Is the use of cetuximab in the first-line treatment of recurrent/metastatic head and neck cancer still important?

KEYWORDS:

• Recurrent/metastatic head and neck cancer
• cetuximab
• PD-L1
• pembrolizumab
• chemotherapy
• combined positive score

1. Introduction

Head and neck squamous cell carcinomas (SCCHN) resulted in approximately 890,000 new cases and 450,000 deaths in 2018, worldwide, representing the seventh most common cancer [1,2]. Squamous cell carcinoma is the most common subtype of SCCHN. In the majority of cases, it is associated with tobacco and alcohol abuse. In a few cases, it is associated with human papilloma virus infection; however, this rate has been increasing over the years [3]. SCCHN is often diagnosed at a locally advanced stage, requiring a multimodal treatment approach, combining radiotherapy, chemotherapy, and surgery. Despite this approach, half of the patients experience disease progression after initial treatment. These patients have a poor prognosis with a median overall survival of less than 1 year [4].

The first-line treatment for SCCHN is based on a chemotherapy backbone, including platinum salts [5]. However, since 2008, cetuximab has been added to the regimen, based on the results of the EXTREME trial [6]. The EXTREME trial was the first trial in 30 years to show an increase in overall survival in patients with SCCHN. The efficacy of this combination was further confirmed in the phase III CHANGE-2 trial that showed an improved median PFS, median OS, and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regime, in a cohort of 243 randomized patients [7] Cetuximab is a monoclonal antibody that targets the EGF receptor, causing inhibition of the tyrosine-kinase cascade resulting in reduced cell proliferation and growth. Unfortunately, there were no developments in the first line of SCCHN until the Keynote 048 trial [8]. The Keynote 048 was a randomized, open-label, three-arm, phase III trial that compared the standard of care (SOC) with cisplatin-5-fluorouracil and cetuximab to pembrolizumab alone or pembrolizumab plus chemotherapy. The study population was stratified according to programmed cell death ligand-1 (PD-L1) status, p16 status, and ECOG score. The primary end-point was overall survival (OS). Although the original primary end-point was progression-free survival (PFS), due to poor response to immunotherapy as observed in previous trials, it was amended to OS in the final protocol. After a median follow-up of 45 months, the trial showed an improvement in the OS of patients treated with pembrolizumab in a population with a combined positive score (CPS) > 20 (14.9 months vs. 10.7 months, p = 0.0007); additionally, patients with CPS > 1 showed an improvement in OS (12.3 months vs. 10.3 months, p = 0.0086). Moreover, it was non-inferior in the total population, in which the OS improved to 13.0 months from 10.7 months (p = 0.00994). The study also had a pembrolizumab chemotherapy versus an extreme arm and showed that, for pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median OS was 14.7 months versus 11.1 months in the PD-L1 CPS > 20 population (p = 0.00082), 13.6 months versus 10.6 months in the CPS > 1 population (p = 0.00001), and 13.0 months versus 10.7 months in the total population (p = 0.0008), respectively. Based on these results, first-line chemotherapy for patients with metastatic or recurrent head and neck cancers can be treated with pembrolizumab alone or in combination with chemotherapy, in the CPS > 1 population [9].

In February 2022, a sub-group analysis conducted on the population of the KEYNOTE 048 trial was published. The investigators evaluated the outcome in patients with PD-L1 CPS < 1 and > 1 and < 20. In the sub-group of the population with CPS < 1, the median OS was 7.9 months in the pembrolizumab arm and 11.3 months in the cetuximab plus chemotherapy arm (p = 0.962421). In the sub-group of the population with CPS < 1, the median OS was 11.3 in the chemotherapy plus pembrolizumab arm and 10.7 months in the chemotherapy plus cetuximab arm (p = 0.78932). The PD-L1 sub-group with CPS > 1 and < 20 had a median OS of 10.8 months and 10.1 months, respectively (p = 0.1287), in the pembrolizumab arm versus chemotherapy plus cetuximab arm. Finally, in the sub-group of patients with CPS < 1 and > 20, those in the pembrolizumab plus chemotherapy arm versus the cetuximab plus chemotherapy arm had a median OS of 12.7 months and 9.9 months, respectively (p = 0.00726). The objective response rate (ORR) in the sub-group with CPS < 1 was 4.5% in the pembrolizumab arm and 42.2% in the cetuximab plus chemotherapy arm. In the sub-group with CPS > 1 and < 20 the ORR was 14.5% and 33.8% in the pembrolizumab and cetuximab plus chemotherapy arms, respectively. The ORR in the sub-group of patients with CPS < 1 treated with pembrolizumab plus chemotherapy and chemotherapy plus cetuximab was 30.8% and 39.5%, respectively. In the CPS > 1 and < 20 sub-group, the ORR was 29.3% in the pembrolizumab plus chemotherapy arm and 33.6% in the chemotherapy plus cetuximab arm [10].

