Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Summary

Background

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods

This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m² on day 1 of each cycle) and fluorouracil (1000 mg/m² on days 1–4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings

Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8–12·2) in the panitumumab group and 9·0 months (8·1–11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729–1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6–6·6) in the panitumumab group and 4·6 months (4·1–5·4) in the control group (HR 0·780, 95% CI 0·659–0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7–13·7] vs 8·6 months [6·9–11·1]; HR 0·73 [95% CI 0·58–0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3–12·9] vs 12·6 months [7·7–17·4]; 1·00 [0·62–1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47–1·04]).

Interpretation

Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Funding

Amgen Inc.

Introduction

Platinum-based combination chemotherapy regimens can be used to treat patients with incurable locoregionally recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN).¹ Although these regimens lead to tumour responses in about 10–35% of patients, median survival is less than 1 year and the effects on patients' quality of life are unknown.2, 3, 4, 5, 6

Dysregulation of the EGFR signalling pathway plays a part in the development and progression of SCCHN.7, 8 Clinical trials6, 9 have shown that addition of anti-EGFR monoclonal antibodies to chemotherapy improves clinical outcomes in patients with recurrent or metastatic SCCHN. In a randomised phase 3 study in the USA,⁶ more patients in the group given cisplatin plus cetuximab responded than in the group receiving cisplatin plus placebo; and in a randomised phase 3 study (EXTREME) in Europe,⁹ addition of cetuximab to cisplatin and fluorouracil or to carboplatin and fluorouracil improved overall survival.

Human papillomavirus (HPV) DNA has been detected in up to two-thirds of oropharyngeal SCCHN tumours in patients presenting with locoregionally advanced disease.10, 11 Patients with locoregionally advanced HPV-positive oropharyngeal SCCHN who are treated with radiotherapy with or without chemotherapy have a better outlook than do HPV-negative patients.11, 12, 13, 14, 15, 16 However, the global prevalence and prognostic effect of HPV in patients with recurrent or metastatic SCCHN arising from the oropharynx, oral cavity, larynx, and hypopharynx is not well understood, particularly in the clinical trial setting. HPV-positive and HPV-negative SCCHN tumours differ in terms of biology, histology, genetic alterations, and prognosis.11, 13, 17, 18 HPV-positive SCCHN tumours are characterised by the presence of high-risk HPV DNA (most commonly HPV 16) and the coexpression of the viral oncoproteins E6 and E7, which modulate expression of key cellular proteins (such as the tumour suppressor p53 and retinoblastoma tumour-suppressor protein), leading to upregulated expression of the cyclin-dependent kinase inhibitor p16-INK4A (henceforth, p16).10, 18, 19 How HPV status affects the outlook of patients with recurrent or metastatic disease, or their response to treatment, is unknown. Some studies20, 21, 22, 23, 24 have suggested interactions between HPV and the EGFR signalling pathway. Therefore, HPV status (as assessed by p16 immunohistochemistry of formalin-fixed paraffin-embedded samples) might affect outcomes during anti-EGFR treatment.

Panitumumab is a fully human anti-EGFR monoclonal antibody that is used both as a single agent and combined with chemotherapy for treatment of metastatic colorectal cancer.²⁵ Preclinical data for SCCHN cell lines and xenografts showed more antitumour activity with panitumumab plus radiotherapy than with radiotherapy alone,²⁶ and phase 1 response data for panitumumab plus chemoradiotherapy have suggested that additional investigation of panitumumab in SCCHN is warranted.²⁷ In the Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer (SPECTRUM), we compared panitumumab plus cisplatin and fluorouracil with chemotherapy alone as first-line treatment for recurrent or metastatic SCCHN. Additionally, we investigated the relative effect of treatment with panitumumab combined with chemotherapy in patients with recurrent or metastatic SCCHN who do (p16 positive) or do not (p16 negative) express p16.