Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Procedures
2.3. Outcomes and the Statistical Analysis Plan
2.4. Role of the Funding Source
3. Results
3.1. Patient Characteristics
3.2. Treatment
3.3. DLT Assessment and RP2D Determination
3.4. Adverse Events Across All Cycles of the Therapy
3.5. Tumor Response and Current Patient Status
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Fitzmaurice, C.; Akinyemiju, T.F.; Al Lami, F.H.; Alam, T.; Alizadeh-Navaei, R.; Allen, C.; Alsharif, U.; Alvis-Guzman, N.; Amini, E.; Anderson, B.O.; et al. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018, 4, 1553–1568. [Google Scholar] [CrossRef] [PubMed]
- Burtness, B.; Harrington, K.J.; Greil, R.; Soulieres, D.; Tahara, M.; de Castro, G., Jr.; Psyrri, A.; Baste, N.; Neupane, P.; Bratland, A.; et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 2019, 394, 1915–1928. [Google Scholar] [CrossRef]
- Kim, K.H.; Roberts, C.W.M. Targeting EZH2 in cancer. Nat. Med. 2016, 22, 128–134. [Google Scholar] [CrossRef]
- Jiao, L.; Liu, X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science 2015, 350, aac4383. [Google Scholar] [CrossRef] [PubMed]
- Yan, K.S.; Lin, C.Y.; Liao, T.W.; Peng, C.M.; Lee, S.C.; Liu, Y.J.; Chan, W.P.; Chou, R.-H. EZH2 in cancer progression and potential application in cancer therapy: A friend or foe? Int. J. Mol. Sci. 2017, 18, 1172. [Google Scholar] [CrossRef]
- Kidani, K.; Osaki, M.; Tamura, T.; Yamaga, K.; Shomori, K.; Ryoke, K.; Ito, H. High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas. Oral. Oncol. 2009, 45, 39–46. [Google Scholar] [CrossRef]
- Mochizuki, D.; Misawa, Y.; Kawasaki, H.; Imai, A.; Endo, S.; Mima, M.; Yamada, S.; Nakagawa, T.; Kanazawa, T.; Misawa, K. Aberrant epigenetic regulation in head and neck cancer due to distinct EZH2 overexpression and DNA hypermethylation. Int. J. Mol. Sci. 2018, 19, 3707. [Google Scholar] [CrossRef] [PubMed]
- Lindsay, C.D.; Kostiuk, M.A.; Harris, J.; O’Connell, D.A.; Seikaly, H.; Biron, V.L. Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas. Clin. Epigenetics 2017, 9, 95. [Google Scholar] [CrossRef] [PubMed]
- Zhou, L.; Mudianto, T.; Ma, X.; Riley, R.; Uppaluri, R. Targeting EZH2 enhances antigen presentation, antitumor immunity, and circumvents anti-PD-1 resistance in head and neck cancer. Clin. Can. Res. 2020, 26, 290–300. [Google Scholar] [CrossRef] [PubMed]
- Italiano, A.; Soria, J.-C.; Toulmonde, M.; Michot, J.-M.; Lucchesi, C.; Varga, A.; Coindre, J.-M.; Blakemore, S.J.; Clawson, A.; Suttle, B.; et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: A first-in-human, open-label, phase 1 study. Lancet Oncol. 2018, 19, 649–659. [Google Scholar] [CrossRef]
- Palomba, M.L.; Cartron, G.; Popplewell, L.; Ribrag, V.; Westin, J.; Huw, L.-Y.; Agarwal, S.; Shivhare, M.; Hong, W.-J.; Raval, A.; et al. Combination of Atezolizumab and Tazemetostat in patients with relapsed/refractory diffuse large B-cell lymphoma: Results from a phase Ib study. Clin. Lymphoma Myeloma Leuk. 2022, 22, 504–512. [Google Scholar] [CrossRef] [PubMed]
- Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef] [PubMed]
