Introduction

Squamous cell carcinoma of the head and neck (SCCHN) is a common malignancy worldwide, with more than 800,000 new patients being diagnosed annually [1]. An estimated 60% of such patients present with locally advanced stage III/IV disease. Although multidisciplinary treatment of locally advanced SCCHN has progressed, disease recurs in > 50% of patients within 3 years [2,3,4]. Some patients are eligible for salvage therapy with surgery or chemoradiotherapy, but the only therapy available for most patients with recurrent and/or metastatic disease is palliative treatment [5].

The standard treatment for patients with recurrent and/or metastatic (R/M) SCCHN is a combination of platinum, 5-FU, and cetuximab; namely, the EXTREME regimen [6]. Adding cetuximab to the combination of platinum and 5-FU (FP) as a first-line treatment for R/M SCCHN has significantly improved survival over FP alone [7]. However, the prevalence of grade 3 or 4 toxicity under this regimen is high. Therefore, patients must have good performance status (PS), organ function, and physical status, which means that not all patients can tolerate this therapy. Because the prognosis of R/M SCCHN is poor, the therapeutic target is not a complete cure for cancer, but rather improved survival and palliative care to optimize their quality of life (QOL). Thus, a more appropriate regimen for patients who are contraindicated for platinum-based therapy is needed.

The orally active therapy referred to as S-1 comprises a 1:0.4:1 molar ratio of tegafur (a prodrug that is converted by cells to fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil), and oteracil (which inhibits fluorouracil phosphorylation in the gastrointestinal tract, thus reducing the gastrointestinal toxic effects of fluorouracil) [8, 9]. It is presently used alone or in combination with anti-cancer agents to treat various cancers, such as gastric [9, 10], colon [11, 12], pancreas [13, 14], lung [15, 16], breast [17] and head and neck cancer [18, 19] in adjuvant or systemic chemotherapy setting and it has demonstrated survival benefits with lower toxicity. Because of its lower toxicity and improved radiation sensitivity by gimeracil [20], S-1 has also been used with triplet chemotherapy [21] and radiotherapy [22]. Both in vitro and in vivo studies have demonstrated that a combination of S-1 and cetuximab confers greater antitumor activity than S-1 alone [23, 24], suggesting that cetuximab induces the downregulation of thymidylate synthase (TS). A phase II study of patients with KRAS wild-type unresectable metastatic colorectal cancer showed that this combination treatment was effective and tolerable [25]. The present phase II study evaluates the effects and safety of S-1/cetuximab as a first-line treatment for platinum-ineligible patients with R/M SCCHN.

Patients and methods

Study design

The eligibility criteria were as follows: platinum-ineligible, age ≥ 20 years, histologically confirmed R/M SCCHN, measurable disease according to RECIST, no suitable local therapy, Eastern Cooperative Oncology Group (ECOG) PS 0 to 2, adequate hematological, hepatic and renal functions, predicted survival > 3 months, and no prior chemotherapy other than curative chemoradiotherapy and immunotherapy. We also defined platinum-ineligibility as at least one of the following six criteria: age ≥ 20 to < 70 years with PS 2; age ≥ 70 to < 75 years with PS 1-2; age ≥ 75 years with PS 0-2; comorbidity, platinum-refractory (tumor progression within six months of platinum-based therapy) and refusal to undergo platinum-based therapy.

Key exclusion criteria included previous systemic chemotherapy for R/M SCCHN (except for immune checkpoint inhibitors), surgery (except for diagnostic biopsies and port-a-cath implantation) or radiotherapy within four weeks before study entry (except for palliative radiotherapy administered over two weeks previously), simultaneous or metachronous double cancers within five years before study entry except for carcinoma in situ or intramucosal tumor, symptomatic central nervous system metastases, HBV virus infection, uncontrolled comorbidities (such as severe heart failure, cerebrovascular disease, pulmonary fibrosis, renal failure, liver failure, active peptic ulcer, uncontrolled diabetes mellitus, uncontrolled hypertension), and prior treatment with cetuximab or anti-epidermal growth factor receptor (EGFR) inhibitor.

