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

BackgroundThe 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.MethodsWe 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.ResultsOverall, 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.ConclusionsOur 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.

Exceptional response to cetuximab monotherapy after failure of immunotherapy with a checkpoint inhibitor in a patient with metastatic head and neck squamous cell cancer: case report and review of the literature

“… 27 , 37 , 38 Examples of such immune-suppressive loops include activation of PD-1 expression on immune cells, activation of PD-L1 expression on tumor cells through direct EGFR signaling and indirect interferon/STAT-1 pathway stimulation, and the intra-tumoral increase in the regulatory T (Treg) cells expressing CTLA-4 or PD-L1, known as one of the most immune-suppressive mechanisms. 29 , 46 – 48 Cetuximab is also known for its immune-stimulatory effects. Activation of both the innate and adaptive immune systems stimulates dendritic cells, macrophages, and other immune cells, which leads to the recruitment and priming of effector T cells in the TME.…”

“…Studies have shown that the advanced R/M HNSCC tumors are dominated by an immune-suppressive TME with increased Tregs, immune-inhibitory M2 macrophages, myeloid-derived suppressive cells, and immune-inhibitory cytokines and growth factors or by TME with low immune infiltrate referred to as a ‘cold immune phenotype’. 47 – 51 Patients with ‘hot’ TME, with high levels of CD8 T cells and NK cells, have improved response to ICIs and improved prognosis independent of HPV status. 53 , 54 Substantial research efforts have explored strategies to capitalize upon a ‘hot immune phenotype’ and to convert their ‘cold’ and immune-suppressive counterparts.…”

“…The addition of cetuximab improved the overall response rate and 1-year OS in HPV-negative patients (15% versus 46%, p < 0.001 and 36 versus 59%, p < 0.001) but not in HPV-positive patients (17% versus 18%, p = 0.686 and 40% versus 55%, p = 0.252). 48 Motivated by these results, more clinical trials were initiated to evaluate the efficacy of ICI concurrent with cetuximab in R/M HNSCC ( Table 1 ).…”

Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives

“…Two major Phase 3 trials found cetuximab to be inferior to standard cisplatin treatment in combination with radiotherapy for HPV + OPSCC [ 185 , 186 ]. A recent meta-analysis further revealed that the combination of cetuximab and a PD-1 inhibitor improved the OS rate of HPV − OPSCC only compared to PD-1 inhibitor monotherapy, while patients with HPV + OPSCC did not experience the same benefit [ 187 ]. Another Phase 3 trial investigated adding panitumumab, another anti-EGFR monoclonal antibody, to chemotherapy and found improved OS only in HPV − OPSCC [ 188 ].…”

Rationale for Cotargeting Hepatocyte Growth Factor and Epidermal Growth Factor Receptor in Recurrent/Metastatic Head and Neck Cancer

“…Another potentially promising investigation could be combining ficlatuzumab, cetuximab, and PD-1 ICB, given the clinical synergy recently described between PD-1 inhibitor nivolumab and cetuximab in R/M HPV − HNSCC. 38,39 It may also be interesting to test an EGFR-MET–bispecific antibody such as amivantamab as described in patients with lung cancer in a phase I clinical trial. 40 Finally, RNA expression and/or proteomic analyses of HNSCC from patients or in experimental preclinical models may inform changes in pathways induced by this combination and therefore may identify additional targets of interest—the paradigm of personalized medicine.…”