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This 5-year update should settle the debate for many of us: in 261 patients receiving postoperative chemoradiation for high-risk head and neck squamous cell carcinoma (SCC), weekly cisplatin (40 mg/m²) stayed noninferior to 3-weekly 100 mg/m², and 5-year overall survival (OS) actually ran numerically higher (71% vs 59%), with less acute toxicity and no meaningful difference in late toxicity. Before anyone reads superiority into that, the 3-weekly arm carried more T4, N2–3, and hypopharyngeal disease, the noninferiority margin was generous, and the cohort was all Japanese, small, and treated before immunotherapy. For our postop patients, weekly cisplatin now looks like a fully defensible standard rather than a fallback for patients who can’t tolerate the bolus dose.

Epidermal growth factor receptor (EGFR) and MET are overexpressed in recurrent/metastatic (R/M) head/neck squamous cell cancer (HNSCC).
Subcutaneous amivantamab administered every 3 weeks in participants with non-human papillomavirus R/M HNSCC after PD-(L)1 inhibitor and platinum-based chemotherapy. prior anti EGFR and HPV positive patients were excluded. In 102 participants, blind independent central review assessed objective response rates (ORRs) was 42% (around 20% for second line chemotherapy or cetuximab) the complete response rate was 15%. At a median follow-up of 11.8 months, median progression-free survival (PFS) and overall survival (OS) were 6.8 months and 12.5 months respectively. A non-chemotherapy option for HPV negative patients with promising outcome. Toxicity can still be an issue with those pts

Combination improved progression-free survival (PFS) 6.2 months vs 2.8 months, hazard ratio (HR) 0.64 but not overall survival (OS) (15 months for combination vs 17.9 months for pembro), no safety concerns. Overall, although the combination demonstrated a clinically meaningful PFS advantage, the absence of an OS benefit limits its impact on standard first-line treatment, where survival remains the key endpoint.

Xevinapant (an inhibitor of apoptosis proteins inhibitor) added to chemoradiotherapy did not improve event-free survival (EFS) or overall survival (OS); in fact, OS was worse in the combination arm.

The KEYNOTE-689 trial evaluated perioperative pembrolizumab + SOC (surgery + adjuvant RT ± cisplatin) in resectable, locally advanced head and neck squamous-cell carcinoma (HNSCC) that is at least 1% PDL1 positive. The addition of pembrolizumab significantly improved 3-year event-free survival (EFS) in all PD-L1 subgroups: CPS≥10 (59.8% vs 45.9%), CPS≥1 (58.2% vs 44.9%), and the total population (57.6% vs 46.4%). Three-year overall survival (OS) also favored pembrolizumab: CPS≥10 (68.2% vs 59.2%), CPS≥1 (69.0% vs 60.2%), and total (68.4% vs 61.1%), though OS was not formally tested at this interim. Toxicities were as expected. Bottom line: perioperative pembro is now a part of the treatment paradigm for locally advanced HNCSCC with PDL1 expression.

Based on these findings, Carbo/Taxol+Pembro is an active regimen in met-HNC and an option for those patients who are not good candidates for 5FU based therapy.

Although immunotherapy did not beat chemotherapy but was non inferior and with more favorable safety.

Pembro with chemotherapy or alone better then cetuximab combination, also improved responses to subsequent therapy.

Phase II/III study of weekly docetaxel+RT vs. RT alone in cis-ineligible patients. This study was done in India, where oral cancers are an epidemic and possibly biologically unique, as most are related to the use of oral tobacco + betel nut products. >70% of patients were stage IVA / IVB, and HPV was only positive in 4% of patients. Still, the survival benefit was sizeable, and the treatment was tolerable. This is a good option for cis-ineligible HPV-neg patients with bulky disease.

Again, further evidence of continued efficacy and tolerability of IO and IO/chemotherapy in SCCHN as compared to EGFR-blockade/chemotherapy. The PD-L1 negative space remains a more difficult scenario, hence new biomarkers are critically important. The long-term response and CR of a percentage of patients are real and intriguing (patient characteristics leading to such response).