Recurrent / Metastatic HNSCC: Systemic Therapy

Recurrent / Metastatic HNSCC: overview

This algorithm covers systemic therapy for recurrent or metastatic squamous cell carcinoma of the head and neck, with first-line choices organized by PD-L1 combined positive score (CPS). For CPS 1 or higher, the options are pembrolizumab monotherapy or pembrolizumab plus platinum and 5-FU, both supported by KEYNOTE-048, which showed improved overall survival versus the EXTREME regimen (combination in the total population, monotherapy in CPS-positive disease). For CPS below 1, the chart favors pembrolizumab plus platinum and 5-FU (KEYNOTE-048), with platinum and 5-FU plus cetuximab (EXTREME) as the alternative.

In subsequent lines, nivolumab is the immunotherapy option (CheckMate 141), and single-agent docetaxel, methotrexate, or cetuximab are cytotoxic or targeted alternatives. A biomarker-selected branch lists ipilimumab plus nivolumab for CPS 20 or higher (CheckMate 651, which did not formally meet its primary overall survival endpoint versus EXTREME), erdafitinib for FGFR mutation or fusion, and trastuzumab deruxtecan for HER2 IHC 3+ tumors, based on DESTINY-PanTumor02, where responses were enriched in HER2 3+ disease across tumor types.

Trials behind this algorithm

• KEYNOTE-048 Burtness B et al, Lancet, 2019; PMID: 31679945
• EXTREME trial, Cis/5FU +/- Cetuximab Vermorken J et al, NEJM, 2008, PMID: 18784101
• CHECKMATE 141, nivo vs chemo in 2nd line Ferris, R. et al, NEJM, 2016, PMID 27718784
• CheckMate 651 Haddad RI et al, JCO, 2023; PMID: 36473143
• DESTINY-PanTumor02 Meric-Bernstam F et al., JCO 2024, PMID: 37870536