PARTNER: An open-label, randomized, phase 2 study of docetaxel/cisplatin chemotherapy with or without panitumumab as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck
Introduction
Approximately 686,330 cases of head and neck cancer (including nasopharyngeal carcinoma) occurred worldwide in 2012 [1], and an estimated 48,330 new cases will occur in the United States in 2016 [2]. Ninety percent of these tumors were squamous cell carcinoma of the head and neck (SCCHN) [3]. Approximately 12% of SCCHN cases diagnosed present with distant metastases [4], and ⩾50% of patients with locally advanced disease develop incurable relapse [5]. Notably, recent evidence indicated human papillomavirus (HPV)-positive and HPV-negative SCCHN are clinically and biologically distinct in the primary disease setting [6], [7]. HPV-positive status has been associated with increased disease-free survival and overall survival (OS) in patients with oropharyngeal cancer [8], [9].
Locoregionally, recurrent and/or metastatic SCCHN is usually treated with systemic chemotherapy [8]. Platinum-based combination regimens have activity in incurable SCCHN; however, benefits are limited and improved therapies are needed. Combination cisplatin/5-fluorouracil provides an objective response rate (ORR) of 30%, with median OS of 5–7 months [10], [11]. Numerous clinical trials have shown taxanes are among the most active antitumor agents in SCCHN, with ORR reaching 40% (with paclitaxel) to 42% (with docetaxel) [12]. A phase 2 study using docetaxel/cisplatin to treat recurrent SCCHN demonstrated a median OS of 9.6 months with acceptable safety, suggesting the combination may provide an active but less toxic backbone for the addition of biologic therapies [13].
The epidermal growth factor receptor (EGFR) is an established therapeutic target in SCCHN. The addition of the anti-EGFR monoclonal antibody cetuximab to platinum-based chemotherapy/5-fluorouracil significantly prolonged median OS, progression-free survival (PFS), and ORR versus chemotherapy alone [14]. In the phase 3 SPECTRUM study, the addition of panitumumab to cisplatin/5-fluorouracil did not significantly improve OS (median, 11.1 versus 9.0 months; P = 0.14) versus cisplatin/5-fluorouracil alone, but did significantly improve PFS (median, 5.8 versus 4.6 months; P < 0.004) and ORR (36% versus 25%; P < 0.007). Notably, OS improvements were more pronounced in patients with HPV-negative tumors (HPV-negative, 11.7 versus 8.6 months, P = 0.01; HPV-positive, 11.0 versus 12.6 months, P = 1.0) [15]. Combination of anti-EGFR monoclonal antibodies with docetaxel/cisplatin also appears feasible; in a phase 2 study, cetuximab plus docetaxel/cisplatin led to an ORR of 44% at 12 weeks and median PFS and OS of 6.2 and 14.0 months, respectively, with manageable toxicity [16].
This multicenter, randomized, open-label, phase 2 estimation study (PARTNER; ClinicalTrials.gov, NCT00454779) evaluated the combination of docetaxel/cisplatin with panitumumab versus docetaxel/cisplatin alone as treatment for recurrent/metastatic SCCHN, as well as second-line panitumumab monotherapy for patients who did not respond to docetaxel/cisplatin treatment. The study protocol was amended to further evaluate outcomes by HPV status.
Section snippets
Eligibility
Eligible patients (⩾18 years) had histologically/cytologically confirmed SCCHN; primary tumor of the oropharynx, oral cavity, hypopharynx, larynx, or SCCHN of unknown primary origin; disease considered incurable by surgery/radiotherapy; no prior systemic therapy for recurrent/metastatic disease; Eastern Cooperative Oncology Group (ECOG) performance status ⩽1; and one or more measurable target lesions per modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Eligible
Patients
Overall, 113 patients were enrolled and randomized to first-line treatment between January 29, 2007, and June 11, 2012; two did not receive treatment and were excluded from the safety population (n = 111; Fig. 2). Additionally, eight were excluded from the primary analysis set (n = 103) after the study amendment excluded patients ⩾70 years because of excess toxicity. Demographic and disease characteristics were similar between the panitumumab plus chemotherapy (n = 52) and chemotherapy-alone groups (n =
Discussion
The primary objective of this randomized phase 2 trial was to estimate the effect of first-line panitumumab treatment on PFS when added to docetaxel/cisplatin combination chemotherapy. No formal hypothesis was tested. PFS with first-line panitumumab plus chemotherapy treatment was 6.9 (95% CI = 4.7–8.3) months versus 5.5 (95% CI = 4.1–6.8) months (HR = 0.629) with chemotherapy alone. The ORR for the panitumumab plus chemotherapy arm was 44% versus 37% for the chemotherapy-alone arm; disease control
Conflict of interest statement
LJW has consulted for Eisai, Loxo, Ashion, and Merck. GK has received honoraria from Roche, Celgene, and Sanofi, and has consulted for Merck and Amgen Inc. DA has received clinical research funding from Amgen Inc., Eli Lilly, Celgene, Pfizer, GlaxoSmithKline, Galera Therapeutics, and AstraZeneca. SP has consulted for Celgene and Halozyme Therapeutics. KSO was employed by, and owned stock in, Amgen Inc., at the time the research was conducted. JD and SM are employees of, and own stock in, Amgen
Acknowledgments
The authors thank Meghan Johnson, PhD (Complete Healthcare Communications, LLC), for medical writing assistance, which was funded by Amgen Inc. This study was supported by Amgen Inc.
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