Platinum-based chemotherapy plus cetuximab for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: results of a phase II trial.

OBJECTIVE: To assess the efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.
METHODS: In this open-label, single-arm, multicenter, Phase II study conducted in Japan, patients with confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck received weekly cetuximab (week 1, 400 mg/m(2); subsequent weeks, 250 mg/m(2)) plus a maximum of six three-weekly cycles of cisplatin (100 mg/m(2), day 1) and 5-fluorouracil (1000 mg/m(2)/day, 24-h infusion, days 1-4). The primary endpoint was the best overall response assessed by an independent review committee according to the modified World Health Organization criteria.
RESULTS: In total, 33 patients received treatment. The most frequent primary tumor site was the hypopharynx (42%), and most patients had metastatic disease (85%). The best overall response rate as assessed by the independent review committee was 36% (95% confidence interval: 20, 55) and was significantly greater (P = 0.002) than the protocol-specified threshold of 15% at the one-sided 5% level. The disease control rate was 88%. The median progression-free survival and overall survival were 4.1 and 14.1 months, respectively. There were no unexpected safety concerns. Grade 3 or 4 adverse events were experienced by nearly all patients (32, 97%). No adverse events were fatal.
CONCLUSIONS: The demonstrated efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck justify the further use of this combination treatment in this patient population .

INTRODUCTION

Cancer of the head and neck [oral cavity, pharynx (excluding nasopharynx) and larynx] is estimated to represent around 4% of cancers, globally (1). In Japan in 2006, there were 16 351 patients (12 577 males and 3774 females) with oral/pharyngeal or laryngeal cancer, accounting for 2.5% of all cancer cases (2). A total of 7528 deaths due to oral/pharyngeal or laryngeal cancer occurred in Japan in 2009, representing 2.2% of annual cancer deaths (3). Tumors in Japanese patients are most frequently located in the oral cavity (36% of patients), larynx (25%), hypopharynx (16%) and oropharynx (12%); other sites are the nasal cavity/paranasal sinus (7%) and nasopharynx (4%) (4).

Epidermal growth factor receptor (EGFR) is frequently expressed in squamous cell carcinoma of the head and neck (SCCHN) (5–7). Cetuximab (Erbitux®, Merck KGaA, Darmstadt, Germany) is an EGFR-targeting monoclonal antibody which is widely used in the treatment of SCCHN in countries outside Japan.

In the Phase III EXTREME trial, conducted in Europe in patients with recurrent and/or metastatic SCCHN (R/M SCCHN), the addition of cetuximab to platinum/5-fluorouracil (5-FU) in the first-line setting significantly improved overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) compared with platinum/5-FU alone (8). The median OS time was 7.4 months in the chemotherapy-alone group compared with 10.1 months in the group that received chemotherapy plus cetuximab [hazard ratio for death, 0.80; 95% confidence interval (CI): 0.64, 0.99; P = 0.04]. The addition of cetuximab to chemotherapy also prolonged the median PFS time (from 3.3 to 5.6 months; hazard ratio for progression, 0.54, 95% CI: 0.43, 0.67; P < 0.001) and increased the best ORR (from 20 to 36%; odds ratio 2.33, 95% CI: 1.50, 3.60, P < 0.001). The use of cetuximab plus platinum/5-FU for the first-line treatment of R/M SCCHN is now recommended by a group of European cancer societies (9) and the USA-based National Comprehensive Cancer Network (NCCN) Practice Guidelines (10).

In Japan, cetuximab has not yet been approved for use in head and neck cancers. In other respects, however, the treatment options for R/M SCCHN are not substantially different from those in Europe and the USA. Cisplatin is the mainstay of treatment, and the combination of cisplatin and 5-FU is the most frequently used chemotherapy regimen (11). The dose of cisplatin used in combination with 5-FU at an interval of 3 or 4 weeks is commonly lower in Japan (cisplatin 75–100 mg/m2 on day 1 plus 5-FU 600–1000 mg/m2/day for 4–5 days) than in many Western countries (11,12), in keeping with observations from the treatment of different types of cancer, including head and neck cancers, that Japanese patients are generally not able to tolerate the doses of chemotherapy approved for use in Western patients (13,14). However, others have reported that the incidence of high-grade toxicity associated with standard doses of chemotherapy used in Western patients is not substantially higher in Japanese patients (15,16).

