Elsevier

Oral Oncology

Volume 61, October 2016, Pages 31-40
Oral Oncology

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

https://doi.org/10.1016/j.oraloncology.2016.07.005Get rights and content

Highlights

  • Panitumumab activity in patients with SCCHN <70 years was shown through a trend toward improvement in PFS.

  • Toxicities observed in patients <70 years were consistent with previous studies.

  • Differences between arms in PFS and ORR were greater in the p16-negative group than in the primary analysis set.

  • Safety data suggest careful patient selection is needed to limit possible toxicity.

Abstract

Objective

This phase 2 estimation study evaluated docetaxel/cisplatin with/without panitumumab, an anti–epidermal growth factor receptor monoclonal antibody, as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).

Patients and methods

Randomized patients received docetaxel/cisplatin (75 mg/m2 each) with/without panitumumab (9 mg/kg) in 21-day cycles. Patients randomized to panitumumab + chemotherapy could continue panitumumab monotherapy after completing six chemotherapy cycles without progression; patients randomized to chemotherapy alone could receive second-line panitumumab after progression. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), overall response rate (ORR), time to response (TTR), duration of response (DOR), and safety. A protocol amendment limited enrollment to patients <70 years owing to excess toxicity in older patients and added mandatory pegfilgrastim/filgrastim support. Outcomes were also analyzed by human papillomavirus status.

Results

103 of the 113 enrolled patients were evaluable and randomized to receive ⩾1 dose of first-line treatment. Median PFS for panitumumab + chemotherapy was 6.9 (95% CI = 4.7–8.3) months versus 5.5 (95% CI = 4.1–6.8) months for chemotherapy alone (hazard ratio [HR] = 0.629; 95% CI = 0.395–1.002; P = 0.048). ORR for panitumumab + chemotherapy was 44% (95% CI = 31–58%) versus 37% (95% CI = 24–51%) for chemotherapy alone (odds ratio [OR] = 1.37; 95% CI = 0.57–3.33). Median OS for panitumumab + chemotherapy was 12.9 (95% CI = 9.4–18.5) months versus 13.8 (95% CI = 11.8–22.9) months for chemotherapy alone (HR = 1.103; 95% CI = 0.709–1.717). Median TTR for panitumumab + chemotherapy treatment was 6.9 weeks versus 11.0 weeks for chemotherapy alone. Median DOR was 8.0 (95% CI = 5.7–11.1) months with panitumumab + chemotherapy versus 5.1 (95% CI = 4.4–7.2) months with chemotherapy alone. Grade 3/4 adverse event incidence was 73% with panitumumab + chemotherapy versus 56% with chemotherapy alone. 41% and 55% of patients in the panitumumab + chemotherapy and chemotherapy-alone arms, respectively, received panitumumab monotherapy.

Conclusion

The addition of panitumumab to docetaxel/cisplatin may improve PFS in recurrent/metastatic SCCHN and has the potential to improve outcomes in these fully, or mostly, active patients.

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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