Efficacy and Safety of Cetuximab Plus Cisplatin Alone or in Combination With Paclitaxel in Patients With Head and Neck Squamous Cell Carcinoma: A Randomized Trial.

OBJECTIVES: The aim of this study was to assess the clinical usefulness of cetuximab and cisplatin alone or in combination with paclitaxel as the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
METHODOLOGY: Three hundred patients with confirmed HNSCC from 20 different hospitals were included in this study. Patients in group I underwent a 2-hour infusion of 400 mg/m2 cetuximab (day 1), followed by a 1-hour infusion of 250 mg/m2 cetuximab weekly and 1-hour infusion of 100 mg/m2 cisplatin (days 1 and 21) per treatment cycle. Patients in group II were treated with a combination of cetuximab, cisplatin, and paclitaxel. Patients received 6 cycles of 175 mg/m2 paclitaxel given on days 1 and 21. The primary outcome of the study was progression-free survival (PFS); overall survival (OS) and objective response rate (ORR) were the secondary endpoints.
RESULTS: The median PFS was 5 months and 8 months for patients in groups I and II, respectively (HR, 0.93; 95% CI, 0.85-1.78; P > 0.05). Similarly, we found no significant differences in OS between the 2 groups (median OS, 13 vs. 11 months, respectively; HR, 0.67; 95% CI, 0.42-1.43; P = 0.198). Moreover, we observed no significant difference in ORR between the 2 groups (ORR, 63.3% vs 69.9%, respectively; HR, 0.87; 95% CI, 0.36-1.67; P = 0.231).
CONCLUSIONS: The combination of paclitaxel with cetuximab and cisplatin did not improve patient outcomes compared to cetuximab plus cisplatin alone. Therefore, the 2-drug regimen could be used as first-line treatment in patients with recurrent or metastatic HNSCC.

Introduction

The incidence of squamous cell carcinoma of the head and neck (HNSCC) is high, with approximately 6 million new cases per year worldwide. The prognosis for patients with metastatic or recurrent HNSCC remains poor, with a median survival time of less than 1 year. In HNSCC patients, the 5-year tumor recurrence rate is almost 50%, and metastasis develops in approximately 10% of cases. Therefore to manage disease progression, improve the quality of life, and decrease the mortality rate in HNSCC patients, combinational therapeutic approaches are needed.

The EXTREME protocol, which combines the anti-epidermal growth factor receptor monoclonal antibody cetuximab with platinum-based chemotherapy (cisplatin or carboplatin) and 5-fluorouracil, is the current first-line standard of treatment for patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The overall survival rate of HNSCC patients was increased in this chemotherapy protocol relative to polychemotherapy alone, which was previous first-line therapy. However, high toxicity and adverse outcomes were associated with the administration of this 3-agent regimen. Especially, 5-FU was associated with cardiac toxicity and other life-threatening side effects, as well as with high mortality rates.

Several authors have supported category 1 evidence that the EXTREME protocol is not always preferred by clinicians, especially in the United States, where taxane is routinely paired with first-line cisplatin-based chemotherapy instead, and thus monotherapy with cetuximab is administered in the second row (a treatment sequence allowed by the treatment guidelines but not supported by category 1 evidence). Therefore, there is an urgent need to characterize more tolerable systemic therapy alternatives to the landmark EXTREME regimen that produce comparable efficacy benefits. Furthermore, in the later-line setting, emerging immune control point inhibitors nivolumab and pembrolizumab have demonstrated activity and are currently being investigated as first-line treatment options. The combination of nivolumab and pembrolizumab in several countries is currently being investigated. The management strategies of R/M HNSCC seek to reduce the burden of tumors, enhance the quality of life and increase the overall survival rate. In order to boost the objective response rate (ORR) and minimize treatment-related adverse events, the use of taxanes was suggested as an alternative to 5-FU. Multiple studies have shown that the combination of taxanes with cisplatin and cetuximab enhances the quality of life and overall survival rate. Among the taxanes used as anti-cancer agents, docetaxel and paclitaxel are the most commonly used.