The use of cetuximab in combination with radiotherapy for patients with locally advanced SCCHN showed significant benefits over radiotherapy alone in a Phase III trial in Western patients (17), and the efficacy and safety of cetuximab plus radiotherapy has since been demonstrated in a Phase II trial in Japanese patients (18).

The primary objective of the current trial was to assess the antitumor activity of cetuximab when given in combination with cisplatin and 5-FU for the first-line treatment of R/M SCCHN in Japanese patients. Of note, cisplatin was used at a dose of 100 mg/m2 in line with the dose used in the EXTREME trial. Secondary objectives included the assessment of safety, pharmacokinetic (PK) parameters, biomarkers, pharmacogenomics and the immunogenicity of cetuximab in Japanese patients. This paper reports the efficacy, safety and PK results.

PATIENTS AND METHODS

Patient eligibility criteria and treatment regimens were consistent with those used in the EXTREME trial (8).

Patient Selection

Japanese adults with histologically or cytologically confirmed R/M SCCHN, unsuitable for local therapy, with at least one bidimensionally measurable [computed tomography (CT) scan or magnetic resonance imaging (MRI)] lesion and confirmed expression of EGFR by immunohistochemistry (IHC) were eligible for entry to the trial. The exclusion criteria included nasopharyngeal carcinoma, prior systemic chemotherapy (except as part of multimodal therapy completed >6 months before the trial entry), surgery or irradiation within 4 weeks of trial entry, current or prior cardiac or pulmonary disease, high risk of uncontrolled arrhythmia or cardiac insufficiency and active infection. A written informed consent was provided by all patients taking part in the trial, and additional consent was provided by those also taking part in PK and biomarker analyses.

Trial Design

This was an open-label, single-arm, multicenter, Phase II trial conducted in Japan. Patients received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus three-weekly cycles of cisplatin (100 mg/m2, day 1) and 5-FU (1000 mg/m2/day, 24-h infusion, day 1–4). Patients could switch to carboplatin (AUC5 on day 1 of each cycle) in the event of non-hematologic toxicities to cisplatin. All drugs were administered by intravenous infusion. Chemotherapy was continued for up to six cycles, or until unacceptable toxicity or progressive disease (PD). Patients received cetuximab until PD or unacceptable toxicity.

Response was assessed every 6 weeks until PD occurred, including in those patients who discontinued treatment before PD. Partial response (PR), complete response (CR) and PD were confirmed with CT or MRI within 4 weeks. Adverse events (AEs) were recorded from the start of treatment until the end of treatment (EOT) visit (30 days after the last trial treatment, or immediately prior to the initiation of any subsequent anticancer treatment). After the EOT visit, patients were followed up every 3 months until death, loss to follow-up or withdrawal of consent.

A PK investigation was carried out in patients enrolled at centers with PK sampling facilities. Blood samples were taken at the following times: days 1, 8 and 15, immediately before and after cetuximab infusion; day 22, directly before and at several time points (up to 168 h) after cetuximab infusion; days 36, 43 and 50, directly before the cetuximab infusion. Serum prepared from each blood sample was divided into two aliquots and stored at −20°C. Samples were analyzed by Celerion, Zurich, Switzerland, for concentrations of cetuximab using a validated enzyme-linked immunosorbent assay (ELISA). PK analysis was monitored and conducted under the supervision of the Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany. The PK parameters of cetuximab after the fourth dose (day 22) were calculated according to the standard non-compartmental methods using the PK software program KINETICA™, version 4.1.1.

Tumor EGFR expression was assessed by SRL medisearch, Tokyo, Japan, using the EGFR pharmDx™ kit (Dako Denmark A/S, Glostrup, Denmark) on archived tumor material or a biopsied specimen collected at the screening visit. EGFR-positive staining was defined as any IHC staining of tumor cell membranes above the background level, whether complete or incomplete circumferential staining. The tumor KRAS mutation status was assessed by Merck Serono Ivrea, Colleretto Giacosa (Turin), Italy, by pyrosequencing using the PyroMark Q24 system (developed by QIAGEN Manchester Ltd, Manchester, UK).

