Emerging Role of Lenvatinib in Treating Platinum-Refractory Head and Neck Cancer in Resource-Limited Settings

Abstract

Lenvatinib, an oral multiple tyrosine kinase inhibitor, is currently being explored in the area of head and neck squamous cell carcinoma (HNSCC). Two-thirds of total patients are presented in the advanced stage leading to poor prognosis with conventional treatment. The addition of immunotherapy is the standard approach to it. However, in developing nations and resource-limited setups, affordability is the major concern. To encounter this, lenvatinib has become a novel cost-effective treatment for HNSCC. Lenvatinib targets a varied range of receptors including vascular endothelial growth factor receptor, platelet-derived growth factor receptor α, fibroblast growth factor receptor, KIT (stem cell factor receptor), and rearranged during transfection, all of which are involved in the pathogenesis of HNSCC leading to the establishment of its role in HNSCC. It inhibits angiogenesis in endothelial cells and proliferation in tumor cells. Instances of resistance were observed in monoreceptor targeting agents, which are also overcome by lenvatinib, leading to potent antitumor activity. Clinical studies are being conducted to establish the role of lenvatinib as a third-line therapy in HNSCC. In this review, we discuss the role of lenvatinib in resource-limited, platinum-refractory, and recurrent/metastatic HNSCC.

Keywords

lenvatinib - advanced head and neck cancer - platinum-refractory - resource-limited settings - clinical trials

Data Availability Statement

The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Authors' Contributions

A.K., R.K., M.M.: Conceptualization. K.R.M., N.H.S., V.G.K.: Writing original draft, data collection, and interpretation. A.K.: Supervision. A.K., R.K., M.M.: Writing review and editing. All authors read and approved the final content.

Patient Consent

Patient consent is not required as no patients were involved in the preparation of this article.

