Are immune checkpoint inhibitors ineffective in treating patients with head and neck squamous cell carcinoma aged 75 years or Older? A Meta-Analysis.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) is unclear in patients aged ≥ 75 years with head and neck squamous cell carcinoma (HNSCC). We conducted a systematic review and meta-analysis of randomized trials that compared ICIs with standard-of-care (SOC) therapy for recurrent/metastatic HNSCC. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched for eligible trials. We evaluated the overall survival (OS) benefit of ICIs versus SOC according to patient age (<75 versus ≥ 75 years). The OS benefit was evaluated and compared between the age subgroups using hazard ratios (HRs). Data were pooled using a random-effects model. RESULTS: Five phase 3 trials involving 3437 patients were included. In patients aged ≥ 75 years (n = 207), ICIs did not improve OS compared to SOC (HR = 1.30, 95 % confidence interval [CI]: 0.93-1.81, P = 0.127). However, an improvement in OS was observed in patients aged < 75 years (n = 3230, HR = 0.90, 95 % CI: 0.83-0.99, P = 0.025). There is a significant difference in OS benefit between patients aged < 75 and ≥ 75 years (ratio of HR = 0.69, 95 % CI: 0.49-0.98, P = 0.036). Subgroup, meta-regression, and sensitivity analyses supported the reliability of the results. CONCLUSIONS: Given the small sample size, our findings showing no improvement in OS suggest a lack of evidence to support the use of ICIs in patients with recurrent/metastatic HNSCC aged ≥ 75 years. Therefore, prospective studies are needed to clarify their efficacy among this age group.

Efficacy of cetuximab plus PD-1 inhibitor differs by HPV status in head and neck squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: The addition of cetuximab significantly increased the antitumor effect of programmed cell death protein 1 (PD-1) inhibitors in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, preliminary analyses suggested that human papillomavirus (HPV)-positive disease benefited less than HPV-negative disease. Therefore, we conducted a meta-analysis to assess whether the efficacy of the combination therapy varied according to HPV status in HNSCC. METHODS: We identified clinical trials of patients with recurrent or metastatic HNSCC who received PD-1 inhibitor monotherapy or the combination therapy of cetuximab plus a PD-1 inhibitor. The participants were divided into four groups based on the type of therapy (combination vs monotherapy) and HPV status (positive vs negative). We focused on three comparisons (monotherapy vs combination therapy by HPV status and HPV-positive vs HPV-negative disease in combination therapy). The primary and secondary endpoints were objective response rate (ORR) and 1-year overall survival (OS) rate, respectively. The ORR and 1-year OS rate were pooled using random-effects models for each group and were compared for the different comparisons. RESULTS: Overall, 802 patients from seven trials were eligible for the ORR assessment; of which, 684 patients received PD-1 inhibitor monotherapy and 118 patients underwent the combination therapy. Compared with PD-1 inhibitor monotherapy, the addition of cetuximab improved the ORR in HPV-negative disease (pooled ORR in monotherapy vs combination therapy: 15% vs 46%, p<0.001) but not in HPV-positive disease (17% vs 18%, p=0.686). The efficacy of adding cetuximab was consistent for the 1-year OS rate in HPV-negative disease (pooled 1-year OS rate in monotherapy vs combination therapy: 36% vs 59%, p<0.001) and in HPV-positive disease (40% vs 55%, p=0.252). After the combination therapy, HPV-positive disease had a significantly lower ORR than HPV-negative disease (odds ratio: 0.29, p=0.004), but no differences were shown in the 1-year OS rate. CONCLUSIONS: Our meta-analysis suggests that the addition of cetuximab to a PD-1 inhibitor is more effective compared with PD-1 inhibitor monotherapy only in patients with HPV-negative HNSCC. Despite the retrospective nature of this meta-analysis, these findings should help in designing relevant clinical trials rationally.

The primary site of head and neck squamous cell carcinoma predicts survival benefits of EGFR inhibitors: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: To assess the survival benefits associated with epidermal growth factor receptor (EGFR) inhibitors in head and neck squamous cell carcinoma (HNSCC) according to the primary site. MATERIALS AND METHODS: A systematic review and meta-analysis were conducted for randomized phase III trials comparing treatment with or without EGFR inhibitors in locoregionally advanced, recurrent, or metastatic HNSCC. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. Data were pooled using a random-effects model. RESULTS: Seven trials with a total of 3391 patients were included. The addition of EGFR inhibitors improved OS in patients with oral cavity-oropharyngeal carcinoma (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.67-0.87, P < 0.001) but not in patients with hypopharyngeal-laryngeal carcinoma (HR 0.94, 95% CI 0.82-1.08, P = 0.398). A significant interaction was found in favor of oral cavity-oropharyngeal carcinoma (P = 0.029). The addition of EGFR inhibitors increased PFS in both patients with oral cavity-oropharyngeal carcinoma (HR 0.67, 95% CI 0.52-0.85, P = 0.001) and patients with hypopharyngeal-laryngeal carcinoma (HR 0.81, 95% CI 0.69-0.94, P = 0.005). A trend towards significant interaction was found in favor of oral cavity-oropharyngeal carcinoma (P = 0.161). Comparable results were observed in the pre-specified subgroup analyses. Meta-regression analyses suggested that the primary site appeared to be a predictor of survival benefits in HNSCC patients who received treatment with EGFR inhibitors over those who did not. CONCLUSION: Our meta-analysis suggests that the survival benefits of EGFR inhibitors might depend on primary sites in HNSCC. Further studies are needed to confirm this finding.