The trial protocol was approved by the institutional review boards of each center, and the trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization (ICH) Note for Guidance on Good Clinical Practice (GCP) (ICH Topic E6, 1996), the Japanese ministerial ordinance on GCP, the standard stipulated in Articles 14–3 and 80–2 of the Japanese Pharmaceutical Affairs Law, and applicable regulatory requirements.

Endpoints

The primary endpoint was the best overall response (CR or PR) assessed by an independent review committee (IRC) according to the modified World Health Organization (WHO) criteria. The ORR was the proportion of patients with a CR or a PR. The best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) criteria was also assessed by the IRC as a secondary efficacy endpoint (19). Other secondary efficacy endpoints were: disease control rate (CR plus PR plus stable disease); duration of response (in patients achieving a CR or PR); time-to-treatment failure (PD assessed by the investigator, discontinuation of treatment due to PD or due to an AE, start of any new anticancer therapy or withdrawal of consent or death within 60 days of the last tumor assessment or first administration of trial treatment); PFS (time from the first administration of trial treatment to the first observation of PD, or death due to any cause when death occurred within 60 days of the last tumor assessment) and OS.

Adverse events were assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0). AEs considered to be of special interest in patients receiving cetuximab and based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms were also investigated: skin reactions and acne-like rash, infusion-related reactions (IRRs) and cardiac events.

Statistics

In the EXTREME trial, patients treated with chemotherapy plus cetuximab achieved a best ORR of 36% (95% CI: 29, 42) compared with 20% (95% CI: 15, 25) for those receiving chemotherapy alone (8). The lower confidence limit in the chemotherapy arm (15%) was considered to be the reference value for this trial, and an exact one-sided test (significance level α = 5%) was used to test the null hypothesis that the response rate was <15%. Assuming a response rate of 35% (similar to that in the EXTREME trial), a patient sample size of 31 was required to achieve a power of >80%.

Efficacy analyses were performed on the intention-to-treat (ITT)/safety population (all patients who received at least one dose of trial medication). Continuous variables were summarized using descriptive statistics; qualitative variables were summarized by means of counts and percentages. Unless otherwise stated, the calculation of proportions included the missing category and CIs were calculated as two-sided with a confidence probability of 95%.

All analyses were performed using SAS® Software version 9.1.

RESULTS

Patient Disposition

In total, 46 patients were enrolled at nine centers in Japan between 22 July 2009 and 3 September 2010. Of these patients, 35 were eligible for the trial and 33 were treated (ITT/safety population). Two patients were not treated due to worsening condition (n = 1) and creatinine clearance of <60 ml/min (n = 1). At the data cutoff of 14 December 2011, one patient remained on treatment.

Patient Baseline Characteristics

Patients were predominantly male (30, 91%), with good Karnofsky performance status (31, 94% had KPS 90–100), and mainly metastatic (including recurrent) cancer (28, 85%, Table 1). Almost one-third of patients were 65 years or older. All patients had EGFR-positive tumors. The most frequent primary tumor location was the hypopharynx. In one-third of patients (n = 11), tumors were reported as non-classifiable, but were specified as tongue (n = 8), and maxillary, hard palate and mandibular tumors (n = 1, each).

Table 1.

Baseline patient and disease characteristics

Characteristic	(n = 33)
Age (years)
Median (range, years)	61 (31–71)
<65, n (%)	23 (70)
≥65, n (%)	10 (30)
Sex, n (%)
Male	30 (91)
Female	3 (9)
Karnofsky performance status, n (%)
100	17 (52)
90	14 (42)
80	2 (6)
Disease duration (from initial diagnosis to informed consent) (months), median (range)	14.3 (0–79)
Frequency of the extent of disease, n (%)
Recurrent, not metastatic	5 (15)
Metastatic, including recurrent	28 (85)
Location of primary tumor, n (%)
Hypopharynx	14 (42)
Larynxa	5 (15)
Oropharynx	3 (9)
Non-classifiableb	11 (33)
Histology
Well differentiated	4 (12)
Moderately differentiated	13 (39)
Poorly differentiated	4 (12)
None otherwise specified/unknown/missing	12 (36)
Stage according to UICC at diagnosis, n (%)
Stage I	3 (9)
Stage II	2 (6)
Stage III	4 (12)
Stage IV	24 (73)

UICC, Union for International Cancer Control.

aThe tumor in one patient was ‘non-classifiable’ but was specified as ‘larynx’ and was therefore analyzed as such.

bThe location of the primary tumor was non-classifiable, but was specified as tongue (n = 8), and maxillary, hard palate and mandibular (n = 1, each).

Most patients (30, 91%) had received prior therapy for cancer-related disease: surgery (28, 85%), radiotherapy (11, 33%), chemotherapy (11, 33%) and other types of therapy (10, 30%).

Treatment Exposure

All 33 patients received at least one dose of cetuximab, and 29 (88%) patients received cetuximab at a relative dose intensity (RDI) of ≥80%. The median duration of cetuximab treatment was 19 (range 1−98) weeks, the median number of infusions was 18 (range 1–91) and the median cumulative dose was 4650 (range 166–16 877) mg/m². In total, 21 (64%) patients received at least one dose of cetuximab monotherapy.

Thirty-two patients (97%) received at least one dose of cisplatin. The median duration of therapy was 11.3 (range 3–23) weeks, and the median cumulative dose was 300 (range 100–600) mg/m2. RDI was ≥80% in 21 (66%) patients. Seven (21%) patients received two or more doses of carboplatin. The median duration of therapy was 12 (range 6–18) weeks, and the median cumulative dose was 1264 (range 676–2257) mg. Most patients, 32 (97%), received at least one dose of 5-FU. The median duration of therapy was 18.5 (range 3–23) weeks, and the median cumulative dose was 20 000 (range 4000–24 000) mg/m2. RDI was ≥80% in 19 (59%) patients.

Twenty-seven (82%) patients received post-trial anticancer therapy, comprising chemotherapy (23, 70%), radiotherapy (9, 27%), surgery (2, 6%), immunotherapy (1, 3%) and/or other forms of treatment (2, 6%).

Efficacy

The best ORR assessed by the IRC according to the modified WHO criteria (primary endpoint) was 36% (95% CI: 20, 55) (Table 2), with a CR in one patient. The ORR was significantly greater than the protocol-specified threshold of 15% (P = 0.002). The best ORR assessed by the IRC according to RECIST was 45%, with a CR in one patient (Table 2): three patients with stable disease (SD) according to modified WHO criteria were considered to have a PR according to RECIST.

Table 2.

Tumor response results

	Response rates, n = 33
Characteristic, n (%)	Modified WHO criteriaa	RECIST criteriaa
ORR	12 (36)b	15 (45)
[95% CI]c	[20, 55]	[28, 64]
Best overall response
CR	1 (3)	1 (3)
PR	11 (33)	14 (42)
SD	17 (52)	14 (42)
PD	1 (3)	1 (3)
Not evaluable	3 (9)	3 (9)

CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; WHO, World Health Organization.

aAssessed by an Independent Review Committee.

bP = 0.002 vs. the protocol-specified 15% threshold.

cTwo-sided Clopper–Pearson.

The median PFS was 4.1 (95% CI: 4.0, 5.5) months (Fig. 1a). The PFS rate was 70% (95% CI: 53, 86) at 3 months and 23% (95% CI: 7, 39) at 6 months. The median OS was 14.1 (95% CI: 10.2, 15.4) months (Fig. 1b). At last follow-up, 24 patients had died due to PD. The OS rates at 3, 6, 9 and 12 months were 100, 85 (95% CI: 73, 97), 67 (95% CI: 51, 83) and 61% (95% CI: 44, 77), respectively. The disease control rate was 88%. The median duration of response (first assessment of CR or PR until PD) was 2.8 (95% CI: 2.8, 5.5), with a median time-to-treatment failure of 4.2 (95% CI: 4.1, 5.6) months.

