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ICI HNSCC
My Thoughts on IO in HNSCC Today

Released: September 12, 2023

Barbara Burtness
Barbara Burtness, MD
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Key Takeaways
  • Pembrolizumab monotherapy or in combination with platinum-based chemotherapy is recommended as front-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma and tumor combined positive score ≥1 based on findings from the KEYNOTE-048 trial.
  • Trials evaluating continuing ICI therapy in patients who progress after previous ICI therapy are ongoing.

Analysis of transcriptomic data in head and neck squamous cell carcinoma (HNSCC) demonstrated that whether the cancer is human papilloma virus (HPV) negative, or HPV associated, there is evidence for infiltration of T cells and other immune cells, along with CD8‑positive T cells and regulatory T cells (Tregs). The degree of Treg and NK infiltration appeared to be associated with outcomes. These findings provide context for the study of immune checkpoint inhibitors (ICIs) in HNSCC. 

ICIs Early in the Course for Recurrent/Metastatic Disease
The PD-1 inhibitors nivolumab and pembrolizumab are approved as single agents in patients with recurrent or metastatic (R/M) HNSCC with disease progression on or after platinum-containing chemotherapy. There was clear interest to see how the PD-1 inhibitors could be utilized earlier in the course for people with R/M disease and whether their inclusion would lead to improved survival. Immunotherapy in patients with R/M HNSCC who had not received prior systemic therapy has been evaluated in recent trials, with additional study of the relationship between PD‑L1 expression level and outcomes. When my team and I designed KEYNOTE-048, we took 2 approaches. The first was recognizing that benefit from pembrolizumab may have a relationship with the degree of PD‑L1 expression, so a PD‑L1 biomarker‑driven approach was added to the analysis. The second was to evaluate pembrolizumab together with the chemotherapy backbone, so this trial had 3 arms: pembrolizumab monotherapy, pembrolizumab-chemotherapy, and cetuximab-chemotherapy representing the control arm. Pembrolizumab monotherapy was noninferior to cetuximab-chemotherapy in overall survival (OS) at 45 months in the entire population. For those patients with any tumor PD‑L1 expression, whether combined positive score (CPS) ≥1 or ≥20, pembrolizumab monotherapy was superior to cetuximab-chemotherapy in OS. Pembrolizumab is now approved as a single agent for first-line treatment of patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 CPS ≥1. With pembrolizumab-chemotherapy compared to cetuximab-chemotherapy, OS was superior in the entire population and all PD-L1 expressing subgroups. Among the patients with CPS ≥20, 4‑year survival was over 25%, which has previously not been described in head and neck cancer. Pembrolizumab is now approved in combination with platinum and 5-fluorouracil for first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC.

The combination of nivolumab and ipilimumab was compared to cetuximab-chemotherapy in the phase III CheckMate-651 trial. In this study there was clear activity for nivolumab and ipilimumab, but no evidence of a benefit over standard of care in terms of OS. The median OS in the standard cetuximab-chemotherapy arm was longer than expected, which makes this study a little harder to interpret. In the patients who responded, there was a remarkable finding of a 16.6‑month median duration of response, which was consistent with that in KEYNOTE‑048 for pembrolizumab responders. 

The PD‑L1 inhibitor durvalumab, either given alone or combined with tremelimumab (a CTLA4 inhibitor) were compared to cetuximab-chemotherapy in the KESTREL trial. No significant difference in OS was found in all randomized patients or in those with PD‑L1 high expression (PD-L1 tumor cell ≥50% or immune cells ≥25%). In contrast to some other diseases, there may be a preference for PD-1 inhibitors in HNSCC.

Options for Patients Who Experience Disease Progression After Platinum-Based Chemotherapy Plus Pembrolizumab
In this setting, there are ongoing trials now looking at continuing ICIs in combination with other agents, like the LEAP‑009 study. There was a report from the original CheckMate 141 trial that looked at a small subset of patients who continued nivolumab beyond asymptomatic progression, but that was in people who had tolerated therapy well. Our ECOG EA3202 trial in patients with recurrent HNSCC and disease progression after prior therapy with an ICI also has an arm where patients would continue atezolizumab, and bevacizumab after they had progressed on pembrolizumab. This arm will be compared with chemotherapy-cetuximab or chemotherapy-bevacizumab. This is another intriguing question, but we do not have clear evidence yet supporting a defined standard of care in this disease setting.

Your Thoughts?
What are your thoughts and questions on current management approaches with immunotherapy for patients with HNSCC? Answer the polling question and leave a comment to join the discussion.

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Is the KEYNOTE-048 combination regimen of pembrolizumab with platinum-based chemotherapy your most selected regimen for patients with unresectable R/M HNSCC who require initial therapy?  

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