Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer (2025)

The present cetuximab U.S. Food and Drug Administration submission seeks to expand the squamous cell head and neck cancer indication to include recurrent locoregional or metastatic disease. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil (FU), is compared to platinum-based therapy and 5-FU alone.

Learning Objectives

1. Compare survival outcomes among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.

2. Compare adverse event profiles among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.

3. Describe potential risk-benefit issues identified in the EU and US studies.

Abstract

On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m² intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m²/day continuous intravenous infusion days 1–4) were administered every 3 weeks. Cetuximab, 400 mg/m² intravenously, was administered initially followed by cetuximab, 250 mg/m² intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m² weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability study in monkeys. Overall survival, the primary efficacy endpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64–0.98; p = .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46–0.72; p < .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50–3.60; p = .0001). Adverse reactions (≥25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia.

Implications for Practice:

Cetuximab (Erbitux, Branchburg, New Jersey) in combination with cisplatin or carboplatin and 5-fluorouracil is shown to prolong survival of patients with recurrent locoregional or metastatic squamous cell head and neck cancer (SCCHN) compared with the same chemotherapy without cetuximab. Other benefits include increased progression-free survival and increased objective response rate. Toxicities observed with the combined treatment were consistent with the known toxicities of the individual drugs and were acceptable in relation to the survival benefit. Thus, there is now an additional treatment option for appropriate SCCHN patients.

Introduction

Epidermal growth factor receptor (EGFR) is overexpressed in the large majority of patients with squamous cell cancer of the head and neck (SCCHN) [1, 2]. Overexpression often correlates with a more advanced stage of disease, a poorer prognosis, and a worse response to chemotherapy [3, 4]. Cetuximab, an immunoglobulin G1 subclass chimeric mouse-human antibody, binds with high affinity to the extracellular domain of EGFR. Cetuximab competes with natural ligands of EGFR for binding to the receptor, thus preventing receptor activation. In addition to receptor binding, cetuximab might also trigger the internalization and degradation of the receptor [5]. An antineoplastic effect mediated by immune mechanisms has also been postulated [6, 7].

Cetuximab has been approved in the U.S. since 2006 for two SCCHN indications: as first-line treatment, in combination with radiation therapy, of locally or regionally advanced SCCHN [8, 9] and as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed [10–12]. For the first indication, it was found that cetuximab plus radiation therapy significantly increased overall survival compared with radiation therapy alone. With a median duration of follow-up time of 54.0 months, the median survival duration was 49.0 months for combined therapy patients and 29.3 months among those treated with radiotherapy alone (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.57–0.97; p = .03). Radiotherapy plus cetuximab also significantly prolonged progression-free survival (HR: 0.68; 95% CI: 0.52–0.89; p = .005). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, was not significantly different between the two randomized treatment groups.

For the refractory disease indication, three phase II studies were performed—one in the U.S. and two outside of the U.S. Two studies evaluated cetuximab combined with other agents and one evaluated cetuximab monotherapy. The latter multicenter clinical trial included 103 patients with recurrent or metastatic SCCHN who had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of cetuximab on day 1, followed by a 400 mg/m² initial dose and 250 mg/m² weekly until disease progression or unacceptable toxicity. The objective response rate was 13% (95% CI: 7%–21%). Median duration of response was 126 days [8]. The present cetuximab U.S. Food and Drug Administration (FDA) submission seeks to expand the SCCHN indication to include recurrent locoregional or metastatic disease. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil (5-FU), is compared with platinum-based therapy and 5-FU alone.

Patients and Methods

The pivotal study was a phase III randomized trial conducted in 80 European centers [6, 13, 14]. The study period was between December 14, 2004 and December 28, 2005. Data cutoff was March 12, 2007. The primary efficacy objective was to assess whether treatment of recurrent and/or metastatic SCCHN with cetuximab plus cisplatin or carboplatin plus 5-FU resulted in prolonged overall survival (OS) times compared with treatment with cisplatin or carboplatin plus 5-FU alone. Secondary objectives were to compare progression-free survival (PFS) time, disease control, best overall response rate, duration of response, time to treatment failure, safety, and quality of life (QoL). QoL was assessed using European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire and its head and neck symptomatic module. Results were not reviewed by the FDA and are not included in this submission.

