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Immunotherapy for HNSCC
Experts Discuss the Use of Immunotherapy in HNSCC

Released: July 16, 2025

Expiration: January 15, 2026

Barbara Burtness
Barbara Burtness, MD
Robert Haddad
Robert Haddad, MD
Cristina Rodriguez
Cristina Rodriguez, MD
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Key Takeaways
  • Immune checkpoint inhibitor–based combinations form the first-line standard of care for patients with recurrent/metastatic non-nasopharyngeal and nasopharyngeal HNSCC.
  • Immune checkpoint inhibitors are being integrated into the curative-intent setting for locally advanced HNSCC, with recent trials supporting improved patient survival.

Immunotherapy has transformed the treatment landscape for head and neck squamous cell carcinoma (HNSCC), with ongoing research expanding its role across the disease continuum. In this commentary, expert faculty explore current recommendations and evolving strategies in the use of immune checkpoint inhibitor (ICI) therapy for HNSCC.
 
What are current recommendations regarding systemic therapy for advanced non-nasopharyngeal HNSCC?
Barbara Burtness, MD: 
Current national guidelines state that for recurrent unresectable or metastatic HNSCC not amenable to curative surgery or radiation, first-line therapy should be pembrolizumab/platinum-based therapy . Pembrolizumab monotherapy is also an option for tumors that express PD-L1 with a combined positive score (CPS) ≥1. Other first-line options include combination regimens such as cetuximab/platinum-based chemotherapy, which is often reserved for patients who are PD-L1 negative.

In previously treated patients, the choices are shaped by what agents the patient has received in the first line. If the patient has not received prior immunotherapy, nivolumab or pembrolizumab is recommended. Additional options for later lines of therapy are cisplatin/cetuximab; platinum and a taxane; cisplatin with 5-FU; platinum/taxane/cetuximab; or pembrolizumab/platinum and a taxane.

What is the current state of neoadjuvant and adjuvant immunotherapy for HNSCC?
Robert Haddad, MD:
With the success of immunotherapy approaches in advanced HNSCC, there was interest in moving immunotherapy into earlier settings. Early phase trials suggested that adjuvant and neoadjuvant therapy for locally advanced HNSCC are safe and active, leading to the initiation of phase III trials, 2 of which were recently shown to be positive.

The results from KEYNOTE-689 were recently presented at the 2025 American Association for Cancer Research annual meeting. This trial randomized 714 patients with newly diagnosed resectable locally advanced HNSCC. The experimental arm received 2 cycles of neoadjuvant pembrolizumab followed by surgery followed by radiation with or without cisplatin (based on risk) with 15 cycles of adjuvant pembrolizumab. The control arm received standard of care (SoC) treatment: surgery followed by risk-based radiation with or without cisplatin. The primary endpoint was event-free survival (EFS), which was significantly improved in the pembrolizumab arm (median EFS: 59.7 months in the pembrolizumab arm vs 26.9 months in the SoC arm) among patients with a CPS ≥10. Moreover, the rate of distant progressive disease was approximately 6% in the pembrolizumab arm and almost 17% in the SoC arm, suggesting that neoadjuvant immunotherapy also impacts the rate of distant metastasis. Among patients with a CPS ≥1—representing nearly 96% of all patients enrolled—and among the total population, similar trends were observed: EFS differed significantly between the pembrolizumab and SoC arms. Pembrolizumab was recently approved by the FDA for adults with resectable locally advanced HNSCC whose tumors express PD-L1 as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin after surgery, and then as a single agent.

The results from the phase III NIVOPOSTOP were presented at the 2025 American Society of Clinical Oncology annual meeting. In this trial, 680 patients with resected locally advanced HNSCC who were free of disease and at high risk for relapse were randomized to either adjuvant nivolumab plus SoC cisplatin and radiation or SoC cisplatin and radiation alone. The primary endpoint of the study was disease-free survival (DFS). At 3 years, the DFS with the adjuvant nivolumab plus SoC vs SoC alone group was 63.1% vs 52.5% (HR 0.76, P = .034). Of note, this finding was observed in PD-L1 all comers.

