Novel Therapeutic Strategies for Squamous Cell Carcinoma of the Head and Neck: Beyond EGFR and Checkpoint Blockade
Abstract
1. Introduction
2. Next-Generation Immunotherapies
2.1. Targeting Alternative Immune Checkpoints
2.2. Bispecific Antibodies
2.3. Chimeric-Antigen Receptor (CAR) T-Cell Therapy
2.4. Cytokine-Based Therapies
2.5. Oncolytic Viruses
3. Targeted Therapies
3.1. EGFR Mutations
3.2. PI3K/AKT/mTOR Pathway
3.3. FGFR Alterations
3.4. HRAS Mutations
3.5. Cell Cycle Regulators
3.6. DNA Damage Response
4. Epigenetic Modifiers
4.1. Histone Deacetylase (HDAC) Inhibitors
4.2. DNA Methyltransferase (DNMT) Inhibitors
4.3. Enhancer of Zeste Homolog 2 (EZH2) Inhibitors
5. Targeting the Tumor Microenvironment (TME)
5.1. Anti-Angiogenic Agents
5.2. Cancer-Associated Fibroblasts (CAFs)
5.3. NOTCH1 Inhibition
5.4. Modulating the Immune Microenvironment
6. Other Innovative Approaches
6.1. Antibody-Drug Conjugates (ADCs)
6.2. Proteolysis Targeting Chimeras (PROTACs)
6.3. Metformin
6.4. Radiopharmaceuticals
7. Challenges and Future Directions
7.1. Overcoming Resistance
7.2. Biomarker Development
7.3. Addressing Tumor Heterogeneity
7.4. Clinical Trial Design
7.5. Toxicity Management
8. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ADC | Antibody drug conjugate |
CAF | Cancer-Associated Fibroblasts |
CAR | Chimeric-antigen receptor |
CCND1 | Cyclin D1 |
CDK 4/6 | Cyclin-Dependent Kinase 4/6 |
CDKN2A | Cyclin-dependent kinase inhibitor 2A |
CPOS | Combined positive score |
CTLA | Cytotoxic T lymphocyte-associated antigen |
DOR | Duration of response |
DNMT | DNA methyltransferase |
EBV | Epstein–Barr Virus |
EGFR | Epidermal growth factor receptor |
ERK | Extracellular Signal-Regulated Kinase |
EZH2 | Enhancer of Zeste Homolog 2 |
FDA | Food and Drug Administration |
FGFR2 | Fibroblast growth factor receptor |
HDAC | Histone deacetylase |
HER3 | Human epidermal growth factor receptor 3 |
HIF | Hypoxia inducible factor |
HPV | Human papillomavirus |
HRAS | Harvey rat sarcoma viral oncogene homolog |
HRD | Homologous repair deficiency |
HSV | Herpes simplex virus |
IL | Interleukin |
LAG-3 | Lymphocyte-activation gene 3 |
LGR-5 | Leucine-rick repeat-containing G-protein |
MAPK | Mitogen-activated protein kinase |
MDSC | Myeloid-derived suppressor cells |
MMAE | Monomethyl auristatin A |
MEK | Mitogen-activated protein kinase |
mTOR | Mammalian target of rapamycin |
LZK | Leucine zipper-bearing kinase |
NPC | Nasopharyngeal cancer |
ORR | Objective response rate |
OS | Overall survival |
PARP | Poly ADP ribose polymerase |
PFS | Progression free survival |
PI3KCA | Phosphatidylinositol 3-kinase catalytic subunit alpha |
RAF | Rapidly accelerated fibrosarcoma |
RAS | Rat sarcoma |
Rb | Retinoblastoma |
R/M | Recurrent or metastatic |
HNSCC | Head and neck squamous cell carcinoma |
SDF1 | Stromal cell derived factor-1 |
SSB | Single strand breaks |
S6K | Ribosomal S6 kinase |
TAM | Tumor associated macrophage |
TF | Tissue factor |
TGF-B | Transforming growth factor-beta |
TGIT | T cell immunoreceptor with Ig and ITIM domains |
Trop | Trophoblast cell surface antigen |
TRT | Targeted radioligand therapy |
TIM-3 | T-cell immunoglobulin and mucin-domain containing-3 |
TKI | Tyrosine kinase inhibitor |
TME | Tumor microenvionment |
VEGF | Vascular endothelial growth factor |
4E-BP1 | Eukaryotic translation initiation factor 4E binding protein 1 |
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Trial Reference No. | Phase | N | Cohort | Investigational Drug | ORR (%) | PFS (Months) | DCR (%) |
---|---|---|---|---|---|---|---|
NCT03005782 | I | 30 | R/M HNSCC 2 cohorts: Anti–PD-1/PD-L1-naïve (Cohort 11) or anti–PD-1/L1-experienced (Cohort 12) | Fianlimab (LAG-3 inhibitor) and Cemiplimab | 33% (Cohort 11) 7% (Cohort 12) | 2 (Cohort 11) 4 (Cohort 12) | 47% (Cohort 11) 67% (Cohort 12) |
NCT03625323 | II | 39 | R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1 | Eftilagimod Alpha (LAG-3 inhibitor) with Pembrolizumab | 29.7% | 2.1 | Not reported |
NCT04429542 | I/Ib | 39 | R/M HNSCC with a tumor PD-L1 CPS ≥ 1 with no prior systemic therapy | BCA 101 (bispecific antibody targeting TGF-B and EGFR) and Pembrolizumab | 46% | Not reached | Not reported |
NCT03526835 | II | 26 | R/M HNSCC with no prior systemic therapy, PDL1 positive | Petosemtamab (bispecific antibody targeting EGFR and LGR-5) and Pembrolizumab | 67% | Not reported | Not reported |