Treatments included cetuximab 400 mg/m² intravenous infusion over 120 minutes on day 1 and 250 mg/m² intravenous infusion over 60 minutes weekly thereafter, together with either cisplatin 100 mg/m² over a 60-minute intravenous infusion on day 1 every 21 days or carboplatin (area under the curve 5) 60-minute intravenous infusion on day 1. 5-FU 1,000 mg/m²/day was administered by continuous intravenous infusion on days 1 through 4 every 3 weeks. Control patients received cisplatin, or carboplatin, plus 5-FU in the same doses and schedules without cetuximab. The cetuximab used in this trial was a European Union (EU)-approved cetuximab, manufactured by Boehringer Ingelheim (BI). The U.S. version of cetuximab (Erbitux; ImClone, Branchburg, New Jersey, USA, http://www.imclone.com) provides approximately 22% higher exposure relative to the BI cetuximab.

The choice of chemotherapy (cisplatin or carboplatin) for individual patients was at the discretion of the investigator. Chemotherapy could be continued for a maximum of six cycles in the absence of progressive disease (PD) or unacceptable toxicity. Patients randomized to cetuximab treatment who had not progressed or developed unacceptable toxicity continued on weekly cetuximab until the occurrence of progressive disease (PD) or unacceptable toxicity. Patients in the chemotherapy-only arm did not receive cetuximab after progression. In the event of chemotherapy intolerance, cetuximab-treated patients could continue receiving cetuximab alone. In the event of cisplatin intolerance, cisplatin could be replaced by carboplatin at the discretion of the investigator.

Eligible patients were ≥18 years of age with a histologically or cytologically confirmed diagnosis of SCCHN that was recurrent and/or metastatic and which was not suitable for local therapy. There was at least one bidimensionally measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) and archived tumor tissue was available for evaluation of EGFR expression by immunohistochemistry (given that almost all SCCHN tumors overexpress EGFR determination of EGFR expression was not required prior to study entry). A Karnofsky performance status (KPS) ≥70 at study entry was required as was adequate organ function (neutrophils ≥1,500/mm³, platelets ≥100,000/mm³, hemoglobin ≥9 g/dL, total bilirubin ≤2 times the upper limit of normality (ULN), aspartate-aminotransferase (AST) and alanine-aminotransferase (ALT) ≤3 times the ULN, creatinine clearance >60 mL/min). Effective contraception for both male and female subjects, if risk of conception existed, was also required.

Patients were excluded from study entry if they had received prior chemotherapy, except if given as part of a multimodal treatment for locally advanced disease that was completed more than 6 months prior to study entry. Patients could not have received surgery (excluding diagnostic biopsy) or radiation therapy within 4 weeks of study entry. Patients were also excluded if they had a diagnosis of nasopharyngeal carcinoma, had an active infection (requiring intravenous antibiotics), had active tuberculosis or human immunodeficiency virus infection, or had uncontrolled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥130 mmHg under resting conditions). Patients receiving other concomitant anticancer therapies were also excluded as were patients with documented brain or leptomeningeal metastasis and those with clinically relevant coronary artery disease, a history of myocardial infarction in the last 12 months, or a high risk of uncontrolled arrhythmia or cardiac insufficiency. Other exclusion parameters included known drug abuse (with the exception of alcohol abuse), previous monoclonal antibody therapy, treatment with other EGFR signal transduction inhibitors, a previous malignancy within the last 5 years, investigational medication within 30 days before study entry, known allergic reaction against any of the components of the study treatment, pregnancy or a medical or psychological condition that would not permit the subject to complete the study or sign informed consent. Eligible patients were stratified by KPS (<80 vs. ≥80) and prior chemotherapy (yes vs. no). Randomization, in a 1:1 ratio, was performed centrally using an interactive voice response system.

Patients were seen weekly for cetuximab administration. Laboratory studies were repeated every 3 weeks. Radiologic studies of tumor response were performed every 6 weeks. Tumor response was based on imaging and classified according to modified World Health Organization criteria as assessed by the investigator. In the event of partial remission (PR) or complete remission (CR), confirmation with CT or MRI had to be performed after 4–6 weeks. If PD was suspected, CT or MRI could be performed earlier. The objective response rate was defined as the proportion of subjects having achieved confirmed CR plus PR according to radiologic assessments.

The primary statistical analysis for OS was based on the intent-to-treat population (i.e., all randomized subjects). The hazard ratio of cetuximab plus chemotherapy over chemotherapy alone was calculated by Cox's proportional hazards model, which included stratification covariates, KPS, and prior chemotherapy, in addition to randomized treatment. Exploratory efficacy analyses were performed to determine the effect of the initial platinum treatment regimen and to determine the predictive value of EGFR determination by immunohistochemisty or by gene copy number (FISH). EGFR expression by immunohistochemistry analysis was performed by a central laboratory (Institut fur Pathologie, Wuppertal, Germany). For each tumor, the percentage of positively stained cells was determined and tumors were classified as EGFR negative (positive staining of <1% of cells) or EGFR positive (positive staining of ≥1% of cells). Primary data were not submitted for the FISH analysis. FISH assay results were provided in a report prepared by Merck KGaA, ImClone's cooperative partner.

