Immunotherapy in locally advanced HNSCC: is there still room for new agents?

The treatment landscape for locally advanced head and neck squamous cell carcinoma (LA HNSCC) has changed significantly. In June 2025, the FDA approved MSD’s Keytruda (pembrolizumab) for resectable LA HNSCC patients with PD-L1 Combined Positive Score (CPS) 1 or higher, supported by KEYNOTE-689 data. The approval covers neoadjuvant monotherapy followed by adjuvant treatment in combination with radiotherapy with or without cisplatin and then as a single agent. Separately, the GORTEC-sponsored NIVOPOSTOP trial demonstrated meaningful results with adjuvant Opdivo (nivolumab), though whether BMS will seek regulatory approval remains to be confirmed. Both trials represent important progress for a sizeable patient population: in 2024, over 63,000 patients were diagnosed with LA HNSCC across the US, France, Germany, Italy, Spain, and the UK. Yet for agents seeking to enter this space, the opportunity remains compelling.

Patients managed non-surgically represent the largest segment outside the current immuno-oncology (IO) approach. According to GlobalData’s high-prescriber survey, approximately 40% of LA HNSCC patients receive definitive chemoradiotherapy without surgery, as clinicians favour organ-preserving approaches for laryngeal, oropharyngeal and hypopharyngeal cancers while oral cavity tumours are mainly treated surgically.

Both KEYNOTE-689 and NIVOPOSTOP were designed around the surgical pathway, leaving this cohort entirely outside their scope and making it a compelling target for therapeutic development aimed at reducing recurrence.

Older patients and those with poor performance status represent another significant group. Patients aged 65 or older currently account for approximately 39% of HNSCC patients and will represent 44% of the population by 2034, according to GlobalData’s ‘Head and Neck Squamous Cell Carcinoma: Eight-Market Drug Forecast and Market Analysis 2024–34‘ (GDHCHT669). Yet, subgroup analysis from KEYNOTE-689 suggested attenuated benefit in patients over 65, and patients with poor performance status remain underrepresented in clinical trials (PMC12776188).

KEYNOTE-689 enrolled relatively few patients with hypopharynx and p16-negative and p16-positive oropharynx, and did not demonstrate benefit in the hypopharyngeal subgroup, where the Event-free survival (EFS) hazard ratio (HR) was 2.28 (95% confidence interval [CI]: 0.79, 6.56). National Comprehensive Cancer Network (NCCN) guidelines do not recommend pembrolizumab for human papillomavirus (HPV)-positive oropharyngeal disease, and a key opinion leader interviewed by GlobalData estimated that pembrolizumab will be offered to around 30% of LA HNSCC patients overall, with the evidence base applying primarily to oral cavity tumours.

Patients with PD-L1 CPS less than 1 were largely excluded from KEYNOTE-689 and are ineligible for pembrolizumab. However, they accounted for approximately 14% of the NIVOPOSTOP population and would remain eligible for nivolumab if approved.

Surgical urgency represents a smaller segment. Patients with borderline resectable or highly symptomatic tumours require immediate resection and may not be suitable candidates for neoadjuvant strategies. In KEYNOTE-689, delays to surgery occurred in 12% of patients in the neoadjuvant IO arm, compared with 3.3% in the standard-of-care arm. Stage IVb patients were also excluded from KEYNOTE-689.

A combination opportunity remains. Keytruda has reduced distant recurrence risk while nivolumab has reduced locoregional control. Since locoregional progression is the primary driver of morbidity and mortality in HNSCC, even in patients who go on to develop distant metastases, a local agent added to a perioperative pembrolizumab backbone could specifically target the residual locoregional risk that IO alone does not fully resolve. Novel agents may also complement IO as part of a cisplatin-sparing strategy.

Taken together, the IO trials in LA HNSCC have moved the field forward, validating the perioperative approach for the first time. But for the substantial share of patients outside the current IO pathway, the opportunity remains wide open.