PD-1 Inhibitors in Recurrent or Metastatic Oral Squamous Cell Carcinoma: Clinical Evidence, Patient Selection, and Immune-Related Toxicities
DOI:
https://doi.org/10.68041/johdt.v1i1/06Keywords:
Biomarkers, Carcinoma, Immune Checkpoint Inhibitors, ImmunotherapyAbstract
Oral squamous cell carcinoma (OSCC) is a difficult disease to treat when local therapy is not curative, particularly if it does recur or metastasize. There is evidence of programmed cell death protein 1 (PD-1) inhibitors available to treat head and neck squamous cell carcinoma ( OSCC) but comes from mixed populations of head and neck cancer. The current narrative review outlines evidence regarding pembrolizumab and nivolumab, focusing on treatment selection and IRTs. Pembrolizumab is used either alone or in combination with chemotherapy, depending on programmed death-ligand 1 combined positive score (PD-L1 CPS), disease burden, urgency, fitness and patient preferences. In eligible post platinum setting, there is evidence for nivolumab and pembrolizumab, though treatment after PD-1 exposure will be affected. Baseline evaluation and monitoring of toxicities is required, as well as rapid management based on severity, for the skin, endocrine, gastrointestinal, hepatic, pulmonary, cardiovascular, renal, neurological, and oral systems. Specific estimates for OSCCs are still scarce. Further treatment studies in the oral cavity region, the establishment of predictive markers, the development of resistance-directed treatments and the standardization of reporting on oral cavity toxicity will help optimize treatment and patient outcomes.
References
1. Badwelan M, Muaddi H, Ahmed A, Lee KT, Tran SD. Oral squamous cell carcinoma and concomitant primary tumors, what do we know? A review of the literature. Curr Oncol. 2023;30(4):3721–3734. https://doi.org/10.3390/curroncol30040283 DOI: https://doi.org/10.3390/curroncol30040283
2. Yin G, Guo W, Duan H, Huang Z. Role of PD-1/PD-L1 inhibitors in the treatment of recurrent/metastatic head and neck squamous cell carcinoma: a systematic review and meta-analysis. Clin Otolaryngol. 2021;46(5):1013–1020. https://doi.org/10.1111/coa.13772 DOI: https://doi.org/10.1111/coa.13772
3. Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study. J Clin Oncol. 2023;41(4):790–802. https://doi.org/10.1200/JCO.21.02508 DOI: https://doi.org/10.1200/JCO.21.02508
4. Liu SV, Babel RA, Kao YH, Chirovsky D, Namakydoust A, Velcheti V. 5-year real-world outcomes with first-line pembrolizumab plus chemotherapy in advanced/metastatic NSCLC. Immunotherapy. 2025;17(14):1005–1013. https://doi.org/10.1080/1750743X.2025.2569856 DOI: https://doi.org/10.1080/1750743X.2025.2569856
5. Al-Azzawi HMA, Hamza SA, Paolini R, Lim M, Patini R, Celentano A. PD-L1/PD-1 expression in the treatment of oral squamous cell carcinoma and oral potentially malignant disorders: an overview of reviews. J Pers Med. 2025;15(4):126. https://doi.org/10.3390/jpm15040126 DOI: https://doi.org/10.3390/jpm15040126
6. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92. https://doi.org/10.1038/s41572-020-00224-3 DOI: https://doi.org/10.1038/s41572-020-00224-3
7. Tian B, Yang Y, Kuang S, Piao M, Li C, Zhao H, et al. Current status of management of immune-related adverse events and practical needs for oncologist education. Cancer Biol Med. 2025;22(12):1515–1536. https://doi.org/10.20892/j.issn.2095-3941.2025.0346 DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0346
8. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J. 2018;24(1):47–53. https://doi.org/10.1097/PPO.0000000000000303 DOI: https://doi.org/10.1097/PPO.0000000000000303