2. Discussion

The KEYNOTE 048 trial demonstrated the potential of pembrolizumab in addition to existing chemotherapy regimens for prolonged survival in patients with head and neck cancer. However, based on the sub-group analysis, this combination is not suitable in all patients with recurrent/metastatic head and neck cancer [9]. In patients with CPS < 1, pembrolizumab plus chemotherapy did not show a clinical and OS benefit, compared with the standard regimen of cetuximab and chemotherapy (the EXTREME trial regimen), which is safe and guarantees a better outcome in such patients [10]. Nevertheless, an important finding is that in the sub-group with CPS > 1 and < 20, there was no improvement in OS with pembrolizumab versus cetuximab plus chemotherapy. Also considering the ORR, a better improvement in OS was observed for the EXTREME regimen. In contrast, the OS improved in the CPS < 1 and < 20 sub-group treated with pembrolizumab plus chemotherapy. Overall, the ORR for the group of patients treated with cetuximab plus chemotherapy was the best. This finding was recently confirmed by the SOCCER trial results that demonstrated a strong correlation between the treatment response and reduced tumor-related symptoms [11]. This trial included a large multicenter prospective cohort of 470 patients, displaying unselected patient data as a relevant number of patients with an ECOG score of 2 and a Charlson comorbidity index ≥ 1. Treatment response rapidly improved tumor-related symptoms with first-line treatment with cetuximab-chemotherapy or cetuximab-radiotherapy combinations, during the first 4 weeks of treatment. Further, the ORR for the treatment response for the entire cohort was 33% and the disease control rate was 56%, which showed an improvement in several patient symptoms, particularly, dysphagia and pain. Therefore, we can assume that cetuximab still plays an important role in treating patients with CPS > 1 and < 20, overall, when we need a more shrinkage in a rapid time [12].

In contrast, the presence of local recurrence rather than distant metastasis may suggest our therapeutical decision. Existing literature shows the effectiveness of EXTREME-like regimens in patients with local relapse. In a recent clinical trial, Chen et al. demonstrated that the median OS and PFS were longer in a loco-regional recurrence patient cohort than in a distant metastasis group [12]. Moreover, immunotherapy is associated with a shorter PFS and a higher probability of hyperprogression in patients with head and neck cancer with local relapse, as reported by Saada-Bouzid et al. [13].

Moreover, several factors, such as age, tumor location, patient preference, and the need for a rapid response, should be considered when selecting the best therapeutic option for patients with PD-L1 CPS from 1 to 20. The therapeutic choice must also consider the toxicity profile of these drugs, both favorable and manageable, but with very different side effects, such as mucositis and dermatitis due to cetuximab, hypothyroidism, and other immune-related adverse events due to pembrolizumab, which are not easily predictable and can influence the clinician’s decision [14]. Based on the most common side effects, cetuximab is not preferred for patients who fear facial changes due to the possibility of skin rash, whereas pembrolizumab should not be administered in patients with anemia, thyroid hormone imbalance, and those who are underweight or suffer from arrhythmia or tachycardia [8].

In SSCHN, the rate of response plays a key role when the tumor is highly symptomatic. Dysphagia and pain make feeding difficult and sometimes lead to a rapid decline in performance status. For these metastatic HNSCC patients, cetuximab-based chemotherapy is the preferred therapeutic choice, also because pembrolizumab can be used for second-line treatment, with good outcome [15].

Today, several data from clinical trials with high patient numbers, such as KEYNOTE-040, Kestrel, Checkmate 651, and CheckMate-141, further support the idea that subsequent immunotherapy following a platinum-containing chemotherapy improves OS [15–20]. In addition, this strategy was also correlated with a higher quality of life and a lower toxicity rate; the toxicity remains a barrier to overcome. However, immunotherapy represents the gold standard in those patients whose tumors express PD-L1. Therefore, although the choice of treatment cannot be standardized, it must be determined by discussion with a multidisciplinary group, based on clinical and tumor factors. This is necessary because the quality of life and the safety profile of the treatment continue to represent a primary landscape that the clinicians must achieve in patients with metastatic or recurrent disease [21].

Immunotherapy has managed to objectively improve the effectiveness of medical treatments, however the combination of existing chemotherapy regimens with cetuximab may represent a valid alternative. The choice of the best medical therapy as well as the sequence that offers the most advantages cannot be determined by the CPS alone. Nevertheless, this molecular driver still has some inherent contradictions and limitations that require further investigation, as suggested by some studies [22,23]. Several factors, such as the sample type, technical requirements to guarantee high-quality immunohistochemistry (IHC) staining, and percentage of stroma, can cause variations in the PD-L1 status, and it is not clear how this affects the response rates. This may explain why PD-L1 CPS has repeatedly been proven to lack robustness as a stand-alone predictive biomarker in tailoring treatment with immunotherapy [24]. Therefore, the therapeutic decision depends on the patient selection, disease burden, tumor location, evaluation of the symptoms, and patient preferences. There are several possible therapeutic options that may result in the development of different treatment sequences (Table 1) must take in account the objectives that the clinicians may aim to achieve: response or survival, quality of life, and safety profile (Figure 1). Cetuximab-based chemotherapy still represents a valid therapeutic option that provides a high response rate for selected patients with metastatic SCCHN.

Figure 1. Clinical drivers for the choice of best medical therapy for patients with squamous cell carcinoma of the head and neck made by a multidisciplinary group.

Table 1. Therapeutic algorithm for the treatment of SCCHN (squamous cell carcinoma of the head and neck) according to CPS score.

	Preferred 1st line option	Preferred 2nd line option	Preferred 3th line option
CPS <1	Chemotherapy + Cetuximab	Nivolumab or Mono-chemotherapy	Mono-chemotherapy
CPS 1–19	Pembrolizumab ± Chemotherapy orChemotherapy + Cetuximab	Pembrolizumab or Nivolumab or Cetuximab ± Taxane	Mono-chemotherapy
CPS >20	Pembrolizumab ± Chemotherapy	Cetuximab ± Taxane or chemotherapy	Cetuximab or chemotherapy
SIMPTOMATIC DISEASE	Chemotherapy or RT + Cetuximab	Pembrolizumab	Mono-chemotherapy
ECOG >2	Pembrolizumab or Cetuximab	Pembrolizumab or Cetuximab	Mono-chemotherapy

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.