Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial

Summary

Background

No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients.

Methods

In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0–2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov, NCT00382031.

Findings

We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6·7 months (95% CI 5·8–7·0) in the zalutumumab group and 5·2 months (4·1–6·4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0·77, 97·06% CI 0·57–1·05; unadjusted p=0·0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0·63, 95% CI 0·47–0·84; p=0·0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3–4 adverse events were rash (39 [21%] patients in the zalutumumab group vs none in the control group), anaemia (11 [6%] vs five [5%]), and pneumonia (nine [5%] vs two [2%]). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 [15%] patients given zalutumumab vs 13 [14%] controls), pneumonia (13 [7%] vs three [3%]), and dysphagia (11 [6%] vs two [2%]).

Interpretation

Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe.

Funding

Genmab.

Introduction

Worldwide, about 634 000 patients are diagnosed with squamous-cell carcinoma of the head and neck every year.¹ 50–60% of patients with stage III or IV disease will relapse locoregionally or with distant metastases despite aggressive multimodal treatment.² Patients with distant metastases or locoregional relapse who are not amenable to radical surgery or radiotherapy are regarded as incurable. In such patients, platinum-based chemotherapy is widely used as first-line therapy. Cetuximab, an anti-epidermal growth factor receptor (EGFR) chimeric IgG1 monoclonal antibody, has been investigated as a first-line treatment in combination with fluorouracil and platinum-based chemotherapy, and has shown an improved overall survival (hazard ratio for death 0·80, 95% CI 0·64–0·99; p=0·04).³ For the same indication and an equivalent study design, panitumumab in combination with cisplatin and fluorouracil did not show significant improvement in overall survival but had clinical activity through an increase in progression-free survival and response rate.⁴

Zalutumumab is a human IgG1κ monoclonal antibody targeting the EGFR. In preclinical models, zalutumumab potently inhibits tumour growth through two mechanisms of action. First, zalutumumab blocks EGFR signalling, as was noted in xenograft tumour models as a reduction in receptor phosphorylation and was most effective at saturating antibody concentrations.5, 6 Second, zalutumumab's antitumour effects are mediated by Fc-mediated antibody-dependent cellular cytotoxicity.⁷

A dose-escalation safety and pharmacokinetics study⁸ assessed zalutumumab in 28 patients with incurable squamous-cell carcinoma of the head and neck and showed that zalutumumab doses were well tolerated. Seven of ten patients treated with zalutumumab 4 mg/kg or 8 mg/kg were classified as having a partial response or stable disease according to response evaluation criteria in solid tumours (RECIST).⁸

Prognosis for patients with squamous-cell carcinoma of the head and neck who are unsuitable for chemotherapy or who have progressed after platinum-based therapy is poor, with a median overall survival of 3·0–6·7 months.9, 10 No standard of care exists for this group of patients. Cetuximab has been assessed as monotherapy or in combination with chemotherapy in cisplatin-refractory patients;11, 12, 13, 14 objective response rate ranged from 10 to 13%. In one study¹⁴ of patients in whom previous platinum-based therapies had failed, pooled efficacy data from three prospective phase 2 studies of cetuximab as monotherapy or combined with a platinum compound were compared with the results from retrospective studies that assessed various second-line treatments. Median overall survival for patients treated with cetuximab was 5·2–6·1 months, which was better than that which was reported in the retrospective studies (median overall survival 3·4 months for best supportive care and 3·6 months for patients treated with chemotherapy).¹⁴ Despite the absence of a randomised trial about this indication, cetuximab was approved in the USA as monotherapy in recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum-based therapy and has widespread use in this patient cohort.

We aimed to assess whether zalutumumab improves overall survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy.