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 1. Landmark Trials in the Recurrent or Metastatic Setting Trial and treatment group Phase Key inclusion criteria

HPV status Primary outcome (95% CI) Hazard ratio

KEYNOTE-012 17-19 : pembrolizumab

ORR, 18% (8%-32%) a

Both

1B

Initial cohort: ≥1% PD-L1 expression; expansion cohort: no biomarker selection Progressed after platinum-based and/or cetuximab therapy

NA

KEYNOTE-055 22 : pembrolizumab KEYNOTE-040 23 Pembrolizumab CheckMate 141 21 Nivolumab Single-agent chemotherapy KEYNOTE-048 24 SOC

2

Both

ORR, 16% (11%-23%)

NA

Progressed during or after platinum containing single-agent or multimodal therapy

OS, 8.4 (6.4-9.4) mo OS, 6.9 (5.9-8.0) mo

3

Both

0.80 (95% CI, 0.65-0.98); P = .02

OS, 7.5 (5.5-9.1) mo OS, 5.1 (4.0-6.0) mo

Progressed after platinum-based therapy

3

Both

0.70 (97.73% CI, 0.51-0.96); P = .01

Total Population

Pembrolizumab Cetuximab + PFU Pembrolizumab + PFU Pembrolizumab Cetuximab + PFU Pembrolizumab + PFU

OS, 11.6 (10.5-13.6) mo OS, 10.7 (9.3-11.7) mo OS, 13.0 (10.9-14.7) mo

0.85 (95% CI, 0.71-1.03); P = .046 b ; 0.77 (95% CI, 0.63-0.93); P = .003 c

3

Previously untreated

Both

CPS≥1

OS, 12.3 (10.8-14.9) mo OS, 10.3 (9.0-11.5) mo OS 13.6 (10.7-15.5) mo

0.78 (95% CI, 0.64-0.96); P = .009 b ; 0.65 (95% CI, 0.63-0.80); P < .001 c

KEYNOTE-B10 25 : pembrolizumab + platinum + paclitaxel

4

Previously untreated

Both

ORR, 49% (38.4%-58.7%); grade 3-5 AE rate, 75%

NA

b Pembrolizumab alone vs cetuximab + platinum + fluorouracil. c Pembrolizumab + platinum + fluorouracil vs cetuximab + platinum + fluorouracil.

nance) in patients with R/M HNSCC (Table 2). Overall, CheckMate-651 29 did not meet its primary end point of improving OS with ICI therapy compared with the EXTREME regimen but showed a favorable safety profile. Importantly, however, median OS for combination nivolumab plus ipilimumab in the group with CPS of 20 or greater was excellent (17.6 months), and the hazard ratio may have been muted due to improved survival noted in the EXTREME treatment group (median OS, 13.5 months) compared with prior studies (10.1 months). 16 To further support the use of first-line ICI in the R/M setting, several retrospective studies have shown that chemotherapy and cetuximab seem more effective af ter patients are exposed to ICI, providing a potentially robust sal vage treatment option should the patient progress on first-line ICI. 35 To expand the applications of ICIs to the curative or definitive setting, investigators have sought to use ICIs in the treatment of patients with previously untreated, unresectable LA disease. The cur rent standard of care for these populations, particularly patients with non–oral cavity disease, has involved concurrent platinum-based chemoradiation. The phase 3 JAVELIN Head and Neck 100 trial 30 assessed the addition of avelumab (anti–PD-L1) to chemoradio therapy compared with placebo with chemoradiotherapy. Unfortu nately, the primary objective of improving progression-free sur vival was not reached. Similarly, in the randomized phase 3 KEYNOTE 412 trial, 31 the addition of pembrolizumab to chemoradiotherapy for patients with unresectable LA HNSCC did not significantly im Abbreviations: AE, adverse event; CPS, combined positive score; HPV, human papillomavirus; NA, not applicable; ORR, objective response rates per RECIST v1.1 criteria; OS, median overall survival; PD-L1, programmed cell death 1 ligand 1; PFU, platinum + fluorouracil; SOC, standard of care. a ORR from pooled analysis of both initial and expansion cohorts.

prove survival compared with chemoradiotherapy alone. The GORTEC-REACH trial 32 also showed no benefit to survival of add ing avelumab to cetuximab and radiotherapy compared with standard of care cisplatin with radiotherapy or cetuximab with ra diotherapy in cisplatin-ineligible patients (Table 2). Given disappointing results from multiple trials of concurrent ICIs with standard-dose radiation or chemoradiotherapy in the definitive setting, alongside preclinical evidence highlighting the importance of preserving regional cervical lymphatic function for anti–PD-1 response, concerns have grown that concurrent radia tion and/or chemotherapy with ICIs may hinder immune responses to ICI therapy. 36 In particular, elective irradiation of noncancerous cervical nodal basins may attenuate immune responses to the tu mor by hindering T cell priming with antigen-presenting cells. 37-39 In light of these concerns, alternative strategies for ICI therapy have been suggested, including staggering its timing with lymphatic ablating radiation or avoiding elective surgical dissection of unin volved cervical nodal basins. In fact, a phase 2 randomized trial was performed to compare concurrent or sequential ICI therapy with chemoradiation. 40 Although the final report is pending, interval results demonstrated that sequential pembrolizumab had superior survival at 1 and 2 years compared with concurrent therapy in previously untreated LA HNSCC, supporting the use of sequential ICI therapy as the preferred regimen to compare with standard of care in future phase 3 trials. 40

(Reprinted) JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 523

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