Cetuximab-a monoclonal antibody selectively binds the tumor cell to the extracellular domain of the epidermal growth factor receptor and prevents the activation of receptor-associated tyrosine kinase. It also increases radiotherapy activity in HNSCC therapy.

The goal of this study was to explore the clinical utility of cetuximab and cisplatin as first-line treatment of patients with R/M HNSCC, alone or in combination with paclitaxel.

Materials and Methods

Study Design

This was a randomized, multicenter, parallel, phase 2b clinical trial assessing the clinical effects of cetuximab and cisplatin alone or in combination with paclitaxel in patients with HNSCCwith allocation ratio of 1:1. The study cohort comprised 300 patients with confirmed HNSCC from 20 different hospitals. The inclusion criteria were histopathologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx, or paranasal sinus and further, who had not previously been treated for R/M HNSCC. However, patients previously treated with cetuximab for locoregional recurrence were also considered eligible for the study. Additionally, only patients with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 were included in this study. Exclusion criteria included the presence of nasopharyngeal carcinoma, pregnancy, or severe comorbidities as well as previous cancer treatment with surgery or radiotherapy.

Parallel random assignment to treatment arms was performed on a 1:1 basis and simple type randomization was used without any restriction. Automated computerized system has been used for the random allocation sequence. Patients in the first arm (group I, n = 150) were received a 2-agent regimen consisting of cetuximab and cisplatin, whereas individuals in the second arm (group II, n = 150) were received a 3-agent regimen consisting of cetuximab, cisplatin, and paclitaxel. The study was approved by the Ethics Committee and Research Board of Shandong University (approval no. QSU/CA/HN-2014). The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. Informed written consent has obtained from all patients before the start of the trial. We have divided the process of randomizing participants into 3 different steps: sequence generation, allocation concealment, and implementation. The physicians working in the hospital were assigned for the sequence generation, allocation was done by the sr. consultants and Implementation was done by the authors. All were blinded at their levels and strict confidentiality was maintained.

Treatment

Patients in group I underwent a 2-hour infusion of 400 mg/m2 cetuximab (day 1), followed by a 1-hour infusion of 250 mg/m2 cetuximab weekly and 1-hour infusion of 100 mg/m2 cisplatin (days 1 and 21) per treatment cycle. Cisplatin was administered for 6 cycles. Patients in group II were treated with a combination of cetuximab, cisplatin, and paclitaxel. Patients received 6 cycles of 175 mg/m2 paclitaxel given on days 1 and 21. Although the same dose of cetuximab was administered to patients in group II, the dose of cisplatin was reduced to 75 mg/m2. Maintenance therapy with cetuximab was administered to all patients until disease progression.

Assessments of Treatment Outcomes

The primary outcome of this study was progression-free survival (PFS). The overall survival (OS), objective response rate (ORR), and presence of prognostic markers were used as secondary endpoints. Response was defined according to the response evolution criteria in solid tumors (RECIST), version 1.1. The endpoints were evaluated using intention-to-treat analysis. In situ hybridization was also performed to determine patients’ human papillomavirus (HPV) status, and p16 status was assessed by immunohistochemistry.

Dose reduction/delay

For ceuximab-related grade 3 skin toxicity, cetuximab can be postponed for up to 2 consecutive weeks, accompanied by dose reductions to 200 mg/m2 and then 150 mg/m2. For grade 3 toxicity persisting for >2 weeks, he was managed through dose restriction or pause. For grade 4 toxicity, the patient was to be excluded from the study. Reduced infusions of cetuximab were allowed for grade 1 and 2 infusion-related reactions (IRRs). Cetuximab was to be withdrawn for grade 3 or 4 cetuximab-related IRRs; paclitaxel doses for grade 3 neurotoxicity, other nonhematological grade 3/4 toxicity, and grade 4 hematologic toxicity were to be lowered by 25%.

Assessment of complete response (CR) or partial response (PR) and follow up plan

Time to response period was described as time from first infusion to full response (CR) or partial response (PR). (PR). Duration of response period was specified as time from first response (CR or PR) until disease progression (PD). PFS was described as the period from first research therapy until PD or death. Overall rate of survival was described from the first administration of study therapy to death from some cause. Follow-up visits were performed every 3 months after PD to assess survival status.

