Nivolumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use

Abstract

Purpose: Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy.

Patients and methods: In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety.

Results: In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62-1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35-0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression (<1% or ≥1%). Grade 3-4 treatment-related adverse event rates favored nivolumab versus IC in both subgroups.

Conclusions: Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.

Figure 1.

Immune activity mediated by cetuximab in the SCCHN tumor microenvironment. Binding of cetuximab to EGFR recruits CD8⁺ T cells, which are activated through MHC complex/TCR and B7/CTLA-4 binding. In responders to treatment, cetuximab-mediated activation of NK cells induces dendritic cell maturation via crosstalk to promote antigen presentation and lyse tumor cells through ADCC. However, cetuximab binding also recruits and expands the Treg population in the tumor microenvironment. These Treg cells inhibit cetuximab-mediated cytotoxicity via expression of immune checkpoint molecules such as PD-1, PD-L1, CTLA-4, and TIM-3. Upregulation of these immune checkpoint molecules is associated with the exhausted T-cell phenotype, as seen in nonresponders to cetuximab treatment. Immunosuppressive TGFβ is also expressed on Treg cells as well as accumulating MDSCs, leading to inhibition of cytolytic activity via reduced levels of granzyme B and perforin. ADCC, antibody-dependent cellular cytotoxicity; APC, antigen presenting cell; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; EGFR, epidermal growth factor receptor; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; SCCHN, squamous cell carcinoma of the head and neck; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; Treg, regulatory T cell.

Figure 2.

A, OS in patients with prior cetuximab exposure; B, OS in patients without prior cetuximab exposure; C, Treatment effect on OS by baseline subgroups. NA, not available, minimum follow-up not reached; nivo, nivolumab.

Figure 3.

Changes in the levels of circulating immune cell phenotypes in patients with and without prior cetuximab exposure in the nivolumab arm. A, CD8⁺ effector T cells. CD8⁺ effector T cells were defined as TCRα/β⁺CD8⁺CCR7⁻CD45RA⁺. B, Regulatory T cells. Regulatory T cells were defined as CD4⁺CD25^hiCD127^loFoxP3⁺. Abbreviations: CR, complete response; IC, investigator's choice; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3.

Changes in the levels of circulating immune cell phenotypes in patients with and without prior cetuximab exposure in the nivolumab arm. A, CD8⁺ effector T cells. CD8⁺ effector T cells were defined as TCRα/β⁺CD8⁺CCR7⁻CD45RA⁺. B, Regulatory T cells. Regulatory T cells were defined as CD4⁺CD25^hiCD127^loFoxP3⁺. Abbreviations: CR, complete response; IC, investigator's choice; PD, progressive disease; PR, partial response; SD, stable disease.