Enrique Grande1, Cristina Rodriguez-Antona2,3, Carlos López4, Teresa Alonso-Gordoa5, Marta Benavent6, Jaume Capdevila7, Alex Teulé8, