Key Ideas

Head and neck cancer treatment has historically advanced roughly once a decade, but two meaningful updates are arriving together this year: perioperative pembrolizumab is now FDA-approved for resectable, locally advanced disease, and a new EGFR-MET bispecific antibody shows substantial activity in the second-line recurrent or metastatic setting where treatment options have been limited.

A Field With Major Advances Arriving in Clusters

Head and neck cancer has seen major treatment advances roughly once a decade: cetuximab in 2006, checkpoint inhibitors in 2016, and now, in 2026, two more genuine advances have been made. The first is FDA approval of perioperative pembrolizumab for surgically resectable disease (June 2025). The second, not yet approved but showing striking second-line activity, is amivantamab, an EGFR-MET bispecific antibody, in recurrent or metastatic, HPV-negative disease.

Perioperative Pembrolizumab for Resectable Disease

The phase 3 KEYNOTE-689 trial enrolled 714 patients with resectable, stage III or IVA locally advanced head and neck squamous cell carcinoma, including laryngeal, hypopharyngeal, oral cavity, and both HPV-negative and higher-stage HPV-positive oropharyngeal disease. Patients were randomized to perioperative pembrolizumab, two cycles of neoadjuvant therapy followed by surgery, then adjuvant pembrolizumab with radiation with or without chemotherapy depending on risk features, and additional adjuvant pembrolizumab, versus surgery followed by standard adjuvant therapy alone. Event-free survival significantly favored the pembrolizumab arm (hazard ratio 0.73), and overall survival was also improved, with median event-free survival of 51.8 months versus 30.4 months with standard of care. This led to FDA approval in June 2025 for patients with a PD-L1 combined positive score of 1 or higher, the first new approval for this population in over two decades.

Oral cavity cancers deserve a specific note: these tumors are treated with surgery first as a matter of principle, since the anatomy of the tongue and oral cavity makes concurrent chemoradiation impractical and poorly tolerated, unlike oropharyngeal or laryngeal primaries where concurrent chemoradiation is a viable alternative to surgery.

Two important caveats temper enthusiasm for this regimen. First, major pathological response after neoadjuvant pembrolizumab alone was uncommon, only about 10% of patients, meaning most tumors do not visibly shrink even when the overall trial benefit is real; tumors can still progress during the neoadjuvant window. In the trial, roughly 30 patients in the pembrolizumab arm stopped treatment during the neoadjuvant phase, about half of them for progressive disease, though most still proceeded to surgery; these were not counted as protocol-defined events since progression during the neoadjuvant window was not prespecified as one. Second, immune-related adverse events were more frequent with pembrolizumab, and the regimen is not appropriate for every resectable patient. Multidisciplinary review before initiating neoadjuvant pembrolizumab is essential, with particular caution for borderline resectable tumors, since a five-week course of neoadjuvant therapy carries real risk of the tumor becoming unresectable if it progresses. Close monitoring and re-evaluation by the original treating surgeon prior to the second surgical opinion is a practical safeguard.

An Adjuvant Alternative for Patients Already Headed to Surgery

For patients proceeding directly to surgery, the phase 3 Gortec 2018-01 NIVOPOSTOP trial offers an alternative model, adding nivolumab to standard adjuvant chemoradiation in patients with high-risk pathological features after resection. Three-year disease-free survival improved from 52.5% with chemoradiation alone to 63.1% with the addition of nivolumab (hazard ratio 0.76). Overall survival trended favorably but had not reached statistical maturity at the time of the primary analysis. A post-hoc blinded independent review found no difference in disease-free survival between arms, which drew some criticism; however, reconciliation of discordant imaging assessments against biopsy results, needed because radiation-related inflammatory changes are notoriously difficult to distinguish from recurrent or residual disease on imaging alone, largely resolved this discrepancy in nivolumab's favor. Notably, the regulatory approval was not sought, so nivolumab in this specific adjuvant indication remains without an FDA label despite the positive trial result. It remains a reasonable option to discuss in selected patients who have already proceeded to surgery.

Emerging data also suggest that combining chemotherapy with immunotherapy in the neoadjuvant setting, rather than immunotherapy alone, may substantially increase pathological complete response rates; this is not yet standard of care, but may be worth considering for patients where the surgical or radiation team is trying to reduce planned treatment volume or improve resectability of a borderline tumor.