Figure 1.

Kaplan–Meier estimates of (a) progression-free survival and (b) overall survival. CI, confidence interval.

Safety

The most common AEs reported were decreased appetite (91%), leukopenia (85%), hypomagnesemia (82%), neutropenia (82%) and stomatitis (79%). Grade 3–4 AEs were reported in 32 (97%) patients, and grade 4 events were reported in 21 (64%) patients. Treatment-related grade 3–4 AEs were reported in 32 (97%) patients. Cetuximab-related grade 3–4 AEs were experienced by 20 (61%) patients, and the most frequent of these (≥10% patients) were diarrhea, hypomagnesemia and neutropenia, each occurring in four (12%) patients. The most common grade 3–4 AEs reported (total and cetuximab-related) are displayed in Table 3.

Table 3.

Most common grade 3–4 adverse events

AE, n (%)	All n = 33	Cetuximab-related n = 33
Any	32 (97)	20 (61)
Neutropenia	21 (64)	4 (12)
Leukopenia	17 (52)	2 (6)
Anemia/hemoglobin decreased	11 (33)	3 (9)
Decreased appetite	7 (21)	0
Lymphopenia	6 (18)	1 (3)
Thrombocytopenia	6 (18)	1 (3)
Diarrhea	5 (15)	4 (12)
Hypomagnesemia	5 (15)	4 (12)
Fatigue	4 (12)	0
Hypokalemia	4 (12)	1 (3)
Hyponatremia	3 (9)	1 (3)
Nausea	3 (9)	0
Syncope	3 (9)	2 (6)
Dermatitis acneiform	2 (6)	2 (6)
Hyperkalemia	2 (6)	2 (6)

Among AEs considered to be of special interest, skin reactions and acne-like rash were each reported in 32 (97%) patients. Grade 3 skin reactions were reported in five (15%) patients, and grade 3 acne-like rash in four (12%) patients. There were no grade 4 events. Only two patients experienced an IRR: hot flush (grade 1) and chills and tremor (grade 3); each resolved within the same day. There were seven cardiac events: six grade 1 and one grade 2 event.

Twelve patients experienced serious AEs (SAEs), nine of which were related to treatment: diarrhea, dysphagia, staphylococcal sepsis, septic shock, syncope, intracardiac mass, esophageal fistula, increased C-reactive protein, dehydration, hypercreatininemia and decreased appetite. No AEs were fatal.

Eighteen (55%) patients permanently discontinued either cetuximab or chemotherapy as a result of AEs. The most frequent AEs (occurring in >5% of patients) leading to permanent discontinuation of chemotherapy were toxic nephropathy and neutropenia (three patients, 9% each), and thrombocytopenia (two patients, 6%). Four (12%) patients had AEs leading to permanent discontinuation of cetuximab (hypomagnesemia, IRR, esophageal fistula and septic shock, each in one patient).

Pharmacokinetics

Cetuximab PK parameters were investigated in 12 patients with available samples. All serum cetuximab concentrations after dosing on day 22 were above the lower limit of quantification (0.25 µg/ml) of the bioanalytical assay (Fig. 2). The mean trough concentrations of cetuximab reached around 70 µg/ml after day 36 (Fig. 3). The mean concentration time profile and derived PK parameters were in good agreement with those described previously in Japanese patients receiving cetuximab monotherapy (20).

Figure 2.

Serum cetuximab concentrations after a dose of 250 mg/m2 on day 22. Linear plot. Points are mean ± standard deviation.

Figure 3.

Serum cetuximab peak and trough concentrations.

Tumor Kras Mutation Status

Twenty-one patients gave consent for further tumor biomarker testing. Of these, 15 had tumor samples that were evaluable. All 15 patients had KRAS wild-type tumors.