If a patient received neoadjuvant or adjuvant immunotherapy and experienced recurrence, what would you recommend as first-line therapy in the advanced disease setting?
Robert Haddad, MD:
This is a great question. I expect that the results of KEYNOTE-689 will profoundly impact first-line treatment in the recurrent metastatic setting. Assuming a patient does not have a curative option, I think the question becomes ‘Should this patient be rechallenged with immunotherapy?’ This depends in part on if the patient experienced recurrence immediately after stopping treatment. I have rechallenged patients with recurrent/metastatic disease who received pembrolizumab as part of the phase III KEYNOTE-048 trial and found that the outcomes were not satisfactory; rechallenge did not result in the profound response initially observed. A number of ongoing clinical trials are examining the addition of a second agent to immunotherapy rechallenge. I believe it is reasonable to rechallenge patients with an ICI, but it should likely be in combination with another drug.

Barbara Burtness, MD:
I would want to know how long the patient was immuno-oncology free. In patients who have been off immunotherapy for some time, we can see nice responses. I would also like to note that in KEYNOTE-048, patients who progressed on single-agent pembrolizumab and their second-line therapy (primarily chemotherapy and cetuximab) had longer time to second progression-free survival [LD1.1](PFS) than patients who had not received pembrolizumab. Expanding the population of anti-tumor immune cells already present allows them to persist over time, which likely contributes to the long tails on survival curves seen in immuno-oncology trials. I would anticipate that prior immunotherapy exposure would lead to a higher response rate and longer duration of response.

What are current recommendations regarding systemic therapy for nasopharyngeal HNSCC?
Cristina Rodriguez, MD:
The NCCN recommendation for first-line therapy for recurrent, unresectable, oligometastatic, or metastatic nasopharyngeal cancer (NPC) with no surgery or radiotherapy option is cisplatin/gemcitabine with toripalimab
A landmark study that changed the SoC for NPC was the randomized phase III JUPITER-02 trial in first-line recurrent/metastatic NPC. The PD-1 inhibitor toripalimab was added to gemcitabine and cisplatin for up to 6 cycles and then used as maintenance. The control arm received placebo plus gemcitabine and cisplatin. The study met its primary endpoint, showing a significant improvement in PFS for patients who received the PD-1 inhibitor plus chemotherapy combination, with an impressive hazard ratio of 0.52, and was actually one of the first phase III trials to show a statistically significant overall survival benefit based on the prespecified analysis. In October of 2023, the FDA granted approval for toripalimab in combination with cisplatin and gemcitabine as first-line treatment for adults with metastatic or recurrent locally advanced NPC.

Recently, the randomized phase III AK105-304 trial reported results in patients with recurrent or metastatic NPC treated with chemoimmunotherapy with penpulimab, a PD-1 monoclonal antibody, vs placebo plus chemotherapy in the first-line setting. This was also a positive study, with an impressive hazard ratio favoring chemoimmunotherapy in terms of PFS (0.45). In April of 2025, penpulimab plus gemcitabine and cisplatin or carboplatin was FDA approved for the first-line treatment of adults with recurrent/metastatic nonkeratinizing nasopharyngeal carcinoma. This regimen is currently listed as an “other recommended regimen” by the NCCN in the first-line setting.

What are your thoughts on moving ICIs to the curative-intent setting for NPC?
Cristina Rodriguez, MD:
There is significant interest in incorporating immune checkpoint inhibitors into the curative intent setting, where standard therapy for high-risk disease involves gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy. In the phase III CONTINUUM trial, patients with high-risk locally advanced NPC were randomized to either standard therapy or standard therapy plus sintilimab, a PD-1 antibody. The addition of sintilimab improved DFS, but longer follow-up is necessary to determine whether this strategy can be considered the new SoC for this population. A randomized phase II trial of toripalimab plus chemoradiation vs placebo plus chemoradiation in patients with high-risk locally advanced NPC showed 2-year PFS rates of 92% vs 74% favoring the toripalimab group. The single-arm phase II NEOSPACE trial of neoadjuvant pembrolizumab plus gemcitabine/cisplatin followed by concurrent pembrolizumab/cisplatin/radiation and maintenance pembrolizumab also suggested survival benefits associated with the addition of pembrolizumab, with a 2-year PFS rate of 70%. The results of these trials are encouraging, and there is much to be expected in the near future regarding this management strategy.

Your Thoughts
What is your experience with immunotherapy for head and neck cancers? Have you recommended immunotherapy in the neoadjuvant or adjuvant settings for your patients? Please leave a comment and answer the question on this page.

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Based on recent data and approvals, do you plan to use ICI therapy in the neoadjuvant and/or adjuvant settings for patients with resectable locally advanced HNSCC?

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