Assessment of adverse events

Adverse events were recorded at each weekly visit and coded according to the National Cancer Institute—Common Terminology Criteria for Adverse Events, version 3.0

Statistics

PFS and hazard ratios (HR) were compared between the 2 groups. A median PFS of 6.5 months was reported by Vermorken et al. in patients treated with the combination of cetuximab, cisplatin, and 5-FU. Sample size was determined using a non-inferiority margin of 1.4 for HR. A total of 278 events were required for 90% power at one-sided α value of 0.1 to reject the null hypothesis (HR ≥ 1.4) versus the alternative hypothesis (HR = 1.0), assuming an exponential distribution with parameter = 0.1134 for PFS in group I. The null hypothesis could be rejected if the upper limit of the one-sided 90% confidence interval (CI) for HR estimated in a PFS Cox model stratified by ECOG PS and tumor site were <1.4. ORR analysis was used to determine the best response during treatment and the maintenance period.

The response duration was defined as the time between the date of tumor regression and the date of disease progression; patients who died without evidence of progression were censored at the time of death, and surviving patients without signs of progression were censored at the date of the last follow-up. The median response duration and the 95% CI were estimated using the Kaplan–Meier method. PFS was defined as the time from randomization until progression or death, whichever occurred first. OS was defined as the time from randomization until death from any cause; patients lost to follow-up were censored at the date of the last follow-up. OS and PFS curves, as well as the median PFS and OS (including 95% CI), were estimated using the Kaplan–Meier method. Survival curves were compared using the log rank test. To assess the significance of ECOG PS and tumor site on PFS and OS, we performed univariate analysis using the Cox proportional-hazards model. All tests were 2-sided at a significance level of α = 0.05, with the exception of the one-sided test of non-inferiority for PFS. All analyses were conducted using SAS and R packages.

Results

Patient Characteristics

The flow chart of randomization of samples as per the CONSORT has been mentioned in Figure 1. A total of 300 patients with R/M HNSCC were enrolled in our study from June 2012 until July 2017. The baseline characteristics of the patients are shown in Table 1 and Figure 2. The median ages of patients in groups I and II were 67 and 69 years, respectively. The male-to-female ratio in the entire cohort was 1:8. Eighty-four of the 300 patients had lesions in the oropharynx, and the others had tumors in other parts of the oral cavity such as the buccal mucosa, lips, tongue, palate, floor of the mouth, and lateral border of the tongue. Among the 300 patients, 74 were positive for HPV, including 36 in group I and 38 in group II; 32.3% (n = 98) of the patients had metastasis, and 22.3% (n = 67) had local or regional recurrence. The mortality rate was similar in the 2 groups (52% in group I and 48% in group II).

Figure 1.

Consort flowchart.

Table 1.

Baseline Characteristics of Patients With Recurrent or Metastatic HNSCC.

Parameter	Patients (n = 300)	Group I, cetuximab + cisplatin (n = 150)	Group II, cetuximab + cisplatin + paclitaxel (n = 150)
Age (years)	Median	67	69
	Female	20 (14%)	14 (10%)
	Male	130 (86%)	135 (90%)
ECOG PS, n (%)	n	150	150
	0	78 (52.0%)	76 (50.6%)
	1	72 (48.0%)	75 (49.4%)
Primary tumor site, n (%)	n	150	150
	Oropharynx	46 (30.7%)	38 (25.4%)
	Other	104 (69.3%)	112 (74.6%)
HPV infection	n	36 (24%)	38 (25%)
(oropharynx only)	HPV negative	31 (67.3%)	10 (26.5%)
	HPV positive	15 (32.7%)	28 (73.5%)
Site of recurrence	n	150	150
	Local recurrence	25 (16.6%)	32 (21.3%)
	Locoregional recurrence	25 (16.6%)	38 (25.3%)
	Metastasis	55 (36.6%)	43 (28.6%)
	Metastasis and local or regional recurrence	35 (23.3%)	32 (21.3%)
	Regional recurrence	10 (6.6%)	5 (3.3%)

Figure 2.

