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Navigating the Evolving Head and Neck Cancer Treatment Continuum: Expert Answers to Common Clinical Questions

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Released: September 02, 2026

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Treatment of head and neck squamous cell carcinoma (HNSCC) continues to evolve across curative-intent and recurrent or metastatic settings, leading to new questions on how emerging evidence should be incorporated into clinical practice. In this changing therapeutic landscape, experts examine the clinical implications of HPV-associated vs HPV-unrelated disease, integration of perioperative immunotherapy together with established multimodality care, treatment selection in recurrent or metastatic HNSCC, and the emerging role of novel EGFR-directed therapies. In addition, the experts provide their insights on toxicity management, supportive care, and multidisciplinary strategies to preserve function and quality of life throughout the treatment continuum.

Barbara Burtness
Barbara Burtness, MD
Robert Haddad
Robert Haddad, MD
Ari J. Rosenberg
Ari J. Rosenberg, MD
HNSCC Treatment Q&A

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Key Takeaways
  • HPV-associated and HPV-unrelated head and neck cancers are biologically and clinically distinct, with different prognoses, treatment strategies, and research priorities.
  • Perioperative immunotherapy is part of multimodality care, with surgery and pathologic risk-adapted postoperative therapy remaining essential.
  • Emerging EGFR bispecific antibodies cotarget pathways such as LGR5, TGF-β, and MET to potentially overcome adaptive resistance, with multiple agents advancing through phase III trials.

Systemic treatment strategies for head and neck squamous cell carcinoma (HNSCC) are evolving across both curative-intent and recurrent or metastatic settings. New perioperative approaches are being integrated with established multimodality care, while emerging targeted agents may expand options after progression in recurrent or metastatic disease. In this expert Q&A-based commentary, the authors discuss how they interpret and apply these therapeutic developments while preserving function, anticipating toxicity, and maintaining multidisciplinary coordination.

Why must HPV-associated and HPV-unrelated head and neck cancers be viewed differently?

Ari Rosenberg, MD:
I think it is important to emphasize that these are distinct biologic and clinical entities that impact management decisions. Human papillomavirus (HPV)–associated disease is driven by the viral oncoproteins E6 and E7, which disrupt tumor suppressor pathways involving p53 and Rb. These tumors are often characterized by wild-type TP53, APOBEC mutational signatures, and alterations such as PIK3CA mutations. Clinically, many patients lack traditional carcinogen exposure, and outcomes are generally more favorable in HPV-associated oropharyngeal cancer.

HPV-unrelated disease is more often associated with carcinogen-driven accumulation of somatic mutations, including TP53 mutations and dysregulation of EGFR and MET. As of now, these patients continue to experience more modest survival outcomes, particularly in the recurrent or metastatic setting.

This distinction influences prognosis and shapes the questions asked in clinical trials. In HPV-associated disease, the goal is often to maintain cure while reducing long-term toxicity. In HPV-unrelated disease, there remains an urgent need to improve survival through treatment intensification and biologically informed therapies.

What are your thoughts about perioperative pembrolizumab and how it has changed in resectable, locally advanced disease?

Robert Haddad, MD: KEYNOTE-689 established that perioperative immunotherapy can improve outcomes when it is incorporated into a complete curative-intent strategy. In the pembrolizumab arm, patients received pembrolizumab before surgery and then continued pembrolizumab with risk-adapted postoperative treatment. Patients with high-risk pathologic features, such as extranodal extension or positive margins, still received chemoradiotherapy. Patients without those features received postoperative radiation according to their risk.

The key point is that pembrolizumab does not replace surgery, radiation, or cisplatin when those treatments are indicated; it is integrated with them. The event-free survival benefit with the addition of perioperative pembrolizumab was clinically meaningful in patients with a tumor PD-L1 combined positive score (CPS) of at least 1, including those with a CPS ≥10. I also consider event-free survival an appropriate endpoint in this disease.

Can response to neoadjuvant therapy be used to reduce the extent of surgery?

Robert Haddad, MD: This is one of the most exciting questions in the field, but it has not yet been answered for routine practice. KEYNOTE-689 did not evaluate reducing the planned extent of surgery in response to neoadjuvant pembrolizumab. The trial also was not designed to evaluate response-adapted surgery or de-escalated postoperative radiotherapy. Smaller studies of neoadjuvant chemoimmunotherapy and bispecific antibody–based combinations have reported high pathologic response rates. When a tumor that initially appeared to require a highly morbid operation becomes dramatically smaller, it is natural to ask whether the surgical approach should change. This is exactly the type of question that should be evaluated in clinical trials. However, at this time, outside of a clinical trial,  radiographic shrinkage or even a strong pathologic response should not be assumed to permit less extensive surgery or postoperative therapy without compromising cure.

Which patients with HPV-associated disease should receive neoadjuvant therapy?