The sample size determination was based on a power of 80% and a significance level of 5%. An increase of the median OS time from 7 months to 9.5 months (i.e., approximately 36% increase in median survival time) was expected. A minimum of 340 deaths (events) were required. A loss to follow-up of 5% of subjects was assumed, which resulted in recruiting 420 subjects. Duration of 20 months was needed to observe 340 deaths approximately 34 months after randomization of the first subject. During the follow-up phase, information on subsequent lines of treatment and survival data was collected every 3 months. Safety information was coded using Medical Dictionary for Regulatory Activities version 8.0 or 10.0 depending on the time of coding. Adverse events (AEs) were summarized by worst severity according to National Cancer Institute-Common Toxicity Criteria version 2.0.

Results

Demographics, KPS, tumor status, prior therapy, and platinum regimen of the study population are shown in Table 1. Approximately 86% of the patients in either arm received prior radiation therapy for the primary tumor and approximately 63% had undergone surgical resection. Approximately 38% of the patients had received adjuvant chemotherapy, approximately 29% had received adjuvant radiochemotherapy, and approximately 13% had received neoadjuvant chemotherapy.

Approximately two thirds of the patients in both arms received cisplatin therapy as the initial chemotherapy regimen. Fifteen of 149 (10.1%) patients in the cetuximab/chemotherapy arm and 20 of 135 (14.8%) patients in the chemotherapy-alone arm switched to carboplatin during the treatment period. Major reasons for change of therapy were nausea/vomiting, neuropathy, and fatigue. No patient who initially received carboplatin switched to cisplatin.

At the time of the data cutoff, seven patients in the cetuximab/chemotherapy arm and one patient in the chemotherapy-alone arm were still on study. The remaining patients had either completed or discontinued study treatment. The major reason for discontinuation was disease progression (56.7% of cetuximab-treated patients and 63.4% of chemotherapy-only patients), followed by death 13.5% and 13.6% of cetuximab and chemotherapy-only patients, respectively. More patients in the cetuximab/chemotherapy arm discontinued study due to adverse events than the chemotherapy-alone arm (12.1% vs. 7.3%). Other reasons for study withdrawal included symptom deterioration, withdrawal of consent, noncompliance, and loss to follow-up.

Overall survival is presented in Figure 1. The hazard ratio for OS after 343 events (167 in the cetuximab/chemotherapy arm and 176 in chemotherapy-alone arm) was 0.80 (95% CI: 0.64–0.99). The median overall survival was 10.1 months (95% CI: 8.6–11.2) for the cetuximab/chemotherapy arm compared with 7.4 months (6.4, 8.3) for the chemotherapy-alone arm (stratified log-rank p = .035).

The combination of cetuximab and platinum-based chemotherapy also resulted in a statistically significant improvement in PFS time compared with chemotherapy alone. The median PFS was 5.5 months (95% CI: 4.4–5.8) for the cetuximab/chemotherapy arm versus 3.3 months (95% CI: 2.9–4.1) for the chemotherapy-alone arm (HR: 0.57, 95% CI: 0.46–0.72; stratified log-rank p < .001).

The objective response rate was significantly higher in the cetuximab/chemotherapy arm (35.6%) compared with the chemotherapy-alone arm (19.5%). The complete response rate was 6.8% versus 0.9%, respectively. The stratified Cochran-Mantel-Haenszel test indicated a significant difference between treatments (p = .0001). The odds ratio for cetuximab plus chemotherapy compared with chemotherapy alone was 2.33, indicating that patients receiving cetuximab plus chemotherapy had nearly 2.3-fold greater odds of CR or PR than those treated with chemotherapy alone. The median duration of response was 5.6 months for subjects in the cetuximab/chemotherapy arm and 4.7 months for chemotherapy alone.

An exploratory analysis was performed to compare results in cisplatin- or carboplatin-treated patients. A statistically significant improvement in survival was observed when cetuximab was combined with cisplatin plus 5-FU compared with cisplatin plus 5-FU alone (HR: 0.71, 95% CI: 0.54–0.93). Median OS times were 10.6 months and 7.3 months for cetuximab/cisplatin/5-FU and cisplatin/5-FU, respectively. For patients receiving carboplatin, a 1.4-month increase in median survival was observed (9.7 months for cetuximab plus carboplatin/5-FU treatment versus 8.3 months for carboplatin/5-FU alone; HR: 0.99, 95% CI: 0.69–1.43).

