Cancer Research and Treatment

Original Articles

Head and Neck cancer

Differential Efficacy of Alpelisib by PIK3CA Mutation Site in Head and Neck Squamous Cell Carcinoma: An Analysis from the KCSG HN 15-16 TRIUMPH Trial: Kyoo Hyun Kim, Shinwon Hwang, Min Kyoung Kim, Keon-Uk Park, Tak Yun, Keun-Wook Lee, Joo Hang Kim, Bhumsuk Keam, Byoung Chul Cho, So Yeon Oh, Sang Hee Cho, Sangwoo Kim, Sung-Bae Kim, Min Hee Hong, Hye Ryun Kim; Cancer Res Treat. 2025;57(4):968-980. Published online January 31, 2025; DOI: https://doi.org/10.4143/crt.2024.1195

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Purpose
The TRIUMPH trial was a biomarker-driven umbrella trial for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). This analysis focuses on the PIK3CAα (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) inhibitor alpelisib (arm 1) in patients with phosphoinositide 3-kinase (PI3K) pathway alterations.
Materials and Methods
Patients with PI3K pathway altered tumors were enrolled in the alpelisib arm of the TRIUMPH study. We conducted a detailed analysis of the correlation between PI3K pathway mutations and treatment outcomes including disease control rate, overall survival (OS), and progression-free survival (PFS).
Results
From October 2017 and August 2020, 203 were enrolled, with 42 treated with alpelisib. Response evaluation was possible for 33 patients. Genomic profiles revealed PIK3CA amplifications in 26.2%, and point mutations in E542K (26.2%), E545K (23.8%), and H1047R (9.5%). Neither PIK3CA amplification nor co-occurring TP53 mutations had a notable influence on alpelisib response or survival outcomes. Although the overall response rates were similar between helical domain mutations (E542, E545) and kinase domain mutation (H1047), patients with H1047 mutation exhibited significantly poorer PFS compared to those with non-H1047 PIK3CA alterations (1.6 vs. 7.3 months, p=0.017). OS in patients with H1047 kinase domain mutation showed a trend toward being shorter compared to others, though this difference did not reach statistical significance.
Conclusion
Alpelisib showed differential efficacy based on PI3K pathway alterations in patients with R/M HNSCC and was well-tolerated. These findings suggest the usefulness of next-generation sequencing testing-based decision-making when using the targeted agents in R/M HNSCC. We need to confirm results in larger cohorts.

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Actualités 2025 par le comité de rédaction du Bulletin du Cancer : congrès ASCO, ESMO et au-delà
Stéphane Vignot, Audrey Bellesoeur, Delphine Borchiellini, Carole Bouleuc, Romain Cohen, Alexandre de Nonneville, Frédéric Delom, Serge Evrard, Nelly Firmin, Virginie Gandemer, Mohamed Khettab, Daniel Orbach, Manuel Rodrigues, Sébastien Thureau, Marie Wis
Bulletin du Cancer.2026; 113(1): 8. CrossRef
Beyond EGFR inhibition in head and neck squamous cell carcinoma: Overcoming resistance mechanisms and novel therapeutic frontiers
Francesca Carosi, Daria Maria Filippini, Laura Fabbri, Andrea Carlini, Andrea Monte, Michela Sgarzi, Matteo Fermi, Giulia Querzoli, Donatella Romaniello, Giuseppe Mercante, Achille Tarsitano, Christophe Le Tourneau, Mattia Lauriola
Critical Reviews in Oncology/Hematology.2026; 221: 105207. CrossRef
Prognostic Biomarkers and Immunotherapeutic Insights of Circulating Tumor DNA Analysis in Advanced Esophageal Squamous Cell Carcinoma From SCRUM-MONSTAR GOZILA Substudy
Yuqing Duan, Tadayoshi Hashimoto, Taro Shibuki, Hiroya Taniguchi, Yu Sunakawa, Yoshito Komatsu, Naoki Takahashi, Yuta Sato, Kensei Yamaguchi, Tomohiro Nishina, Tomonori Nakanoko, Shogen Boku, Taroh Satoh, Hisateru Yasui, Taito Esaki, Mitsuho Imai, Takao F
JCO Precision Oncology.2026;[Epub] CrossRef
Driving progress in recurrent and metastatic head and neck cancer: the NRG Oncology perspective
Mercedes Herrera, Matthew Ward, Glenn J Hanna, Sue S Yom, Dwight Heron, Anna Spreafico
JNCI: Journal of the National Cancer Institute.2026; 118(7): 1158. CrossRef
Functional characterization of PIK3CA E545A mutation in MCF-7 breast cancer cells reveals enhanced proliferation and resistance to Alpelisib
Hoai Thu Le, Nguyen Bao Nghi, Vu Diem My, Hoang Anh Vu, Ma Chi Thanh, Bui Minh Tri, Vo Van Thanh Niem, Huynh Anh Phuong
Biochemical and Biophysical Research Communications.2026; 829: 154189. CrossRef
Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling
Congxiu Huang, Wei Zhang, Xiaoyu Ma, Xuefeng Li, Xiaoge Sun
Molecular Genetics and Genomics.2026;[Epub] CrossRef
PIK3CA Mutations: Are They a Relevant Target in Adult Diffuse Gliomas?
Ana Tomás, Marta Pojo
International Journal of Molecular Sciences.2025; 26(11): 5276. CrossRef