The ethics committees at the participating centers approved the study protocol and the trial was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in the study. This trial was registered in the UMIN clinical trials Registry as UMIN000015123.

Treatment

Chemotherapy consisted of S-1 (80 mg/m2/day, daily for 14 days followed by a seven-day break) and cetuximab (initial dose 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity.

Dose reductions and delays

Chemotherapy doses were modified when hematological or non-hematological toxicity became intolerable. Cetuximab was reduced in the event of ≥ grade 3 skin toxicity or hypomagnesemia. If a patient experienced grade 3 skin toxicity for a second or third time, cetuximab was delayed for up to three consecutive weeks, followed by dose reductions to 200 mg/m2 and then 150 mg/m2. The infusion rate of cetuximab was reduced when grades 1 or 2 infusion-related reactions (IRRs) occurred, and cetuximab was discontinued when grade 3 or 4 IRRs or any grade of cetuximab-related interstitial pneumonia developed. S-1 was gradually reduced by 20 mg/day if the neutrophil count reached < 500/mm3, the platelet count reached < 50,000/mm3 or ≥ grade 3 non-hematological adverse events developed. The dose of each drug was reduced according to dose reduction protocols.

Assessments

Tumor response was assessed using RECIST version 1.1 criteria [26] and computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every six weeks after the start of treatment until progressive disease (PD). Adverse events were monitored weekly throughout the study and evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Design and statistics

This single-arm, multicenter, phase II study evaluated the effects and safety of S-1/cetuximab as a first-line treatment for R/M SCCHN. The primary endpoint was the overall response rate (ORR) based on RECIST version 1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF) and the relative dose intensity of each chemotherapeutic drug.

We defined PFS as the elapsed time between the initial administration of the protocol treatment until PD or death. Overall survival was defined as the elapsed time between the initial administration of the protocol treatment until death from any cause. The primary objective of the study was to establish proof-of-concept for S-1/cetuximab by evaluating ORR. We assumed that the ORR of S-1/cetuximab was 34%, based on an S-1 phase II study [27], and the EXTREME study [7]. Thus, a two-sided test with α = 0.05 and power of 80% required a sample size of 58 patients. Confidence intervals (CI) for ORR were estimated using the binominal method. We analyzed PFS, OS, and TTF using Kaplan–Meier curves. Primary analyses included the full analysis set (FAS) population defined as all registered patients excluding those who were deemed ineligible after enrollment, and no data for efficacy endpoints due to events that were obviously unrelated to the protocol treatment. Safety analyses were conducted for all registered patients who received at least one dose of the protocol treatment. The data cutoff point for OS, PFS, and safety analyses was March 31, 2019. Statistical analyses were performed using SPSS version 22. We initially planned two years of recruitment, but extended the registration period for two more years.

Results

Patient characteristics

Between September 2014 and September 2018, we accrued 23 patients from four sites (Supplementary Fig. S1). The trial was stopped early due to slow accrual. Two patients withdrew before being administered with the S-1/cetuximab combination therapy due to protocol noncompliance (n = 1) and poor PS due to disease progression (n = 1). Thus, data from 21 patients were analyzed. Table 1 shows the characteristics of the patients (male, n = 20; female, n = 1; median age 69 years [range 49–82]). Eighteen patients had good PS (0 or 1) and three patients had poor PS (2). The primary sites were hypopharynx (n = 8), oropharynx (n = 6), oral (n = 3), larynx (n = 2), and other (n = 2). Nineteen patients had previously been treated with definitive radiotherapy (n = 3) or concurrent chemoradiotherapy with cisplatin (n = 16). Among them, two patients received nivolumab due to recurrence after chemoradiotherapy. Thirteen patients had distant metastases with or without locoregional recurrence, and eight had locoregional recurrence. Platinum therapy was contraindicated because of PS 2 (n = 3), age > 75 years (n = 6), comorbidity (n = 9), platinum resistance (n = 9), and refusal of platinum therapy (n = 2).

