ABSTRACT
Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.
Subject(s)
Antibodies, Monoclonal/administration & dosage , B7-H1 Antigen/antagonists & inhibitors , Head and Neck Neoplasms/drug therapy , Tumor Microenvironment/drug effects , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , B7-H1 Antigen/analysis , B7-H1 Antigen/immunology , Dose-Response Relationship, Drug , Female , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/virology , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasm Staging , Papillomaviridae/isolation & purification , Progression-Free Survival , Response Evaluation Criteria in Solid Tumors , Tumor Microenvironment/immunologyABSTRACT
BACKGROUND: Vascular endothelial growth factor (VEGF) and c-kit are highly expressed in adenoid cystic carcinoma (ACC) and associated with biologic aggressiveness. This study aimed to assess the antitumor activity of sunitinib, a multi-targeted inhibitor of vascular endothelial growth factor receptor, c-kit, platelet-derived growth factor receptor, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), in ACC of the salivary gland. PATIENTS AND METHODS: Patients with progressive, recurrent and/or metastatic ACC were treated with sunitinib 37.5 mg daily in this single-arm, two-stage phase II trial. Response was assessed every 8 weeks. RESULTS: Fourteen patients were enrolled on to the study. Among 13 assessable patients, there were no objective responses, 11 patients had stable disease (SD), 8 patients had SD ≥ 6 months and 2 patients had progressive disease as best response. Median time to progression was 7.2 months. Median overall survival was 18.7 months. Toxic effects occurring in at least 50% of patients included fatigue, oral mucositis and hypophosphatemia usually of mild to moderate severity. CONCLUSIONS: Although no responses were observed, sunitinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 62% of assessable patients. The lack of responses is comparable with other trials of molecularly targeted agents in ACC and highlights the need for novel strategies in phase II clinical trial design.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Adenoid Cystic/drug therapy , Indoles/therapeutic use , Molecular Targeted Therapy , Neoplasm Recurrence, Local , Pyrroles/therapeutic use , Salivary Gland Neoplasms/drug therapy , Adult , Aged , Angiogenesis Inhibitors/adverse effects , Carcinoma, Adenoid Cystic/mortality , Carcinoma, Adenoid Cystic/secondary , Disease-Free Survival , Female , Humans , Indoles/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Proto-Oncogene Mas , Pyrroles/adverse effects , Salivary Gland Neoplasms/mortality , Salivary Gland Neoplasms/pathology , Sunitinib , Treatment OutcomeABSTRACT
Ambulatory blood pressure monitoring (ABPM) is now widely used for the assessment of antihypertensive drugs. This procedure may be used in phase II studies in dose-ranging evaluations as well as in phase III in order to assess the drug efficacy in the patient's natural environment. The increase in the reproducibility related to the repetition of blood pressure measurements by ambulatory monitoring may improve the accuracy of the trial and minimize the numbers of subjects required. Placebo fails to lower ambulatory blood pressure in almost all studies. Nevertheless, placebo is always necessary in clinical studies with ABPM at least for the pre-inclusion phase and in order to study the peak-trough ratio. This ratio may be accurately assessed by ABPM. Finally, ABPM may be useful to rule out "white coat" responders, who are not really hypertensive patients.