Exploratory analyses of PFS and RR by initial platinum therapy showed no apparent difference for these efficacy parameters in the subgroups of patients who initially received cisplatin or carboplatin therapy. Additional exploratory analyses were performed to evaluate the predictive value of EGFR by immunohistochemistry and by FISH. For EGFR analysis, tumor samples were available in 413 (93%) of the patients enrolled in the study. EGFR expression was detected in 98% (405/413) of the tumors. About 83% of samples had ≥40% EGFR-detectable cells. No predictive association between EGFR expression by immunohistochemistry and overall survival was detected.

FISH results, based on an evaluation of at least 50 cells, were available from 312 (70.6%) of the 442 intent-to-treat patient population. These 312 subjects were equally distributed between the two treatment groups (158 in the cetuximab plus chemotherapy group, 154 in the chemotherapy group). Highly elevated EGFR gene copy numbers were noted in about 10% of subjects. No association between EGFR gene copy number status and overall survival could be detected in the patients with SCCHN in the current study.

Discussion

A randomized trial conducted outside the U.S., using a European cetuximab formulation with a platinum drug and 5-FU, demonstrated significantly increased overall survival, progression-free survival, and response rate compared with the same chemotherapy without cetuximab in patients with recurrent locoregional or metastatic SCCHN. The study design allowed patients randomized to the cetuximab study arm to continue to receive cetuximab after progression. Patients randomized to chemotherapy only did not receive cetuximab after progression. Thus, the possible benefit of sequential therapy was not evaluated.

One of the primary issues with this application was the use of EU-approved cetuximab. Initial submissions contained no human pharmacokinetic (PK) data comparing the U.S. to the non-U.S. approved drug and the predictiveness of PK differences observed in nonhuman primates to human subjects were not known. Subsequent submission of PK and population pharmacokinetic analyses confirmed that U.S.-licensed Erbitux had slower clearance leading, higher exposure with the same dose compared with the EU-approved product. To help resolve this issue, the sponsor provided limited data from 30 patients with recurrent or metastatic SCCHN who received U.S.-manufactured Erbitux in combination with platinum and 5-FU. Safety data from that trial was consistent with Erbitux toxicities described in the current package insert and with the known toxicities of platinum plus 5-FU treatment. This safety data supports the approval of U.S.-manufactured cetuximab for the proposed indication.

To further resolve the risk-to-benefit issue of U.S. versus EU-approved cetuximab, a postmarketing requirement was to complete and submit a final study report for a randomized, double-blind, phase II safety study of cetuximab using ImClone's U.S.-licensed product versus Boerhinger Ingelheim's EU-approved product, in combination with cisplatin or carboplatin and 5-FU in the first-line treatment of patients with locoregionally recurrent and/or metastatic SCCHN.

Another issue concerns the relative efficacy of cisplatin versus carboplatin for the proposed indication. Although preliminary subgroup analyses suggest greater benefit with cisplatin treatment, the analyses are not independently powered to demonstrate effects on survival or other tumor-related endpoints. Thus, there is insufficient evidence, at present, to limit the indication to cisplatin.

Addition of cetuximab to 5-FU, cisplatin, or carboplatin has an acceptable risk-to-benefit profile given the clinically meaningful improvement in survival time and the fact that no new cetuximab safety signals were identified. The toxicities observed with the combination are consistent with known toxicities of the individual agents. Thus, risk-to-benefit analysis indicates that Erbitux should be approved for the proposed indication: Erbitux is indicated in combination with platinum-based therapy for the first-line treatment of patients with recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head and neck.

Acknowledgments

The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.

Author Contributions

Conception/Design: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Patricia Keegan, Richard Pazdur

Provision of study materials or patients: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Sharon Sickafuse, Patricia Keegan

Collection and/or assembly of data: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Sharon Sickafuse, Patricia Keegan

Data analysis and interpretation: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Patricia Keegan, Richard Pazdur

Manuscript writing: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Patricia Keegan, Richard Pazdur

Final approval of manuscript: Martin H. Cohen, Huanyu Chen, Stacy Shord, Chana Fuchs, Kun He, Hong Zhao, Sharon Sickafuse, Patricia Keegan, Richard Pazdur

Disclosures

Bruce Chabner: Sanofi, Epizyme, PharmaMar,GlaxoSmithKline, Peregrine, Pharmacyclics (C/A); Eli Lilly (H); Gilead, Epizyme, Amgen, Celgene, Exelixis, Rigel (O).

Reviewer “A”: Boehringer-Ingelheim, Alder (RF)

References