Table 1 Patient characteristics (n=21)
Full size table

Efficacy

Twenty-one patients were assessed for efficacy (Table 2). The ORR was 43% (95% CI 22–66), with one patient (5%) achieving complete response (CR), eight patients (38%) achieving partial response (PR), and ten patients (47%) achieving stable disease (SD). The disease control rate (CR, PR plus SD) was 90% (95% CI 77–100). The median follow-up was 10.7 months (range, 4.2–29.3) for all patients, and the median OS was 13.7 months (95% CI 9.0–18.3) with 12 (57%) deaths (Fig. 1). The median PFS was 5.7 months (95% CI 3.1–8.2) (Fig. 2).

Table 2 Response (n=21)
Full size table
Fig. 1
figure 1

Overall survival

Full size image
Fig. 2
figure 2

Progression-free survival

Full size image

Safety

Treatment-related grade 3/4 adverse events (AEs) were reported in 13 patients (62%) (Table 3). They were acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), anorexia (10%), neutropenia (5%), anemia (5%), diarrhea (5%), and shingles (5%). Grade 2 IRR developed in two patients and grade 1 interstitial pulmonary pneumonia associated with cetuximab developed in one patient. No AE-related deaths were recorded and the treatment was generally well tolerated.

Table 3 Adverse events during S-1/Cetuximab (n=21)
Full size table

Treatment compliance

The study treatment was discontinued due to disease progression (n = 10), AEs (n = 8), and patient’s refusal (n = 2). One patient was still under S-1/cetuximab therapy at the time of the cutoff. The median time to treatment failure (TTF) was 4.3 months (95% CI 2.9–5.7) (Supplementary Figure S2). The median number of treatment cycles was 5 (range 1–13). The median relative dose intensity of S-1 and cetuximab was 91.3% (range 52–100) and 87.8% (range 61.1–100), respectively.

Subsequent treatment

One patient was untraceable after hospital transfer. Eleven patients received the following therapy after the experimental regimen was discontinued: off-protocol S-1/cetuximab after long-term discontinuation due to an treatment-unrelated AE (n = 1), S-1 (n = 2), cetuximab (n = 1), paclitaxel plus cetuximab (n = 1), nivolumab (n = 3), docetaxel (n = 2), and carboplatin plus 5-FU (n = 1) because the general status of this patient improved.

Discussion

The results of this phase II study showed that S-1/cetuximab might be an effective combination for treating platinum-ineligible R/M SCCHN, with an ORR of 43%. This combination showed promise in terms of better survival, with a median PFS of 5.7 months and a median OS of 13.7 months. Although the sample size was smaller than planned, our findings were essentially the same as those in the EXTREME trial. Moreover, toxicity was manageable, and the regimen was well tolerated on an outpatient basis with dosage adjustment as necessary.

Given that the phase III EXTREME trial provides gold standard data with a median OS of 10.1 months, a PFS of 5.6 months, and a response rate of 36% [7], it is the most frequently recommended treatment regimen for platinum-eligible patients. However, a certain portion of patients encountered during routine medical practice cannot tolerate platinum-based treatment due to various medical issues. Some recent clinical trials have included the concept of ‘platinum-refractoriness’, defined as tumor progression or recurrence within 6 months after the last dose of platinum-based chemoradiotherapy, adjuvant therapy or systemic chemotherapy as eligibility criteria for patients with R/M SCCHN. The prognosis for such patients is poor [28] and administering another platinum-based regimen results in limited antitumor effects [29, 30]. The response rate of the nine patients with platinum-refractory R/M SCCHN in the present study was 33%, including PR (n = 3) and SD (n = 5). This finding indicated that S-1/cetuximab is effective against platinum-refractory R/M SCCHN. On the other hand, PD-1 immune checkpoint inhibitors have recently been administered to treat platinum-refractory R/M SCCHN [31, 32], and treatment for R/M SCCHN is rapidly changing. Therefore, we included patients treated with a PD-1 immune checkpoint inhibitor for platinum-refractory R/M SCCHN in the present study. Two patients were enrolled after treatment with a PD-1 immune checkpoint inhibitor, including PR (n = 1) and SD (n = 1). Recent data suggest that exposure to an immune checkpoint inhibitor improves response to chemotherapy in various cancer types [33,34,35] including head and neck cancer [36]; therefore, a PD-1 immune checkpoint inhibitor followed by S-1/cetuximab might be an appropriate treatment option for platinum-ineligible patients with R/M SCCHN. Recently, the KEYNOTE-048 study showed that pembrolizumab monotherapy was effective in patients with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) of 1 or more and was well tolerated as a first-line treatment for R/M SCCHN [37]. However, the efficacy of pembrolizumab monotherapy was insufficient compared to the EXTREME regimen in the PD-L1-negative population (CPS < 1) and its response rate was 17% in the full population, lower than that of S-1/cetuximab combination treatment. Therefore, S-1/cetuximab combination treatment may be more appropriate than pembrolizumab monotherapy for patients who are PD-L1-negative and/or who require early tumor shrinkage because of good response rate.

