Abstract
Treatment options for patients with advanced neuroendocrine tumors (NETs) are limited. Preclinical and early clinical evidence suggest that cabozantinib and temozolomide may exert synergistic antitumor activity. We performed an open-label, single-arm, phase 2 study (NCT04893785) to assess the safety and efficacy of cabozantinib and metronomic temozolomide in patients with advanced, progressive, well-differentiated NETs of gastroenteropancreatic, pulmonary or unknown origin. Patients received cabozantinib 40 mg daily and temozolomide 100 mg/m2/day one week on/one week off. The primary endpoint was overall response rate (ORR) by blinded local review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), duration of response (DOR) and safety. Of the 37 patients enrolled, 14 harbored gastrointestinal NETs, 12 pancreatic NETs, 9 lung NETs and 2 NETs of unknown primary. Neoplasms were classified as G1, G2 or G3 in 9, 24 and 4 cases respectively. While all enrolled patients were assessable for toxicity, 33 met the criteria for per protocol assessment of efficacy. The ORR was 15% (95% CI, 5-31%) and did not meet the primary endpoint. However, after a median follow-up of 19.2 months, the CBR was 100% (95% CI, 89.5-100%) and the median PFS was 28.5 months (95% CI, 16.8-28.5 months). The median OS was not reached, with a 3-year OS rate of 68.5% ( ± 9.1%). The median DOR was 19.5 months. Lymphopenia (16%), thrombocytopenia (11%), diarrhea (8%) and colitis (8%) emerged as the most frequent grade ≥3 treatment-related adverse events. No treatment-related deaths were recorded. Deficiency of O⁶-methylguanine–DNA methyltransferase (MGMT) and c-MET expression were associated with response. The proportion of the patients benefitting of the treatment and its safety profile justify larger, controlled studies to further investigate the added role of combining cabozantinib with metronomic temozolomide. ClinicalTrials.gov identifier: NCT04893785.
Data availability
The study protocol is available as Supplementary Note in the Supplementary Information file. The clinical raw data are protected and are not available due to data privacy laws. The data that support the findings of this study are available from the corresponding author (Salvatore Tafuto; s.tafuto@istitutotumori.na.it) upon reasonable request (equivalent purposes to those for which the patients grant their consent to use the data). Data sharing requests will be considered on a case-by-case basis in a timely manner. Response to access requests will be provided within 4 weeks and data will be available for 6 months once access has been granted. Data will be provided anonymized, with no personal identifiable data. Source data of all figures are provided with this paper. Source data are provided with this paper.
References
Cives, M. & Strosberg, J. R. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J. Clin. 68, 471–487 (2018).
Dasari, A. et al. Epidemiology of neuroendocrine neoplasms in the US. JAMA Netw. Open 8, e2515798 (2025).
Rinke, A. et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J. Clin. Oncol. 27, 4656–4663 (2009).
Caplin, M. E. et al. CLARINET investigators. lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med. 371, 224–233 (2014).
Yao, J. C. et al. RAD001 in advanced neuroendocrine tumours, fourth trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387, 968–977 (2016).
Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).
Kunz, P. L. et al. 3rd. Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J. Clin. Oncol. 41, 1359–1369 (2023).
Strosberg, J. et al. NETTER-1 trial investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376, 125–135 (2017).
Singh, S. et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet 403, 2807–2817 (2024).
Chan, J. A. et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N. Engl. J. Med. 392, 653–665 (2025).
Li, M. Y. et al. Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas. Sci. Rep. 6, 21141 (2016).
Zhang, L., Scorsone, K., Woodfield, S. E. & Zage, P. E. Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition. Cancer Chemother. Pharm. 76, 977–987 (2015).
Noh, J. J. et al. Anticancer activity of the combination of cabozantinib and temozolomide in uterine sarcoma. Clin. Cancer Res. 28, 3850–3861 (2022).
Kurzen, H., Schmitt, S., Näher, H. & Möhler, T. Inhibition of angiogenesis by non-toxic doses of temozolomide. Anticancer Drugs 14, 515–522 (2003).
Kim, J. T. et al. Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol. Rep. 16, 33–39 (2006).
Schiff, D. et al. Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas. Cancer 122, 582–587 (2016).
Agulnik, M. et al. A phase II study of cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas. J. Clin. Oncol. 41, 11505 (2023).
Ikeda, S. et al. Synergistic effects of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. J. Clin. Oncol. 33, 5590 (2015).
Grande, E. et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann. Oncol. 26, 1987–1993 (2015).
Garcia-Carbonero, R. et al. A phase II/III randomized double-blind study of octreotide acetate LAR with axitinib versus octreotide acetate LAR with placebo in patients with advanced G1-G2 NETs of non-pancreatic origin (AXINET trial-GETNE-1107). J. Clin. Oncol. 39, 360 (2021).
Capdevila, J. et al. Lenvatinib in patients with advanced grade ½ pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT Trial (GETNE1509). J. Clin. Oncol. 39, 2304–2312 (2021).
Xu, J. et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21, 1489–1499 (2020).
Xu, J. et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21, 1500–1512 (2020).
Al-Toubah, T., Morse, B. & Strosberg, J. Efficacy of capecitabine and temozolomide in small bowel (midgut) neuroendocrine tumors. Curr. Oncol. 29, 510–515 (2022).