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A Phase II Trial of Nintedanib in Patients with Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma: In-Depth Analysis of Nintedanib Arm from the KCSG HN 15-16 TRIUMPH Trial: Kyoo Hyun Kim, Sun Min Lim, Hee Kyung Ahn, Yun-Gyoo Lee, Keun-Wook Lee, Myung-Ju Ahn, Bhumsuk Keam, Hye Ryun Kim, Hyun Woo Lee, Ho Jung An, Jin-Soo Kim; Cancer Res Treat. 2024;56(1):37-47. Published online July 20, 2023; DOI: https://doi.org/10.4143/crt.2023.433

Abstract PDF PubReader ePub

Purpose
Precision oncology approach for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is necessary due to its dismal prognosis. We performed a genomic profile-based umbrella trial of patients with platinum-refractory HNSCC (KCSG-TRIUMPH). Here, we present an in-depth report of the the nintedanib arm (arm 3) of the current trial.
Materials and Methods
The TRIUMPH study was a multicenter, open-label, single-arm phase 2 trial, in which patients were assigned to treatment arms based on next-generation sequencing (NGS)–based, matching genomic profiles. Patients whose tumors harbor fibroblast growth factor receptor (FGFR) alteration were enrolled in the nintedanib arm (arm 3) as part of the TRIUMPH study. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and biomarker analysis.
Results
Between October 2017 and August 2020, 207 were enrolled in the TRIUMPH study, and eight were enrolled in the nintedanib arm. ORR and disease control rate were 42.9% and 57.1%, respectively. The median PFS was 5.6 months and the median duration of response was 9.1 months. Median OS was 11.1 months. One patient maintained the partial response for 36 months. Overall, the toxicity profiles were manageable.
Conclusion
Single-agent nintedanib has demonstrated significant efficacy in FGFR-mutated, recurrent or metastatic HNSCC patients, with tolerable toxicity profiles. The results from the study have provided the basis for routine NGS screening and FGFR-targeted therapy. Because of the small number of patients due to slow accrual in this study, further studies with a larger cohort are warranted for statistical power.

