xRead - An Update on Immunotherapy in Head and Neck Cancer (November 2025)

Review Clinical Review & Education

Immunotherapy in Head and Neck Squamous Cell Carcinoma

Table 3. Selected Ongoing Clinical Trials a

HPV status

Primary outcome(s)

Trial

Phase Key inclusion criteria

Treatment group(s)

Secondary outcome(s)

eVOLVE-HNSCC 43

PFS and OS in all patients, OS in patients with PD-L1–expressing tumors, safety, patient-reported outcomes, pharmacokinetics, immunogenicity

Both

Volrustomig vs observation

3

Locally advanced, not progressed following definitive CT + RT

PFS in patients with PD-L1– expressing tumors

NIVOPOSTOP 44

Both

Nivolumab + CT + RT vs CT + RT

3

Locally advanced, completed definitive surgical resection, pathologic high-risk features (extracapsular extension or positive margins) completed definitive surgical resection, ≥1 high-risk pathologic feature (extranodal extension or positive margins) Treatment-naive, resectable, locally advanced

DFS

OS, toxic effects

Negative Cisplatin + RT vs docetaxel +

Radiation Therapy Oncology Group 1216 45

2/3 Pathologic stage III/IV,

cetuximab + RT vs atezolizumab + cisplatin + RT

Local-regional failure, patterns of cancer failure, toxic effects, patient-reported outcomes

OS

KEYNOTE-689 46

3

Both

Neoadjuvant pembrolizumab > surgery > adjuvant SOC + pembrolizumab vs surgery > adjuvant SOC

OS, major pathologic response, pathologic complete response, safety and tolerability

EFS

IMSTAR-HN 47

3

Treatment-naive, resectable, locally advanced

Negative Neoadjuvant nivolumab > surgery > adjuvant SOC > nivolumab vs neoadjuvant nivolumab > surgery > adjuvant SOC > nivolumab + ipilimumab vs surgery > adjuvant SOC

DFS

Locoregional control, OS

ECOG-ACRIN 3161 48

Positive CT + RT > nivolumab vs CT + RT > observation b

3

Treatment-naive oropharynx SCC; if patient has ≥10 pack-years, stage T1-2N2-N3 or T3-4N0-3; if patient has

PFS; prognostic biomarkers; use of PET/computed tomography to correlate survival, PD-L1 expression, and response

OS

<10 pack-years, stage T4N0-N3 or T1-3N2-3

ICI administration in the perioperative setting (neoadjuvant and ad juvant doses of ICIs), multiple phase 3 multicenter, randomized trials are currently ongoing. KEYNOTE-689 is a phase 3 trial evaluating the efficacy of pem brolizumab as neoadjuvant and adjuvant therapy compared with standard therapy (surgery followed by adjuvant radiotherapy with or without chemotherapy) in patients with previously untreated, re sectable LA HNSCC. 46 This trial builds from encouraging response rates seen in early-phase neoadjuvant perioperative ICI trials, such as the phase 2 trial by Uppaluri et al 53 demonstrating that 1 or 2 doses of neoadjuvant pembrolizumab had pathologic response rates of 44% and 52% respectively. 53,54 Similarly, a phase 2 trial by Wise Draper and colleagues 55 found that neoadjuvant and adjuvant pembrolizumab increased survival compared with historical con trols, with a pronounced benefit in patients who experienced patho logic response to neoadjuvant pembrolizumab. 55 In support of the use of perioperative ICIs, a melanoma trial has shown improved sur vival with neoadjuvant-adjuvant over adjuvant therapy alone. 56 IMSTAR-HN 47 is another perioperative, phase 3 ICI trial that will compare neoadjuvant nivolumab followed by maintenance nivolumab with or without ipilimumab 6 months after adjuvant therapy vs standard adjuvant therapy as first-line treatment, spe cifically for HPV-negative LA HNSCC. Early-phase trials, such as the IMCISION trial 57 and the phase 2 trial completed by Schoenfeld and colleagues, 58 have demonstrated encouraging pathologic re adjuvant, or perioperative use of immune checkpoint inhibitor therapy in the definitive setting of patients with head and neck squamous cell carcinoma (as of December 31, 2024). b Option to cross over to nivolumab maintenance treatment if patients have clearly documented progression during observation within 12 months from the end of CT plus RT therapy.

tion therapy for LA HNSCC. 43,49 Another phase 3 study, NIVOPOSTOP, is evaluating the addition of nivolumab to adjuvant cisplatin and radiotherapy in patients with tumors exhibiting high-risk pathologic features (eg, extra nodal extension and/or positive margins) following primary surgery. 44 Radiation Therapy Oncology Group 1216 45 is actively recruiting a similar patient popu lation in a phase 2/3 trial for pathologic high-risk HNSCC, testing adjuvant radiation therapy combined with cisplatin, docetaxel cetuximab, or cisplatin-atezolizumab. 45 Among patients with inter mediate-risk HPV-positive HNSCC, ECOG-ACRIN 3161 48 will evalu ate maintenance nivolumab vs observation following definitive chemoradiation therapy. An alternative strategy for sequential administration of ICI therapy is its use in the predefinitive treatment or neoadjuvant set ting. Potential benefits of neoadjuvant therapy include enhanced im mune priming due to the presence of tumor burden with intact lym phatics, minimizing the extent of oncologic resection, and possible de-escalation of adjuvant therapies. 50,51 Multiple phase 1 or 2 trials have evaluated the use of ICIs in the neoadjuvant setting for resect able LA HNSCC prior to curative-intent surgical resection. 52 While the findings have been promising, a key limitation of these early phase studies is that they have been typically single-arm, small co hort trials, with most end points focusing on differing definitions of pathologic response rates as surrogates for clinical outcomes. To confirm the effectiveness, safety, and overall benefit to survival of Abbreviations: CT, chemotherapy; DFS, disease-free survival; EFS, event-free survival; HPV, human papillomavirus; OS, overall survival; PD-L1, programmed cell death 1 ligand 1; PET, positron emission tomography; PFS, progression-free survival; RT, radiation therapy; SCC, squamous cell carcinoma; SOC, standard of care. a Only phase 3 clinical trials currently ongoing involving the neoadjuvant,

(Reprinted) JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 525

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