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

Abstract

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.

Keywords: Biomarkers, Tumor; Head and Neck Neoplasms; Immunotherapy.

Figure 1

Flow chart showing trial selection procedure. Note: no eligible trial was identified in Chinese biomedical databases. EGFR, epidermal growth factor receptor; HPV, human papillomavirus; ORR, objective response rate; PD-1, programmed cell death protein 1.

Figure 2

Pooled estimates of clinical benefits according to p16 status and therapy. ^aThe 1-year OS rates and their 95% CIs were reported in the KEYNOTE-040 trial and were calculated by the life-table analysis proposed by Anderson et al in the other trials. ^bKEYNOTE-012 expansion reported neither 1-year OS rate nor provided information to calculate it. CK-141, CheckMate-141; CN, cetuximab plus nivolumab; CP, cetuximab plus pembrolizumab; KN, KEYNOTE; N, nivolumab; ORR, objective response rate; OS, overall survival; P, pembrolizumab.