Citations

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Predictive and Prognostic Value of p16 in Head and Neck Squamous Cell Carcinoma Patients Treated with Molecular Targeted Agents or Immune Checkpoint Inhibitors: Subgroup Analysis of the TRIUMPH Study
Hyerim Ha, Sang Hoon Chun, Yun-Gyoo Lee, Hyun Chang, Jang Ho Cho, Der Sheng Sun, Sang Hee Cho, Jung Hye Kwon, Kyoung Eun Lee, In Gyu Hwang, Hyo Jung Kim, Bhumsuk Keam, Seong Hoon Shin, Sung-Bae Kim, Joo Hang Kim, Hwan Jung Yun
Cancer Investigation.2026; 44(5): 479. CrossRef
GARD: Genomic Data-Based Drug Repurposing in Head and Neck Cancer with Large Language Model Validation
Pradham Tanikella, William Nenad, Christophe Courtine, Yifan Dai, Qingying Deng, Baiming Zou, Nosayaba Osazuwa-Peters, Travis P. Schrank, Di Wu
Cancers.2026; 18(5): 757. CrossRef
Expression and prognostic relevance of FGF19-KLB-FGFR4 pathway proteins and tumor microenvironment-related proteins in oral squamous cell carcinoma
Junichi Misumi, Kenichiro Uchida, Ryo Nonaka, Katsuaki Mishima
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology.2026; 38(6): 1256. CrossRef
Fibroblast growth factor receptor signaling in head and neck tumors: molecular pathogenesis and potential therapeutic targets
Luqin Tang, Hanqi Xia, Zhu Zheng, Yuxin Cheng, Zhixuan Huang, Tai Ma
Clinical and Translational Oncology.2026;[Epub] CrossRef
Targeting fibroblast growth factor receptor (FGFR) with inhibitors in head and neck cancers: Their roles, mechanisms and challenges
Daowen Luo, Sirinart Kumfu, Nipon Chattipakorn, Siriporn C. Chattipakorn
Biochemical Pharmacology.2025; 235: 116845. CrossRef
Functional Characterization of Variants of Unknown Significance of Fibroblast Growth Factor Receptors 1-4 and Comparison With AI Model–Based Prediction
Martin Ziegler, Nadira Khoury, Louisa Maxine Hommerich, Heike Adler, Sonja Loges
JCO Precision Oncology.2025;[Epub] CrossRef
Prevalence and biological impact of clinically relevant gene fusions in head and neck cancers
Emily L. Hoskins, Raven Vella, Julie W. Reeser, Michele R. Wing, Eric Samorodnitsky, Altan Turkoglu, Leah Stein, Elizabeth Breuning, Zachary A. Risch, Wilnelly M. Hernandez-Sanchez, Lianbo Yu, Michelle Churchman, Nancy Single, Jad Chahoud, Antonio Jimeno,
npj Precision Oncology.2025;[Epub] CrossRef
Molecular insights into immune evasion in head and neck squamous cell carcinomas: Toward a promising treatment strategy
HYEON JI KIM, BO KYUNG JOO, JIN-SEOK BYUN, DO-YEON KIM
Oncology Research.2025; 33(6): 1271. CrossRef
One-pot synthesis and pharmacological evaluation of new quinoline/pyrimido-diazepines as pulmonary antifibrotic agents
Michael Atef Fawzy, Karim Hagag Ibrahim, Ashraf A Aly, Asmaa H Mohamed, Sara Mohamed Naguib Abdel Hafez, Walaa Yehia Abdelzaher, Eslam B Elkaeed, Aisha A Alsfouk, El-Shimaa MN Abdelhafez
Future Medicinal Chemistry.2024; 16(21): 2211. CrossRef
Critical review of the current and future prospects of VEGF-TKIs in the management of squamous cell carcinoma of head and neck
Prashant Puttagunta, Saagar V. Pamulapati, James E. Bates, Jennifer H. Gross, William A. Stokes, Nicole C. Schmitt, Conor Steuer, Yong Teng, Nabil F. Saba
Frontiers in Oncology.2023;[Epub] CrossRef

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Phase II Trial of Combined Durvalumab Plus Tremelimumab with Proton Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Hana Kim, Sehhoon Park, Hyun Ae Jung, Se-Hoon Lee, Keunchil Park, Yong Chan Ahn, Dongryul Oh, Myung-Ju Ahn; Cancer Res Treat. 2023;55(4):1104-1112. Published online May 17, 2023; DOI: https://doi.org/10.4143/crt.2023.502

Abstract PDF Supplementary Material PubReader ePub

Purpose
This phase II study investigated whether durvalumab/tremelimumab with proton therapy improves the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients.
Materials and Methods
Patients who previously received more than one chemotherapy, including at least one platinum-based regimen, and who had at least two measurable lesions were enrolled. Patients received 1,500 mg durvalumab intravenously combined with 75 mg tremelimumab intravenously every 4 weeks for four cycles followed by 1,500 mg durvalumab every 4 weeks. After one cycle of the durvalumab/tremelimumab treatment, proton therapy was given with a total dose of 25 Gy in 5 Gy daily fractions to one of the measurable lesions. We also assessed the ORR in the target lesion outside the radiation field to evaluate the abscopal effect.
Results
Thirty-one patients were enrolled between March 2018 and July 2020. With 8.6 months of follow-up, the ORR was 22.6% (7/31), including one complete response and six partial responses. The median OS was 8.4 months (95% confidence interval [CI], 2.5 to 14.3) and the median PFS was 2.4 months (95% CI, 0.6 to 4.2). Among the 23 evaluable patients who completed proton therapy, the ORR was 30.4% (7/23). The median OS was 11.1 months (95% CI, 6.5 to 15.8), and the median PFS was 3.7 months (95% CI, 1.6 to 5.7). Grade 3 or higher adverse events were observed in six patients (19.4%) as follows: anemia (n=1), constipation (n=1), electrolyte imbalances (n=2), hyperglycemia (n=1), and pneumonia (n=1).
Conclusion
The combination of durvalumab/tremelimuab with proton therapy was tolerated well and had encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients.

Citations

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