A New Option for Second-Line Recurrent or Metastatic, HPV-Negative Disease

EGFR is overexpressed in most HPV-negative head and neck cancers, and MET upregulation is a recognized compensatory resistance mechanism to EGFR-targeted therapy, providing rationale for a dual-targeting approach. Amivantamab, an EGFR-MET bispecific antibody already familiar from lung cancer, was evaluated as monotherapy in the second-line setting for HPV-negative recurrent or metastatic head and neck cancer after progression on platinum-based chemotherapy and a checkpoint inhibitor, in cohort 1 of the phase 1b/2 OrigAMI-4 trial. Among 102 patients, the blinded independent review committee-assessed objective response rate was 42%, with 56% of responses lasting six months or longer, a substantial improvement over the roughly 21% to 24% response rates historically reported with single-agent chemotherapy or cetuximab in this setting. The toxicity profile is consistent with known EGFR and MET-related effects. Amivantamab is not yet FDA-approved in this indication; an FDA decision is anticipated by the end of this year, and NCCN guideline inclusion is expected in near future. Another bispecific antibody, petosemtamab, which targets EGFR and LGR5 is being investigated in a phase 3 randomized study in 2<sup>nd</sup> line setting in both HPV positive and negative recurrent/metastatic head and neck cancer, with anticipated release of the result in the next year. 

Practical Considerations

For locally advanced head and neck cancer patients being managed surgically, starting with immunotherapy is a genuine option but is not appropriate for every patient; the tradeoff between potential benefit and the risk of losing a window for optimal surgery requires careful multidisciplinary evaluation. For recurrent or metastatic disease after progression on chemotherapy and immunotherapy, antibody-drug conjugates and bispecific antibodies such as amivantamab or petosemtamab should be considered once available. The field is moving quickly, with ongoing trials combining chemotherapy and EGFR-targeted agents in the surgically unresectable, locally advanced setting, adjuvant trials in the unresectable population, and multiple additional EGFR-targeting agents and T-cell engagers under investigation for recurrent and metastatic disease.

For Patients

Head and neck cancer treatment has historically changed very slowly, with major advances arriving roughly once every decade, so it is notable that two meaningful updates are emerging together this year. For patients whose tumor can be surgically removed, a checkpoint immunotherapy drug called pembrolizumab, given both before and after surgery, was recently approved and has been shown to improve how long patients live cancer-free after treatment. It is not the right choice for every patient, however, and it requires close coordination between the surgical and oncology teams, since delaying surgery to give this treatment carries some risk if the tumor does not respond well. For patients whose cancer has returned or spread despite prior chemotherapy and immunotherapy, particularly those without an HPV-related cancer, a new type of antibody drug called amivantamab has shown promising results in shrinking tumors and is currently being reviewed by the FDA for approval. If you or a loved one is facing a decision about head and neck cancer treatment, particularly around the timing of surgery relative to other therapies, it is worth having a detailed conversation with a multidisciplinary team that includes both surgical and medical oncology input.

Key Takeaways

  • Perioperative pembrolizumab (KEYNOTE-689) is FDA-approved for resectable, locally advanced head and neck squamous cell carcinoma with PD-L1 CPS ≥1, improving both event-free and overall survival, but requires careful multidisciplinary selection given real risk of progression during the neoadjuvant window.

  • Adjuvant nivolumab added to standard chemoradiation (NIVOPOSTOP) improved 3-year disease-free survival from 52.5% to 63.1% in high-risk resected patients, though it currently lacks an FDA label in this indication.

  • Amivantamab, an EGFR-MET bispecific antibody, achieved a 42% objective response rate with 56% of responses lasting six months or longer in second-line, HPV-negative recurrent or metastatic disease (OrigAMI-4); FDA decision expected by year's end.

  • Oral cavity cancers should be treated with surgery first as a matter of anatomic principle, unlike oropharyngeal or laryngeal primaries.

  • Combining chemotherapy with immunotherapy in the neoadjuvant setting may improve pathological response rates but is not yet standard of care.

References

  1. Uppaluri R, et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer (KEYNOTE-689). N Engl J Med. 2025; FDA approval June 12, 2025.

  2. Bourhis J, et al. NIVOPOSTOP (GORTEC 2018-01): a phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in resected head and neck squamous cell carcinoma at high risk of relapse. Presented at ASCO 2025.

  3. Harrington KJ, Ji D, Calderon B, et al. Amivantamab in recurrent/metastatic HNSCC after checkpoint inhibitor and chemotherapy: pivotal results from the phase Ib/II OrigAMI-4 study. J Clin Oncol. 2026.