Cancer Research and Treatment

Original Articles

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; Received December 11, 2024 Accepted January 27, 2025 Published online January 31, 2025; DOI: https://doi.org/10.4143/crt.2024.1195 [Accepted]

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 PIK3CAɑ 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 (DCR), overall survival (OS), and progression-free survival (PFS).
Results
From Oct 2017 and Aug 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 mutations (H1047), patients with H1047 mutations 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 mutations 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 NGS testing-based decision-making when using the targeted agents in R/M HNSCC. We need to confirm results in larger cohorts.

Citations

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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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Head and Neck cancer

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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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
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

Citations to this article as recorded by

Abscopal Effects and Immunomodulation in Skin Cancer Therapy
William J. Nahm, Goranit Sakunchotpanit, Vinod E. Nambudiri
American Journal of Clinical Dermatology.2025;[Epub] CrossRef
Abscopal effect in maxillary sinus cancer: Insights from two case reports and a literature review
Akihiro Sakai, Koji Ebisumoto, Hiroaki Iijima, Mayu Yamauchi, Daisuke Maki, Tsuyoshi Fukuzawa, Kenji Okami
Cancer Reports.2024;[Epub] CrossRef
Solid tumours showing oligoprogression to immune checkpoint inhibitors have the potential for abscopal effects
Makoto Ito, Souichiro Abe, Sou Adachi, Yukihiko Oshima, Arisa Takeuchi, Wataru Ohashi, Takashi Iwata, Tetsuya Ogawa, Akiko Ota, Yasuaki Kubota, Takahito Okuda, Kojiro Suzuki
Japanese Journal of Radiology.2024; 42(4): 424. CrossRef
Durvalumab with or without tremelimumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a systematic review and meta-analysis
Xiao Han, Haidong Zhang, Kai Sun, Jing Li, Wanjuan Wu, Kai Liu, Zhenkun Yu
Frontiers in Immunology.2024;[Epub] CrossRef
Kaplan lecture 2023: lymphopenia in particle therapy
Marco Durante
International Journal of Radiation Biology.2024; 100(5): 669. CrossRef
Clinical application of high‐LET radiotherapy combined with immunotherapy in malignant tumors
Kexin Meng, Haijun Lu
Precision Radiation Oncology.2024; 8(1): 42. CrossRef
Research progress of immunotherapy for advanced head and neck cancer
Anchi Sun, Zhiwei Xing, Rongrong Lv, Pengyuan Niu, Bao Zhao, Shiyin Ma, Hui Li
Medical Oncology.2024;[Epub] CrossRef
A review and bibliometric analysis of global research on proton radiotherapy
Ge Song, Zhi Zheng, Yingming Zhu, Yaoting Wang, Song Xue
Medicine.2024; 103(19): e38089. CrossRef
Cutaneous Squamous Cell Carcinoma: An Updated Review
Rina Jiang, Mike Fritz, Syril Keena T. Que
Cancers.2024; 16(10): 1800. CrossRef
Radiotherapy and immunology
Liangliang Wang, Connor Lynch, Sean P. Pitroda, András Piffkó, Kaiting Yang, Amy K. Huser, Hua Laura Liang, Ralph R. Weichselbaum
Journal of Experimental Medicine.2024;[Epub] CrossRef
The Evolving Paradigm of Immunotherapy in Head-and-neck Squamous Cell Cancers
Riccardo Gili, Paolo Bossi
Journal of Head & Neck Physicians and Surgeons.2024; 12(1): 13. CrossRef
Neoadjuvant Immunotherapy in Head and Neck Cancers: A Paradigm Shift in Treatment Approach
Alessia Zotta, Maria Luisa Marciano, Francesco Sabbatino, Alessandro Ottaiano, Marco Cascella, Monica Pontone, Massimo Montano, Ester Calogero, Francesco Longo, Morena Fasano, Teresa Troiani, Fortunato Ciardiello, Fabiana Raffaella Rampetta, Giovanni Salz
Biomedicines.2024; 12(10): 2337. CrossRef
Emerging Radiotherapy Technologies for Head and Neck Squamous Cell Carcinoma: Challenges and Opportunities in the Era of Immunotherapy
Carmen Kut, Harry Quon, Xuguang Scott Chen
Cancers.2024; 16(24): 4150. CrossRef

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