9. Cheng Y, Song Z, Chen J, Tang Z, Wang B. Molecular basis, potential biomarkers, and future prospects of OSCC and PD-1/PD-L1 related immunotherapy methods. Heliyon. 2024;10(4):e25895. https://doi.org/10.1016/j.heliyon.2024.e25895 DOI: https://doi.org/10.1016/j.heliyon.2024.e25895
10. Ramalingam S, Shantha S, Muralitharan S, Sudhakar U, Thamizhchelvan H, Parvathi VD. Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma. Med Oncol. 2023;40(10):303. https://doi.org/10.1007/s12032-023-02169- DOI: https://doi.org/10.1007/s12032-023-02169-5
11. Xue N, Wang Y, Wang Z, Zeng X, Wang J, Zhang X. Trends in immunotherapy for oral squamous cell carcinoma. Cell Oncol. 2025;48(5):1159–1179. https://doi.org/10.1007/s13402-025-01068-3 DOI: https://doi.org/10.1007/s13402-025-01068-3
12. Deuss E, Kürten C, Fehr L, Kahl L, Zimmer S, Künzel J, et al. Standardized digital image analysis of PD-L1 expression in head and neck squamous cell carcinoma reveals intra- and inter-sample heterogeneity with therapeutic implications. Cancers (Basel). 2024;16(11):2103. https://doi.org/10.3390/cancers16112103 DOI: https://doi.org/10.3390/cancers16112103
13. Marković F, Hochmair M, Müser N, Fabikan H, Rodriguez VM, Janzic U, et al. The efficacy of first-line pembrolizumab monotherapy in patients with metastatic NSCLC aged ≥70 years with high PD-L1 (TPS ≥50%) expression: a multicenter real-world study. Cancers (Basel). 2025;17(13):2190. https://doi.org/10.3390/cancers17132190 DOI: https://doi.org/10.3390/cancers17132190
14. Gillison ML, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Long-term outcomes with nivolumab as first-line treatment in recurrent and metastatic head and neck cancer: subgroup analysis of CheckMate 141. Oncologist. 2022;27(2):e194–e198. https://doi.org/10.1093/oncolo/oyab036 DOI: https://doi.org/10.1093/oncolo/oyab036
15. Li J, Ab Rahman N, Mohamad S, Yang G, Zhao C. Efficacy of immune checkpoint inhibitors in the treatment for head and neck cancer patients: a systematic review and network meta-analysis. Oncol Res. 2025;33(9):2263–2278. https://doi.org/10.32604/or.2025.065911 DOI: https://doi.org/10.32604/or.2025.065911
16. Dzienis M, Cundom J, Fuentes CS, Spreafico A, Nordlinger M, Pastor AV, et al. Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-B10): a single-arm phase IV trial. J Clin Oncol. 2024;42(25):2989–2999. https://doi.org/10.1200/JCO.23.02625 DOI: https://doi.org/10.1200/JCO.23.02625
17. Haddad RI, Harrington K, Tahara M, Ferris RL, Gillison ML, Fayette J, et al. Nivolumab plus ipilimumab versus EXTREME regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck: the final results of CheckMate 651. J Clin Oncol. 2023;41(12):2166–2180. https://doi.org/10.1200/JCO.22.00332 DOI: https://doi.org/10.1200/JCO.22.00332
18. Dang S, Zhang S, Zhao J, Li X, Li W. Efficacy and safety of immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and meta-analysis of randomized clinical trials. Cancer Med. 2023;12(20):20277–20286. https://doi.org/10.1002/cam4.6564 DOI: https://doi.org/10.1002/cam4.6564
19. Meliante PG, Barbato C, Zoccali F, Ralli M, Greco A, de Vincentiis M, et al. Programmed cell death-ligand 1 in head and neck squamous cell carcinoma: molecular insights, preclinical and clinical data, and therapies. Int J Mol Sci. 2022;23(23):15384. https://doi.org/10.3390/ijms232315384 DOI: https://doi.org/10.3390/ijms232315384
20. Yeong J, Lum HYJ, Teo CB, Tan BKJ, Chan YH, Tay RYK, et al. Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy. Gastric Cancer. 2022;25(4):741–750. https://doi.org/10.1007/s10120-022-01301-0 DOI: https://doi.org/10.1007/s10120-022-01301-0
