Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial

The oncologist

article

Enrique Grande¹  Cristina Rodriguez-Antona²  Carlos López⁴  Teresa Alonso-Gordoa⁵  Marta Benavent⁶  Jaume Capdevila⁷  Alex Teulé⁸  Ana Custodio⁹  Isabel Sevilla^1,10  Jorge Hernando⁷  Pablo Gajate⁵  Javier Molina-Cerrillo⁵  Juan José Díez^1,11  María Santos²  Javier Lanillos²  Rocío García-Carbonero^1,12 

[1]Medical Oncology Department, MD Anderson Cancer Center Madrid

[2]Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre

[3]Centro de Investigación Biomédica en Red de Enfermedades Raras

[4]Medical Oncology, Hospital Universitario Marqués de Valdecilla, Instituto de investigación sanitaria Valdecilla

[5]Medical Oncology, Hospital Universitario Ramón y Cajal

[6]Medical Oncology Department, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla

[7]Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology

[8]Institut Català d'Oncologia ,(ICO)–Institut d'Investigació Biomèdica de Bellvitge ,(IDIBELL), L'Hospitalet del Llobregat

[9]Medical Oncology Department, Hospital Universitario La Paz

[10]Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Málaga ,(IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria

[11]Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro Segovia de Arana

[12]Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre ,(i+12), Universidad Complutense de Madrid

关键词: Biomarkers;    Pancreatic neuroendocrine tumor;    Safety;    Evofosfamide;    Sunitinib;   

DOI  :  10.1002/onco.13885

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs). Methods Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m 2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1. Results From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete ( n  = 1) or partial response ( n  = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX , ATRX , MEN1 , SETD2 , and PTEN gene mutations. Conclusion SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. ( Clinical trial identification number : NCT02402062) Implications for Practice Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.

【 授权许可】

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