- Seymour, L.; Bogaerts, J.; Perrone, A.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; Lin, N.U.; Litière, S.; et al. iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017, 18, e143–e152. [Google Scholar] [CrossRef] [PubMed]
- Harris, P.A.; Taylor, R.; Thielke, R.; Payne, J.; Gonzalez, N.; Conde, J.G. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009, 42, 377–381. [Google Scholar] [CrossRef] [PubMed]
- Harris, P.A.; Taylor, R.; Minor, B.L.; Elliott, V.; Fernandez, M.; O’Neal, L.; McLeod, L.; Delacqua, G.; Delacqua, F.; Kirby, J.; et al. The REDCap consortium: Building an international community of software partners. J. Biomed. Inform. 2019, 95, 103208. [Google Scholar] [CrossRef]
- Yasumatsu, R.; Wakasaki, T.; Hashimoto, K.; Nakashima, K.; Manako, T.; Taura, M.; Matsuo, M.; Nakagawa, T. Monitoring the neutrophil-to-lymphocyte ratio may be useful for predicting the anticancer effect of nivolumab in recurrent or metastatic head and neck cancer. Head. Neck 2019, 41, 2610–2618. [Google Scholar] [CrossRef] [PubMed]
- Ho, W.J.; Yarchoan, M.; Hopkins, A.; Mehra, R.; Grossman, S.; Kang, H. Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas. J. Immunother. Cancer 2018, 6, 84. [Google Scholar] [CrossRef]
- Ferris, R.L.; Blumenschein, G.; Fayette, J.; Guigay, J.; Colevas, A.D.; Licitra, L.; Harrington, K.; Kasper, S.; Vokes, E.E.; Even, C.; et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 2016, 375, 1856–1867. [Google Scholar] [CrossRef] [PubMed]
- Cohen, E.E.W.; Soulieres, D.; Le Tourneau, C.; Dinis, J.; Licitra, L.; Ahn, M.-J.; Soria, A.; Machiels, J.-P.; Mach, N.; Mehra, R.; et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study. Lancet 2018, 393, 156–167. [Google Scholar] [CrossRef]
- Samaržija, I.; Tomljanović, M.; Novak Kujundžić, R.; Trošelj, K.G. EZH2 inhibition and cisplatin as a combination anticancer therapy: An overview of preclinical studies. Cancers 2022, 14, 4761. [Google Scholar] [CrossRef] [PubMed]
- Gounder, M.; Schoffski, P.; Jones, R.L.; Agulnik, M.; Cote, G.M.; Villalobos, V.M.; Attia, S.; Chugh, R.; Chen, T.W.-W.; Jahan, T.; et al. Tazemetostat in advanced epitheliod sarcoma with loss of INI1/SMARCB1: An international, open-label phase 2 basket study. Lancet Oncol. 2020, 21, 1423–1432. [Google Scholar] [CrossRef] [PubMed]
- Morschhauser, F.; Tilly, H.; Chaidos, A.; McKay, P.; Phillips, T.; Assouline, S.; Batlevi, C.L.; Campbell, P.; Ribrag, V.; Damaj, G.L.; et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: An open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020, 21, 1433–1442. [Google Scholar] [CrossRef] [PubMed]
Characteristic | Phase 1 (n = 12) |
---|---|
Age (years), median | 63 (Range: 41–79) |
Sex | |
Male | 11 |
Female | 1 |
Race | |
Caucasian | 8 |
African American | 3 |
Asian | 1 |
ECOG Performance Status a | |
0 | 8 |
1 | 4 |
Smoking History | |
Yes | 7 |
No | 5 |
HPV b Status and Primary Site | |
HPV positive (oropharynx only) | 1 |
HPV negative | 11 |
| 4 |
| 3 |
| 2 |
| 1 |
| 1 |
PD-L1 | |
≥1 | 10 |
1–19 | 7 |
≥20 | 3 |
0 | 1 |
Unknown | 1 |
Lines of Prior Treatment for RM-HNSCCs | |
1–2 | 6 |
3+ | 6 |
Prior anti-PD1 therapy for RM-HNSCCs | |
Yes | 8 |
<6 months ago | 5 |
≥6 months ago | 3 |
No | 4 |