21. Ott PA, Bang YJ, Piha-Paul SA, Abdul Razak AR, Bennouna J, Soria JC, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37(4):318–327. https://doi.org/10.1200/JCO.2018.78.2276 DOI: https://doi.org/10.1200/JCO.2018.78.2276
22. Jeong J, Seo S, Kim SB, Song JS, Kim HR, Cho BC, et al. Real-world outcomes and biomarker analysis based on routine clinical, laboratory, and pathologic parameters in metastatic or unresectable esophageal cancer treated with first-line anti-PD-1 plus fluoropyrimidine and platinum. Cancers (Basel). 2025;17(19):3149. https://doi.org/10.3390/cancers17193149 DOI: https://doi.org/10.3390/cancers17193149
23. Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chávez A, Keegan N, Khamashta MA, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):38. https://doi.org/10.1038/s41572-020-0160-6 DOI: https://doi.org/10.1038/s41572-020-0160-6
24. Williams CP, Miller-Sonet E, Nipp RD, Kamal AH, Love S, Rocque GB. Importance of quality-of-life priorities and preferences surrounding treatment decision making in patients with cancer and oncology clinicians. Cancer. 2020;126(15):3534–3541. https://doi.org/10.1002/cncr.32961 DOI: https://doi.org/10.1002/cncr.32961
25. Tacchi C, Convertino I, Bocci G. Immune-related adverse events associated with immune checkpoint inhibitors: a scoping review. Pharmaceuticals (Basel). 2026;19(2):276. https://doi.org/10.3390/ph19020276 DOI: https://doi.org/10.3390/ph19020276
26. Dökmetaş M, Muğlu H, Özcan E, Bayram Kuvvet B, Helvacı K, Kalacı E, et al. Endocrine adverse events in patients treated with immune checkpoint inhibitors: a comprehensive analysis. Medicina (Kaunas). 2025;61(1):123. https://doi.org/10.3390/medicina61010123 DOI: https://doi.org/10.3390/medicina61010123
27. Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S238–S247. https://doi.org/10.1016/j.jaci.2009.09.041 DOI: https://doi.org/10.1016/j.jaci.2009.09.041
28. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714–1768. https://doi.org/10.1200/JCO.2017.77.6385 DOI: https://doi.org/10.1200/JCO.2017.77.6385
29. Morgado M, Plácido A, Morgado S, Roque F. Management of the adverse effects of immune checkpoint inhibitors. Vaccines (Basel). 2020;8(4):575. https://doi.org/10.3390/vaccines8040575 DOI: https://doi.org/10.3390/vaccines8040575
30. Huang JJ, YousefiAsl M, Singh N, Grivas P, Bhatia S. Steroid-sparing strategies for managing immune-related adverse events. J Immunother Cancer. 2026;14(1):e013776. https://doi.org/10.1136/jitc-2025-013776 DOI: https://doi.org/10.1136/jitc-2025-013776
31. Anaya JM. The diagnosis and clinical significance of polyautoimmunity. Autoimmun Rev. 2014;13(4–5):423–426. https://doi.org/10.1016/j.autrev.2014.01.049 DOI: https://doi.org/10.1016/j.autrev.2014.01.049
32. Chen CH, Yu HS, Yu S. Cutaneous adverse events associated with immune checkpoint inhibitors: a review article. Curr Oncol. 2022;29(4):2871–2886. https://doi.org/10.3390/curroncol29040234 DOI: https://doi.org/10.3390/curroncol29040234
33. Husebye ES, Castinetti F, Criseno S, Curigliano G, Decallonne B, Fleseriu M, et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an European Society of Endocrinology clinical practice guideline. Eur J Endocrinol. 2022;187(6):G1–G21. https://doi.org/10.1530/EJE-22-0689 DOI: https://doi.org/10.1530/EJE-22-0689
34. Zoghbi M, Burk KJ, Haroun E, Saade M, Cruz Carreras MT. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer. 2024;32(10):680. https://doi.org/10.1007/s00520-024-08889-2 DOI: https://doi.org/10.1007/s00520-024-08889-2
