed, locally advanced HNSCC. The 20 mg daily dosing is consistent with the phase II dosing determined by a phase Ib trial of afatinib in a combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (5-FU) in patients with advanced solid tumors which included patients with unresectable and/or metastatic cancers in
Grant funding
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). These studies were supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) through National Comprehensive Cancer Network Oncology Research Program (ORP). BIPI had no role in the design, analysis or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances,
Conflict of interest statement
Christine H. Chung received research funding from Boehringer Ingelheim for preclinical research. Sarah Bonerigo received honorarium from Boehringer Ingelheim for serving in a focus group. All other authors have no conflict of interest.
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