Publication History

Article published online:
27 May 2025

• References

• 1 Simard EP, Torre LA, Jemal A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. Oral Oncol 2014; 50 (05) 387-403
• 2 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
• 3 Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Med Sci (Basel) 2023; 11 (02) 42
• 4 Francis CJK. 374P Trends in incidence of head and neck cancers in India. Ann Oncol 2016; 27: ix116
• 5 Bagal S, Budukh A, Thakur JS. et al. Head and neck cancer burden in India: an analysis from published data of 37 population-based cancer registries. Ecancermedicalscience 2023; 17: 1603
• 6 Mohamad I, Glaun MDE, Prabhash K. et al. Current Treatment Strategies and Risk Stratification for Oral Carcinoma. Am Soc Clin Oncol Educ Book 2023; 43: e389810
• 7 Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J 2022; 233 (09) 780-786
• 8 de Martel C, Ferlay J, Franceschi S. et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13 (06) 607-615
• 9 Galati L, Chiocca S, Duca D. et al. HPV and head and neck cancers: towards early diagnosis and prevention. Tumour Virus Res 2022; 14: 200245
• 10 Concurrent Chemoradiation Therapy With Weekly Cisplatin for Locally Advanced Head and Neck Squamous Cell Carcinoma - The ASCO Post. . Accessed August 4, 2024 at: https://ascopost.com/issues/september-10-2022/concurrent-chemoradiation-therapy-with-weekly-cisplatin-for-locally-advanced-head-and-neck-squamous-cell-carcinoma/
• 11 Joshi P, Dutta S, Chaturvedi P, Nair S. Head and neck cancers in developing countries. Rambam Maimonides Med J 2014; 5 (02) e0009
• 12 Agarwal AK, Sethi A, Sareen D, Dhingra S. Treatment delay in oral and oropharyngeal cancer in our population: the role of socio-economic factors and health-seeking behaviour. Indian J Otolaryngol Head Neck Surg 2011; 63 (02) 145-150
• 13 Fulcher CD, Haigentz Jr M, Ow TJ. Education Committee of the American Head and Neck Society (AHNS). AHNS Series: do you know your guidelines? Principles of treatment for locally advanced or unresectable head and neck squamous cell carcinoma. Head Neck 2018; 40 (04) 676-686
• 14 Ionna F, Bossi P, Guida A. et al. Recurrent/metastatic squamous cell carcinoma of the head and neck: a big and intriguing challenge which may be resolved by integrated treatments combining locoregional and systemic therapies. Cancers (Basel) 2021; 13 (10) 2371
• 15 Goel B, Tiwari AK, Pandey RK. et al. Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-an update on clinical trials. Transl Oncol 2022; 21: 101426
• 16 Ferris RL, Blumenschein Jr G, Fayette J. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375 (19) 1856-1867
• 17 Burtness B, Harrington KJ, Greil R. et al; KEYNOTE-048 Investigators. 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 (10212): 1915-1928
• 18 Patil V, Noronha V, Dhumal SB. et al. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial. Lancet Glob Health 2020; 8 (09) e1213-e1222
• 19 Low Dose of Cancer Immunotherapy Effective in Trial in India - NCI. Accessed August 6, 2024 at: https://www.cancer.gov/news-events/cancer-currents-blog/2022/cancer-immunotherapy-low-dose
• 20 Suyama K, Iwase H. Lenvatinib: a promising molecular targeted agent for multiple cancers. Cancer Control 2018; 25 (01) 1073274818789361
• 21 Hsu HW, Wall NR, Hsueh CT. et al. Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol 2014; 50 (01) 19-26
• 22 Motzer RJ, Taylor MH, Evans TRJ. et al. Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies. Expert Rev Anticancer Ther 2022; 22 (04) 383-400
• 23 Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 2013; 153 (01) 13-19
• 24 Wang L, Liu WQ, Broussy S, Han B, Fang H. Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis. Front Pharmacol 2024; 14: 1307860
• 25 Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE 2001; 2001 (112) re21
• 26 Patel SA, Nilsson MB, Le X, Cascone T, Jain RK, Heymach JV. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clin Cancer Res 2023; 29 (01) 30-39
• 27 Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 2006; 7 (05) 359-371
• 28 Karaman S, Leppänen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development 2018; 145 (14) dev151019
• 29 Ye X, Gaucher JF, Vidal M, Broussy S. A structural overview of vascular endothelial growth factors pharmacological ligands: from macromolecules to designed peptidomimetics. Molecules 2021; 26 (22) 6759
• 30 Mäkinen T, Veikkola T, Mustjoki S. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 2001; 20 (17) 4762-4773
• 31 Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 2006; 12 (17) 5018-5022
• 32 Xue WJ, Li MT, Chen L, Sun LP, Li YY. Recent developments and advances of FGFR as a potential target in cancer. Future Med Chem 2018; 10 (17) 2109-2126
• 33 Mikhaylenko DS, Alekseev BY, Zaletaev DV, Goncharova RI, Nemtsova MV. Structural alterations in human fibroblast growth factor receptors in carcinogenesis. Biochemistry (Mosc) 2018; 83 (08) 930-943
• 34 Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem 2011; 149 (02) 121-130