Schematic representation of the sample distribution.

Efficacy

In total, 215 patients (115 in group I and 102 in group II) showed no signs of progression for the duration of the study. The upper boundary limit of the one-sided HR at 95% CI was 1.25, which is below the pre-defined non-inferiority level of 1.4. The median PFS was 5 months and 8 months for patients in groups I and II, respectively (HR, 0.93; 95% CI, 0.85–1.78; P > 0.05). Similarly, we found no significant differences in OS between the 2 groups (median OS, 13 vs. 11 months, respectively; HR, 0.67; 95% CI, 0.42–1.43; P = 0.198) (Figure 3). Moreover, we observed no significant difference in ORR between the 2 groups (ORR, 63.3% vs 69.9%, respectively; HR, 0.87; 95% CI, 0.36–1.67; P = 0.231; Table 2, Figure 3.

Figure 3.

Kaplan Meier survival curves for overall survival.

Table 2.

Response to Treatment.

Response	Group I (n = 150)	Group II (n = 150)
Complete response rate, n (%)	15 (10%)	20 (13.33%)
Partial response rate, n (%)	80 (53.3%)	85 (56.6%)
Stable disease rate, n (%)	55 (36.6%)	45 (30%)
Overall response rate, %	63.3%	69.9%

Safety

A total of 278 patients experienced adverse events of any grade, with the majority showing more than one side effect. Treatment-related toxicities occurred in 140 (93.33%) and 138 (92%) patients in groups I and II, respectively. Severe adverse events (grade 3 or 4) occurred in 82 and 78 patients in groups I and II, respectively (Table 3). None of the patients developed sepsis or cardiotoxicity. Additionally, we observed no treatment-related deaths.

Table 3.

Adverse Events.

Events	Group I (n = 150)	Group II(n = 150)
Total	140 (93.3%)	138 (92%)
Neutropenia	32 (21.3%)	38 (25.3%)
Leukopenia	12 (8%)	27 (18%)
Fatigue	17 (11.3%)	24 (16%)
Skin rash	18 (12%)	14 (9.3%)
Fever/infection	1 (0.6%)	8 (5.3%)
Anemia	10 (6.6%)	6 (4%)
Lymphopenia	7 (4.6%)	5 (3.3%)
ALT or AST increase	6 (4%)	4 (2.6%)
Hypokalemia	4 (2.6%)	4 (2.6%)
Oral mucositis	13 (8.6%)	4 (2.6%)
Other toxicity	3 (2%)	4 (2.6%)
Allergic reaction	2 (1.3%)	3 (2%)
Nausea	10 (6.6%)	3 (2%)
Paronychia	5 (3.3%)	3 (2%)
Peripheral sensory neuropathy	6 (4%)	3 (2%)
Thrombocytopenia	7 (4.6%)	3 (2%)
Alopecia	0 (0.0%)	2 (1.3%)
Diarrhea	0 (0.0%)	2 (1.3%)
Hypomagnesemia	4 (2.6%)	2 (1.3%)
Hyponatremia	7 (4.6%)	2 (1.3%)
Musculoskeletal disorders	0 (0.0%)	2 (1.3%)
Vomiting	3 (0.0%)	2 (1.3%)
Cardiac toxicity	0 (0.0%)	1 (0.6%)
Hypocalcemia	2 (1.3%)	1 (0.6%)
Pain	0 (0.0%)	1 (0.6%)
Weight loss	0 (0.0%)	1 (0.6%)
Anorexia	0 (0.0%)	0 (0.0%)
Creatinine increase	1 (0.6%)	0 (0.0%)
Hyperglycemia	1 (0.6%)	0 (0.0%)

Discussion

In this study, we investigated the clinical usefulness of cetuximab and cisplatin alone or in combination with paclitaxel as the first-line treatment of patients with R/M HNSCC. We found no significant differences between the 2-drug and 3-drug regimens in terms of PFS, OS, and ORR. Notably, the ORR in patients treated with the 3-drug regimen was less than 50%. Vermorken et al. reported that the ORR in patients treated with cetuximab, cisplatin, and paclitaxel was 36%, which is similar to that in patients treated with the 2-drug regimen.