Adverse Event | 400 mg Dose Level d (n = 3) | 600 mg Dose Level d (n = 3) | 800 mg Dose Level d, Evaluable for DLT (n = 3) | 800 mg Dose Level d, Non-Evaluable for DLT (n = 3) | All Patients (n = 12) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Grade | Grade | Grade | Grade | Grade | |||||||||||
1–2 | 3 | 4 | 1–2 | 3 | 4 | 1–2 | 3 | 4 | 1–2 | 3 | 4 | 1–2 | 3 | 4 | |
Alanine aminotransferase increase | 2 | 1 b | 2 | 1 b | |||||||||||
Alkaline phosphatase increase | 3 | 1 | 3 | 7 | |||||||||||
Anemia | 2 | 1 a | 3 | 1 c | 2 | 1 c | 7 | 3 a,c | |||||||
Anorexia | 1 | 1 | 2 | 4 | |||||||||||
Aspartate aminotransferase increase | 1 | 2 | 3 | ||||||||||||
Confusion | 1 | 1 | |||||||||||||
Creatinine increase | 1 | 1 | |||||||||||||
Dehydration | 1 | 1 | |||||||||||||
Delirium | 1 a | 1 a | |||||||||||||
Diarrhea | 1 | 1 | |||||||||||||
Dizziness | 2 | 2 | |||||||||||||
Dry skin | 3 | 2 | 5 | ||||||||||||
Dyspnea | 2 | 1 | 3 | ||||||||||||
Edema limbs | 1 | 1 | |||||||||||||
Fatigue | 1 | 1 a | 3 | 3 | 7 | 1 a | |||||||||
Generalized muscle weakness | 1 | 1 | |||||||||||||
Headache | 2 | 1 | 3 | ||||||||||||
Hoarseness | 1 | 1 | 2 | ||||||||||||
Hypercalcemia | 1 | 1 | |||||||||||||
Hyperkalemia | 1 | 1 | |||||||||||||
Hypertension | 3 | 1 | 1 a | 4 | 1 a | ||||||||||
Hypoalbuminemia | 2 | 1 | 1 | 1 | 5 | ||||||||||
Hypocalcemia | 1 a | 1 | 1 | 1 a | |||||||||||
Hypokalemia | 1 | 1 | |||||||||||||
Hyponatremia | 2 | 2 | 2 | 1 | 7 | ||||||||||
Hypophosphatemia | 2 | 2 | |||||||||||||
Hypotension | 1 | 1 | 2 | ||||||||||||
Hypoxia | 1 | 1 | |||||||||||||
Hypothyroidism | 1 | 1 | |||||||||||||
Lung infection | 1 a | 2 a | 3 a | ||||||||||||
Lymphedema | 1 | 1 | |||||||||||||
Lymphocyte count decrease | 1 a | 1 a | 2 a | ||||||||||||
Myalgia | 1 | 1 | |||||||||||||
Non-cardiac chest pain | 1 | 1 | |||||||||||||
Platelet count decrease | 1 | 1 | |||||||||||||
Pleural effusion | 1 a | 1 a | |||||||||||||
Pneumonitis | 1 | 1 | |||||||||||||
Proteinuria | 1 | 1 | |||||||||||||
Pruritus | 2 | 1 | 3 | ||||||||||||
Respiratory failure | 1 a | 1 a | |||||||||||||
Sinus tachycardia | 2 | 1 | 3 | ||||||||||||
Syncope | 1 a | 1 a | |||||||||||||
Thromboembolic event | 1 | 1 | |||||||||||||
Tracheal obstruction | 1 a | 1 a | |||||||||||||
Tumor pain | 1 a | 1 | 1 | 1 | 1 a | 3 | 2 a | ||||||||
Weight loss | 1 | 1 b | 1 | 2 | 1 b | ||||||||||
White blood cell decrease | 1 | 1 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Oppelt, P.J.; Puram, S.V.; Liu, J.; Ley, J.C.; Adkins, D. Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial. Cancers 2025, 17, 437. https://doi.org/10.3390/cancers17030437
Oppelt PJ, Puram SV, Liu J, Ley JC, Adkins D. Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial. Cancers. 2025; 17(3):437. https://doi.org/10.3390/cancers17030437
Chicago/Turabian StyleOppelt, Peter J., Sidharth V. Puram, Jingxia Liu, Jessica C. Ley, and Douglas Adkins. 2025. "Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial" Cancers 17, no. 3: 437. https://doi.org/10.3390/cancers17030437
APA StyleOppelt, P. J., Puram, S. V., Liu, J., Ley, J. C., & Adkins, D. (2025). Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial. Cancers, 17(3), 437. https://doi.org/10.3390/cancers17030437