35. Yu X, Wu J, Su C. Progress in diagnosis and treatment of checkpoint inhibitor pneumonitis. Curr Opin Oncol. 2023;35(1):31–36. https://doi.org/10.1097/CCO.0000000000000909 DOI: https://doi.org/10.1097/CCO.0000000000000909
36. Sprangers B, Leaf DE, Porta C, Soler MJ, Perazella MA. Diagnosis and management of immune checkpoint inhibitor-associated acute kidney injury. Nat Rev Nephrol. 2022;18(12):794–805. https://doi.org/10.1038/s41581-022-00630-8 DOI: https://doi.org/10.1038/s41581-022-00630-8
37. Raschi E, Rossi S, De Giglio A, Fusaroli M, Burgazzi F, Rinaldi R, et al. Cardiovascular toxicity of immune checkpoint inhibitors: a guide for clinicians. Drug Saf. 2023;46(9):819–833. https://doi.org/10.1007/s40264-023-01320-5 DOI: https://doi.org/10.1007/s40264-023-01320-5
38. Srivastava A, Nogueras-Gonzalez GM, Geng Y, Singh J, Myers JN, Li Y, et al. Oral toxicities associated with immune checkpoint inhibitors: meta-analyses of clinical trials. J Immunother Precis Oncol. 2024;7(1):24–40. https://doi.org/10.36401/JIPO-23-14 DOI: https://doi.org/10.36401/JIPO-23-14
39. Su WY, Su CW, Chang DC, Chuang SL, Chen S, Hsu ACY, et al. Impact of varying anatomic sites on advanced stage and survival of oral cancer: 9-year prospective cohort of 27 717 cases. Head Neck. 2019;41(5):1475–1483. https://doi.org/10.1002/hed.25579 DOI: https://doi.org/10.1002/hed.25579
40. Muralidharan S, Nikalje M, Subramaniam T, Koshy JA, Koshy AV, Bangera D. A narrative review on oral squamous cell carcinoma. J Pharm Bioallied Sci. 2025;17(Suppl 1):S204–S206. https://doi.org/10.4103/jpbs.jpbs_593_25 DOI: https://doi.org/10.4103/jpbs.jpbs_593_25
41. López-Galindo M, de Sousa-Roques M. Biomarkers in oral squamous cell carcinoma: a systematic review. Med Oral Patol Oral Cir Bucal. 2026;31(1):e82–e88. https://doi.org/10.4317/medoral.27565 DOI: https://doi.org/10.4317/medoral.27565
42. Smit Y, Verweij L, Currie A, Janssen JJWM, Posthuma EFM, Dekker A, et al. Benefits and limitations of real-world patient-reported toxicity symptom monitoring for guidelines and care, as perceived by patients, clinicians, and guideline developers. Cancer Med. 2025;14(8):e70880. https://doi.org/10.1002/cam4.70880 DOI: https://doi.org/10.1002/cam4.70880
43. Kotecha R, La Rosa A, Brown PD, Vogelbaum MA, Navarria P, Bodensohn R, et al. Multidisciplinary management strategies for recurrent brain metastasis after prior radiotherapy: an overview. Neuro Oncol. 2025;27(3):597–615. https://doi.org/10.1093/neuonc/noae220 DOI: https://doi.org/10.1093/neuonc/noae220
Published
Issue
Section
License
Copyright (c) 2026 Zafar Junaid, Khalida Rizwan (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Journal of Oral Health and Dental Therapeutics (JOHDT) follows the Attribution Creative Commons-Non commercial (CC BY-NC 4.0) license which allows the users to copy and redistribute the material in any medium or format, remix, transform and build upon the material. The users must give credit to the source and indicate, provide a link to the license, and indicate if changes were made. However, the CC BY-NC 4.0 license restricts the use of material for commercial purposes (Further details are available at website. The Editorial Board of the JOHDT endeavors to ensure the accuracy, integrity, and quality of all published content. However, the responsibility of opinions, interpretations, and conclusions expressed in the published articles rests entirely with the authors and do not necessarily reflect the views of the Editorial Board, publisher, or affiliated institutions.