DISCUSSION

Data from this open-label, multicenter, Phase II trial demonstrated that the combination of platinum-based chemotherapy with cisplatin administered at a dose of 100 mg/m2, and cetuximab as the first-line treatment for R/M SCCHN was effective and well tolerated in Japanese patients. Furthermore, the efficacy and safety results obtained in the present trial were similar to those obtained in the Phase III EXTREME trial in a Western population (8).

The best ORR achieved (36% assessed by IRC according to modified WHO criteria) was significantly higher than the protocol-specified 15% at the one-sided 5% level, thereby meeting the primary endpoint of the trial. The ORR was equal to that observed for the chemotherapy plus cetuximab arm in the reference EXTREME trial (36%) (8).

The secondary endpoints further supported the efficacy of the combination of chemotherapy and cetuximab in this Japanese patient population. The median OS (14.1 months) was longer than that reported for the platinum/5-FU/cetuximab arm of the EXTREME trial (10.1 months) (8). This may be due to the small number of patients in our trial. In addition, an influence on OS of post-trial anticancer treatment cannot be discounted. The number of patients who received anticancer treatment after the completion of the present trial was higher than in the platinum/5-FU/cetuximab arm of the EXTREME trial [27 patients (82%) vs. 91 patients (41%)]. The apparently shorter median PFS in this trial, compared with the EXTREME trial, is probably due to the small population size. However, given that the 95% CIs of the median PFS in the two trials are overlapping, it may be suggested that the PFS in our trial is similar to that in the platinum/5-FU/cetuximab arm of the EXTREME trial.

In colorectal cancer, the benefits of cetuximab are restricted to patients with KRAS wt tumors (21,22). All patients in this trial whose tumors were tested for KRAS mutation status had KRAS wt tumors, as would be expected, given the low rate of KRAS mutations reported previously in head and neck cancers (23–25).

The efficacy reported here is particularly encouraging, given that the patient population in the present trial was older than that in the chemotherapy plus cetuximab arm of the EXTREME trial (30% ≥65 years compared with 18%) and had characteristics indicative of a poorer prognosis, including a higher proportion of patients with recurrent and metastatic primary tumors (85 vs. 47%) and localization of the primary tumor in the hypopharynx (42 vs. 13%). It is also notable that this efficacy was achieved despite dose modifications in platinum therapy made for the management of adverse events, which led to patient exposure to platinum being lower than in the EXTREME trial. For example, 89% of patients in the chemotherapy plus cetuximab arm of the EXTREME trial received ≥80% of RDI of cisplatin compared with 66% of patients in this trial.

The AEs observed in this trial are consistent with the underlying disease, administration of chemotherapy and the known safety profile of cetuximab. No new safety findings were identified in this trial. The overall safety profile observed in the present trial was also similar to that observed in the chemotherapy plus cetuximab arm in the EXTREME trial (8), and it is notable that no AEs had a fatal outcome. However, the incidence of a number of grade 3–4 AEs was higher compared with the EXTREME trial, notably neutropenia, leukopenia, decreased appetite (anorexia) and hypomagnesemia. This might be explained by the poor tolerability of cytotoxic chemotherapy reported for Japanese patients that has been documented previously (13). However, it may also reflect the poorer prognosis of the patient population in the present trial, as discussed briefly in the previous paragraph. The AEs concerned were mostly those known to be chemotherapy related and were manageable by dose adjustments or switches from cisplatin to carboplatin.

In conclusion, the demonstrated efficacy of platinum-based chemotherapy plus cetuximab in Japanese patients with R/M SCCHN, together with a predictable safety profile and PK, justifies the further use of this combination treatment in this patient population.

Funding

This work was supported by Merck Serono Co, Ltd, Tokyo, Japan, an affiliate of Merck KGaA, Darmstadt, Germany.

Conflict of interest statement

Takayuki Yoshino received honoraria from Chugai, Takeda, Bristol-Myers Squibb, Yakult and Merck Serono, a research grant from Bayer, Taiho, Daiichi-Sankyo and ImClone and consulting fees from Takeda. Makoto Tahara received consulting fees from Merck Serono. Barbara de Blas and Frank Beier are employees of Merck KGaA, Darmstadt, Germany. The other authors declare no conflicts of interest.