Robert Haddad, MD: Outside a clinical trial, we generally do not use neoadjuvant therapy routinely for HPV-positive disease. Many of these patients have favorable outcomes, and much of the research focuses on de-escalation, less chemotherapy, less radiation, or surgery alone. However, an induction strategy may be considered for a smaller subset of patients with very advanced, symptomatic disease. These decisions are individualized and should not obscure the fact that HPV-associated cancer is not always low risk.

Barbara Burtness, MD: Patients with T4 disease, high nodal burden, extranodal extension, or substantial smoking exposure may remain at higher risk. Neoadjuvant PD-1 inhibitor monotherapy has produced modest pathologic response rates in HPV-associated disease. We need to better understand the mechanisms underlying this limited response. Immune silencing may contribute. Strategies involving vaccines, demethylating agents, and other approaches remain under investigation.

How do you approach first-line recurrent or metastatic disease today?

Barbara Burtness, MD: Treatment selection remains guided by PD-L1 expression, disease burden, symptoms, performance status, and the urgency of tumor shrinkage. For patients with a CPS of at least 1, pembrolizumab monotherapy may be appropriate, particularly when rapid tumor shrinkage is not required. For patients with a CPS below 1, pembrolizumab monotherapy should not be offered because KEYNOTE-048 did not demonstrate a survival benefit in this subgroup.

Pembrolizumab plus platinum and fluorouracil chemotherapy remains an important option across PD-L1 subgroups, particularly for patients with pain, a threatened airway, swallowing difficulty, or other symptoms requiring a prompt response. After up to 6 cycles of platinum and fluorouracil chemotherapy, patients without disease progression generally stop chemotherapy and continue pembrolizumab maintenance. Chemotherapy alone would usually be considered only if pembrolizumab must be discontinued because of toxicity.

Where might emerging EGFR-directed bispecific antibodies fit?

Barbara Burtness, MD: These agents offer genuine promise, particularly for HPV-unrelated disease. Resistance to EGFR inhibition may involve partial epithelial-to-mesenchymal transition, alternative receptor signaling, stem-cell populations, and an immunosuppressive tumor microenvironment. EGFR-directed dual-target strategies have paired EGFR with MET, LGR5, TGF-β, or HER3 targeting. Current EGFR-directed dual-target approaches under clinical evaluation in HNSCC pair EGFR with MET, LGR5, or TGF-β.

Amivantamab, which targets EGFR and MET, demonstrated encouraging activity in heavily pretreated patients with HPV-unrelated recurrent or metastatic HNSCC after progression on platinum-based chemotherapy and PD-(L)1 inhibition. Several EGFR-directed bispecific antibodies are now being evaluated in phase III studies, including petosemtamab in the first-line LiGeR-HN1 trial (NCT06525220) and previously treated LiGeR-HN2 trial (NCT06496178), ficerafusp alfa in FORTIFI-HN01 (NCT06788990), and amivantamab in the first-line OrigAMI-5 trial (NCT07276399)

These data are encouraging, but overall survival remains the gold standard. We also do not yet know the optimal sequence for these therapies or whether progression on 1 EGFR bispecific antibody will confer cross-resistance to another.

Ari Rosenberg, MD: Biomarkers such as MET expression are of considerable interest, but they remain investigational. At present, we need phase III results and experimental evidence before we can define a biomarker-driven sequencing strategy.

What supportive care is needed with EGFR/MET-directed treatment with amivantamab?

Barbara Burtness, MD: I favor a proactive, early-intervention approach. These therapies may cause dermatologic, oral, metabolic, nutritional, and fluid-related toxicities. We should assess the skin, oral cavity, nutritional status, albumin, peripheral edema, swallowing, pain, and functional status from the start of treatment. When indicated, referrals to dermatology, nutrition, oral medicine, rehabilitation, or speech-language pathology should be made early rather than waiting until the patient experiences functional decline.

Robert Haddad, MD: The same proactive approach applies to immune-related adverse events. Endocrine toxicities can often be managed in oncology clinics, whereas pneumonitis, myocarditis, hepatitis, or colitis may require immunotherapy interruption or discontinuation, corticosteroids, and specialist care. Management should be guided by the affected organ and toxicity grade.

Summary

Robert Haddad, MD: Care for patients with HNSCC is becoming more biologically informed, but successful implementation still depends on multidisciplinary judgment. Perioperative immunotherapy should be integrated with established curative treatments, not substituted for them. In recurrent or metastatic disease, pembrolizumab-based therapy remains a first-line standard of care, while emerging EGFR-directed agents may address an important unmet need after progression on platinum and PD-(L)1 therapy. Across every disease setting, preserving speech, swallowing, nutrition, and quality of life must remain central to the treatment plan.

Your Thoughts
How is your multidisciplinary team incorporating perioperative immunotherapy for your patients with HNSCC? How often do you discuss clinical trials with emerging EGFR-directed therapies with your patients with HPV-negative HNSCC? Please leave a comment or ask the experts a question below.

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