The OS rate for patients treated with cetuximab plus cisplatin was more encouraging that than for patients treated with the 3-drug regimen. In the CSPOR HN02 trial, the combination of paclitaxel, carboplatin, and cetuximab (PCE) provided an OS rate of 37.8%. However, in the TPEx trial, the combination of cetuximab, cisplatin, and docetaxel provided an OS rate of 51.8%. These findings suggested that the combination of taxanes with cetuximab and cisplatin could provide a higher ORR. However, future large cohort phase 3 clinical trials are required to determine the clinical benefit of the combination of taxanes with cetuximab and cisplatin.

The safety profiles of the 2-drug and the 3-drug regimens did not differ significantly. Notably, both regimens showed improved safety profiles compared to other combinational therapeutic approaches involving the use of 5-FU, which have been associated with severe cardiotoxicity. In contrast, none of the patients in this study experienced cardiac toxicity. The rate of febrile neutropenia in patients treated with the 3-drug regimen was similar to that reported in patients treated with the combination of cetuximab, cisplatin, and 5-FU. Vermorken et al. reported septic shock in 4% of cases. In contrast, none of our patients developed septic shock. Moreover, fever was observed in 2% and 8%, and grade 4 toxicities were observed in 13% and 31% of patients treated with the 2-drug and the 3-drug regimens, respectively. Similarly, the EXTREME trial reported that 31% of patients treated with the 3-drug regimen developed grade 4 toxicities.

Previous reported trials have found that Cetuximab could be paired with Paclitaxel with potential compatibility and positive effectiveness following Platinum loss and could be stronger than the EXTREME schedule for chosen patients. Thus, integrating the 3 agents Platinum, Paclitaxel and Cetuximab may be of considerable interest. In reality, a randomized phase II study recorded 51.7% first-line responses with Cisplatin-Paclitaxel-Cetuximab and 11-month OS. Similarly, another phase II study combining Cisplatin Docetaxel and Cetuximab showed 44.4% first-line responses and 14-month OS.

In 31 patients with locally advanced, distant metastases or recurring head and neck squamous cell carcinoma, another research illustrated safety and effectiveness of weekly Carboplatin and Paclitaxel. Median OS was 12.8 months [95% CI 8.6–15.5] and the greatest toxicity was hematologic, with 22% neutropenia grade >3, 12% anemia grade >3 and 0% thrombopenia grade >3.

Therefore, the 2-drug regimen is relatively safer than the 3-drug regimen. In contrast to the combination of 5-FU with cetuximab and cisplatin, the 3-drug regimen used in this study improved patients’ quality of life. The quality of life was similar in patients treated with the 2-drug regimen and 3-drug regimen.

Yadav et al concluded that using nimotuzumab to chemotherapy didn’t lead to toxicity. The frequency and intensity of rash and electrolyte imbalances such as hypomagnesemia reported in the present trial with nimotuzumab is far lower compared to that observed in the cetuximab arm in the EXTREME trial and in the SPECTRUM trial. Moreover, authors reveled that, there was no statistically meaningful difference in the frequency of these harmful effects in nimotuzumab with chemotherapy arm versus chemotherapy arm.

Conclusions

In this study, we investigated the clinical usefulness of cetuximab and cisplatin alone or in combination with paclitaxel as the first-line treatment for patients with R/M HNSCC. Although the combination of paclitaxel with cetuximab and cisplatin did not improve patient outcomes compared to cetuximab plus cisplatin alone, it is more efficient and safer compared to other 3-drug regimens involving the use of 5-FU. The applicability of this study is basically for the Head and neck surgeons and physicians and further, beneficial for the patients who were suffering from the head and neck cancer. We are proposing that the 2-drug regimen could be used as first-line treatment in patients with recurrent or metastatic HNSCC

Limitations

The study has been conducted in phase 2b with limited sample size, however, large patient data cohort in phase 3 clinical non interventional study has been required for the future outcome. Secondly, head to head comparison of this regime with the Extreme regime should be assessed to further validate the results.