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 and Objective:The addition of cetuximab significantly increased the antitumor effect of programmed death protein 1(PD-1)inhibitors in recurrent or metastatic head and neck squamous cell carcinoma(R/M HNSCC).However,preliminary analysis suggested that human tumor virus(HPV)-positive disease benefited less than HPV-negative disease.Therefore,we conducted a meta-analysis to assess whether the efficacy of combination therapy varied according to HPV status in HNSCC and whether the difference in efficacy of cetuximab plus PD-1 inhibitor versus PD-1 inhibitor monotherapy was influenced by HPV status.Methods:We used Pub Med,Web of Science,EMBASE,Clinical Trials.gov and China Database(Chinese Science and Technology Journals Database,Wanfang and CNKI)for clinical trials of PD-1 inhibitor monotherapy or cetuximab in combination with PD-1 inhibitor.Strict inclusion and exclusion criteria were developed,and two review authors independently conducted literature search,study screening and data extraction to jointly decide which trials to include.Quality assessment was performed using the MINORS scale for nonrandomised trials and the Cochrane Risk of Bias assessment tool for randomised controlled trials.The primary and secondary endpoints were objective response rate(ORR)and 1-year overall survival(OS)rate,respectively.The randomeffects model was used for meta-analysis.Statistical sign significance was defined as a two-sided p-value < 0.05.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% vs18%,P = 0.686).The efficacy of adding cetuximab was consistent for the1-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 HPVnegative disease(odds ratio: 0.29,P = 0.004),but no differences were shown in the 1-year OS rate.Conclusions:1.In HPV-negative HNSCC patients,PD-1 inhibitor combined with cetuximab is more effective than PD-1 inhibitor monotherapy,while in HPV-positive patients,the efficacy of combination therapy is not better than PD-1 inhibitor monotherapy.2.In combination therapy with cetuximab and PD-1 inhibitors,HPVnegative patients had better ORR benefits than HPV-positive patients.3.Our findings suggest that HPV status is related to predicting the efficacy of PD-1 inhibitors combined with cetuximab,which is helpful to clarify the population who benefits from treatment and provides a theoretical basis for rational design of relevant clinical trials.