• 35 Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015; 4 (03) 215-266
• 36 Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010; 10 (02) 116-129
• 37 Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J. Critical role for the docking-protein FRS2 α in FGF receptor-mediated signal transduction pathways. Proc Natl Acad Sci U S A 2001; 98 (15) 8578-8583
• 38 Zhang P, Yue L, Leng Q. et al. Targeting FGFR for cancer therapy. J Hematol Oncol 2024; 17 (01) 39
• 39 Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018; 15 (05) 325-340
• 40 Kimura T, Kato Y, Ozawa Y. et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci 2018; 109 (12) 3993-4002
• 41 Adachi Y, Kamiyama H, Ichikawa K. et al. Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies. Cancer Res 2022; 82 (02) 292-306
• 42 Zou X, Tang XY, Qu ZY. et al. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a review. Int J Biol Macromol 2022; 202: 539-557
• 43 Chen PH, Chen X, He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim Biophys Acta 2013; 1834 (10) 2176-2186
• 44 Kazlauskas A. PDGFs and their receptors. Gene 2017; 614: 1-7
• 45 Demoulin JB, Essaghir A. PDGF receptor signaling networks in normal and cancer cells. Cytokine Growth Factor Rev 2014; 25 (03) 273-283
• 46 Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal 2013; 11 (01) 97
• 47 Pandey P, Khan F, Upadhyay TK, Seungjoon M, Park MN, Kim B. New insights about the PDGF/PDGFR signaling pathway as a promising target to develop cancer therapeutic strategies. Biomed Pharmacother 2023; 161: 114491
• 48 Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 2018; 15 (03) 151-167
• 49 Kawai K, Takahashi M. Intracellular RET signaling pathways activated by GDNF. Cell Tissue Res 2020; 382 (01) 113-123
• 50 Belli C, Anand S, Gainor JF. et al. Progresses toward precision medicine in RET-altered solid tumors. Clin Cancer Res 2020; 26 (23) 6102-6111
• 51 Pilloni L, Bianco P, Difelice E. et al. The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions. Eur J Histochem 2011; 55 (02) e20
• 52 Pathania S, Pentikäinen OT, Singh PK. A holistic view on c-Kit in cancer: structure, signaling, pathophysiology and its inhibitors. Biochim Biophys Acta Rev Cancer 2021; 1876 (02) 188631
• 53 Phung B, Sun J, Schepsky A, Steingrimsson E, Rönnstrand L. C-KIT signaling depends on microphthalmia-associated transcription factor for effects on cell proliferation. PLoS One 2011; 6 (08) e24064
• 54 Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 2012; 92 (04) 1619-1649
• 55 Regua AT, Najjar M, Lo HW. RET signaling pathway and RET inhibitors in human cancer. Front Oncol 2022; 12: 932353
• 56 Sheikh E, Tran T, Vranic S, Levy A, Bonfil RD. Role and significance of c-KIT receptor tyrosine kinase in cancer: a review. Bosn J Basic Med Sci 2022; 22 (05) 683-698
• 57 Li Q, Tie Y, Alu A, Ma X, Shi H. Targeted therapy for head and neck cancer: signaling pathways and clinical studies. Signal Transduct Target Ther 2023; 8 (01) 31
• 58 Sweeny L, Zimmermann TM, Liu Z, Rosenthal EL. Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts. Oral Oncol 2012; 48 (12) 1242-1249
• 59 Koole K, Brunen D, van Kempen PMW. et al. FGFR1 is a potential prognostic biomarker and therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res 2016; 22 (15) 3884-3893
• 60 Long Z, Grandis JR, Johnson DE. Emerging tyrosine kinase inhibitors for head and neck cancer. Expert Opin Emerg Drugs 2022; 27 (03) 333-344
• 61 Dunn L, Ho AL, Eng J. et al. A phase I/Ib study of lenvatinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 2020; 38 (15) x
• 62 Taylor MH, Lee CH, Makker V. et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 2020; 38 (11) 1154-1163
• 63 Chen TH, Chang PMH, Yang MH. Combination of pembrolizumab and lenvatinib is a potential treatment option for heavily pretreated recurrent and metastatic head and neck cancer. J Chin Med Assoc 2021; 84 (04) 361-367
• 64 Powell SF, Liu SV, Sukari A. et al. KEYNOTE-055: a phase II trial of single agent pembrolizumab in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who have failed platinum and cetuximab. J Clin Oncol 2015; 33 (15, suppl): TPS3094
• 65 Padda IS, Patel P, Parmar M. Lenvatinib. Cancer Control 2025; 25 (01) 107327481878936
• 66 Wirth LJ, Durante C, Topliss DJ. et al. Lenvatinib for the treatment of radioiodine-refractory differentiated thyroid cancer: treatment optimization for maximum clinical benefit. Oncologist 2022; 27 (07) 565-572
• 67 Zhao Y, Zhang YN, Wang KT, Chen L. Lenvatinib for hepatocellular carcinoma: from preclinical mechanisms to anti-cancer therapy. Biochim Biophys Acta Rev Cancer 2020; 1874 (01) 188391
• 68 Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: a review in hepatocellular carcinoma. Drugs 2019; 79 (06) 665-674
• 69 Bo W, Chen Y. Lenvatinib resistance mechanism and potential ways to conquer. Front Pharmacol 2023; 14: 1153991
• 70 Elebiyo TC, Rotimi D, Evbuomwan IO. et al. Reassessing vascular endothelial growth factor (VEGF) in anti-angiogenic cancer therapy. Cancer Treat Res Commun 2022; 32: 100620