Melhorn, P., Raderer, M. & Kiesewetter, B. Selecting systemic treatment for metastatic neuroendocrine tumors of the lung-current evidence and clinical implications. Cancer Treat. Rev. 133, 102878 (2025).
Tafuto, S. et al. Safety and activity of metronomic temozolomide in second-line treatment of advanced neuroendocrine neoplasms. J. Clin. Med. 8, 1224 (2019).
Von Arx, C. et al. A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial. ESMO Open 9, 103003 (2024).
Natale, G. & Bocci, G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 432, 28–37 (2018).
Liu, Z. L., Chen, H. H., Zheng, L. L., Sun, L. P. & Shi, L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct. Target Ther. 8, 198 (2023).
Kulke, M. H. et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J. Clin. Oncol. 24, 401–406 (2006).
Koumarianou, A. et al. Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide for malignant neuroendocrine tumours. Endocr. Relat. Cancer 19, L1–L4 (2012).
Chan, J. A. et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 30, 2963–2968 (2012).
Ünal, Ç & Sağlam, S. Metronomic temozolomide (mTMZ) and bevacizumab—the safe and effective frontier for treating metastatic neuroendocrine tumors (NETs): a single-center experience. Cancers 15, 5688 (2023).
Templeton, A. J., Amir, E. & Tannock, I. F. Informative censoring—a neglected cause of bias in oncology trials. Nat. Rev. Clin. Oncol. 17, 327–328 (2020).
Labadie, B. W. & Fojo, A. T. Requirements for meaningful progress in the therapy of neuroendocrine cancers. JAMA Oncol. 9, 606–608 (2023).
Walter, T. et al. “Groupe d’étude des tumeurs endocrines (GTE)” and the French ENDOCAN-RENATEN network. Oxaliplatin-based versus alkylating agent in neuroendocrine tumors according to the o6-methylguanine-DNA methyltransferase status: a randomized phase II study (MGMT-NET). J. Clin. Oncol. 43, 960–971 (2025).
Ghosh, R. et al. MEN1-related neuroendocrine tumors show c-MET overexpression. J. Endocr. Soc. 9, bvaf147 (2025).
Hansel, D. E. et al. Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin. Cancer Res. 10, 6152–6158 (2004).
Song, J. et al. Expression patterns of PAX5, c-met and paxillin in neuroendocrine tumors of the lung. Arch. Pathol. Lab. Med. 134, 1702–1705 (2010).
La Rosa, S. et al. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum. Pathol. 34, 18–27 (2003).
Pellat, A. et al. Clinical and biomarker evaluations of sunitinib in patients with grade 3 digestive neuroendocrine neoplasms. Neuroendocrinology 107, 24–31 (2018).
Tsoti, S. M. & Pinato, D. J. AXL receptor tyrosine kinase expression as a prognostic marker and therapeutic target in neuroendocrine tumours. ESMO Open 3, A323 (2018).
Klimstra, D. S. et al. WHO Classification of Tumors of the Digestive System 5th edn, Vol. 1 (IARC Press, 2019).
WHO classification of tumours editorial board. Thoracic tumours. In: WHO Classification of Tumours 5th edn, Vol. 5.6 (IARC Publications, 2021).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
Aaronson, N. K. et al. The European organization for research and treatment of cancer QLQ- C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl. Cancer Inst. 85, 365–376 (1993).
Yadegarfar, G. et al. EORTC Quality of Life Group. Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours. Br. J. Cancer 108, 301–310 (2013).
Cros, J. et al. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. Endocr. Relat. Cancer 23, 625–633 (2016).
Della Monica, R. et al. Evaluation of MGMT gene methylation in neuroendocrine neoplasms. Oncol. Res. 28, 837–845 (2022).
Acknowledgements
IPSEN provided cabozantinib and awarded a grant to Dr. Tafuto to pay the costs of the study. The funder did not have a role in designing or conducting the study, and was not involved in the analysis and interpretation of study results. The authors thank all patients and families, investigators, and study staff involved in the CABOTEM trial.
Author information
Authors and Affiliations
Contributions
S.T. and D.V.S.G. were responsible for the study design and coordination. M.C. and E.L. drafted the manuscript. All authors (M.C., G.D.V.S., O.C., E.L., A.B., G.B., P.D., L.C., C.P., A.R., N.C., R.D.M., A.D.M., A.P., J.S., M.B., G.I., F.P, P.P, F.G., C.P., and S.T.) made substantial contributions to data acquisition, interpretation of study results, critical manuscript revision for important intellectual content, provided approval to the final version to be published and agreed to be accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.
Corresponding author
Ethics declarations
Competing interests
Prof. Cives has performed a consultation for Ipsen. Prof. Badalamenti has performed a consultation for Ipsen and has received speaker’s fees from Ipsen. Prof. Porta has performed consultations for Ipsen and Exelixis and has received speaker’s fees from Exelixis. Dr. Tafuto has received grants or consulting fees from Ipsen. All remaining authors have declared no conflicts of interest.
Peer review
Peer review information
Nature Communications thanks Xianming Tan, Yong Teng, and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Cives, M., Della Vittoria Scarpati, G., Clemente, O. et al. Cabozantinib and temozolomide in patients with advanced progressive neuroendocrine tumors: a phase 2 study. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71756-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-71756-7