NCT05054439 | I/Ib | 29 | R/M HNSCC progressed on prior anti-PD-1/L1 with or without platinum-based chemotherapy and received no more than two lines of treatment | Group A, pts without prior exposure to paclitaxel
| Group A: 64.3% Group B: 12.5% | Group A: 5.6 Group B: 1.9 | Group A: 92.9% Group B: 62.5% |
NCT03381183 | Ib | 16 | R/M HNSCC, may or may not have had PD1 inhibitor therapy before | IRX2 and Durvalumab | 5.3% | 6.18 | 42% |
EudraCT2005-000777-21 | I/II | 17 | Stage III/IVA/IVB HNSCC | Intratumoral injections of oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), with chemoradiotherapy followed by surgical resection | 82.3% | Not reported | Not reported |
NCT04083976 | II | 178 (10 HNSCC) | Advanced or metastatic solid tumors of any histology with predefined FGFR1-4 alterations, progressed on 1 or more lines of systemic therapy | Erdafitinib | 40% | 5.2 | Not reported |
NCT02383927 | II | 30 | R/M HNSCC patients with ≥1 prior platinum-containing regimen | Tipifarnib (farnesyltransferase inhibitor that disrupts HRAS function) | 55% | 5.6 | Not reported |
NCT02101034 | II | 30 | Platinum-resistant, cetuximab-naive HPV (−) R/M HNSCC | Palbociclib and Cetuximab | 35% | 6.4 | Not reported |
NCT04643379 | II | 12 | R/M HNSCC with no prior treatment | Olaparib, Carboplatin and Pembrolizumab | 67% | Not reported | Not reported |
NCT02538510 | II | 25 | Incurable HNSCC progressed on standard therapy but no prior immunotherapy | Vorinostat and Pembrolizumab | 32% | 4.5 | Not reported |
NCT03019003 | Ib | 12 | R/M HNSCC who progressed on anti-programmed cell death protein PD-1 (anti-PD-1) therapy | Azacitidine, Durvalumab and Tremelimumab | Not reported | Not reported | Not reported |
NCT04624113 | I-II | 12 | R/M HNSCC with PD-L1 positive tumors, progressed through standard therapies | Tazometostat with Pembrolizumab | 0% | 2.1 | 41% |
NCT04225117 | II | 46 | R/M HNSCC progressed through platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy, with ≤2 previous lines of cytotoxic therapy | Enfortumab Vedotin (antibody drug conjugate targeting Nectin-4) | 23.9% | 3.9 | 56.5% |
NCT03485209 | II | 40 | R/M HNSCC progressed through platinum based chemotherapy and checkpoint inhibitors | Tisotumab Vedotin (antibody drug conjugate targeting tissue factor) | 32.5% | 4.2 | Not reported |
NCT03964727 | II | 43 | Locally advanced or metastatic HNSCC that progressed following platinum-based chemotherapy and anti-PD-(L)1 therapy | Sacituzumab Govitecan (antibody drug conjugate targeting Trop 2) | 16% | 4.1 | Not reported |
NCT05688605 | I/II | 33 (6 HNSCC) | EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (HNSCC) | MRG003 (antibody drug conjugate targeting EGFR) with Pucotenlimab | 60% | Not reported | Not reported |
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Sim, R.H.Z.; Voon, P.J.; Cheo, S.W.; Lim, D.W.-T., on behalf of the Asian Clinical Trials Network for Cancers Project—Head and Neck Cancer Group (ATLAS-HNCG). Novel Therapeutic Strategies for Squamous Cell Carcinoma of the Head and Neck: Beyond EGFR and Checkpoint Blockade. Biomedicines 2025, 13, 1972. https://doi.org/10.3390/biomedicines13081972
Sim RHZ, Voon PJ, Cheo SW, Lim DW-T on behalf of the Asian Clinical Trials Network for Cancers Project—Head and Neck Cancer Group (ATLAS-HNCG). Novel Therapeutic Strategies for Squamous Cell Carcinoma of the Head and Neck: Beyond EGFR and Checkpoint Blockade. Biomedicines. 2025; 13(8):1972. https://doi.org/10.3390/biomedicines13081972
Chicago/Turabian StyleSim, Rachel Hui Zhen, Pei Jye Voon, Seng Wee Cheo, and Darren Wan-Teck Lim on behalf of the Asian Clinical Trials Network for Cancers Project—Head and Neck Cancer Group (ATLAS-HNCG). 2025. "Novel Therapeutic Strategies for Squamous Cell Carcinoma of the Head and Neck: Beyond EGFR and Checkpoint Blockade" Biomedicines 13, no. 8: 1972. https://doi.org/10.3390/biomedicines13081972
APA StyleSim, R. H. Z., Voon, P. J., Cheo, S. W., & Lim, D. W.-T., on behalf of the Asian Clinical Trials Network for Cancers Project—Head and Neck Cancer Group (ATLAS-HNCG). (2025). Novel Therapeutic Strategies for Squamous Cell Carcinoma of the Head and Neck: Beyond EGFR and Checkpoint Blockade. Biomedicines, 13(8), 1972. https://doi.org/10.3390/biomedicines13081972