Platinum-ineligible patients are often elderly, have comorbidity or poor PS, and are usually treated with single agents, such as taxanes, cetuximab, or methotrexate. However, single agents have limited effectiveness and responses are transitory [5]. Few reports have described combination regimens without platinum for platinum-ineligible patients. Hitt et al. [38] described a prospective phase II study of combination of cetuximab and weekly paclitaxel as a first-line treatment for patients with R/M SCCHN that was promising, as the ORR was 54%, and the median PFS and OS were 4.2 and 8.1 months, respectively. As a background to these findings, although cetuximab is only about 13% effective as a single agent [39], combining it with a cytotoxic agent might result in a synergistic effect. This notion was addressed in the EXTREME trial, which showed that adding cetuximab to FP improved survival compared with FP [7]. We found that S-1/cetuximab was also promising, with an ORR of 43% in platinum-ineligible patients with R/M SCCHN. Thus, S-1/cetuximab treatment might be a beneficial alternative to paclitaxel/cetuximab in the setting of platinum-ineligibility for the following reasons. The frequency of myelosuppressive toxicity was low. Only one (5%) patient each developed grade 3 neutropenia and anemia. Peripheral neuropathy is a common AE associated with paclitaxel, but it did not arise in the present study. This is very important for maintaining the therapeutic effect and patient QOL, because severe neuropathy often results in treatment discontinuation. Pre-treatment steroids to prevent IRRs were discontinued after a second infusion of cetuximab in the present study. Cetuximab is unlikely to cause IRRs after a few doses, but pre-treatment steroids need to be continued to suppress allergic reactions to paclitaxel. Thus, our regimen helped to maintain stable blood sugar levels in patients with diabetes. The frequency of alopecia was very low during treatment with S-1/cetuximab, as only two patients developed grade 1 alopecia. This is also beneficial for patients who participate in social activities. On the other hand, 8 patients in our study discontinued treatment due to AEs. Specifically, 5 patients discontinued due to treatment-related AEs including grade 1 cetuximab-related pneumonitis. However, 2 of these 5 were able to switch to S-1 or cetuximab monotherapy after discontinuation. The other 3 of the 8 patients discontinued due to grade 2 radiation pneumonitis, aspiration pneumonia, and off-protocol S-1/cetuximab after long-term discontinuation due to trouble with gastrostomy. Although treatment-related grade 3/4 AEs were reported in 13 patients (62%), the treatment was generally well tolerated with appropriate dose reductions and administration delays according to dose reduction protocols. Two patients refused to continue treatment due to personal reasons unrelated to AEs: one for economic reasons and the other because of durable complete response. Based on the above evidence, S-1/cetuximab might be an appropriate treatment option for platinum-ineligible patients with R/M SCCHN.

Limitations

This study was prematurely closed due to slow accrual, and it was underpowered to determine statistical significance for the primary endpoint due to the small patient cohort. On the other hand, we did confirm survival data and the safety profile of S-1/cetuximab. Factors that contributed to the insufficient closure comprised competing trials in Japan at the time, strict patient criteria, and an overlap with the approval of nivolumab in routine medical practice for R/M SCCHN.

Conclusions

Our study suggests that S-1/cetuximab might be an effective first-line treatment (or after therapy with an immune checkpoint inhibitor) for patients with R/M SCCHN. Whereas platinum/5-FU/cetuximab remains one of the standard first-line treatments, S-1/cetuximab is an appropriate alternative for platinum-ineligible patients with R/M SCCHN.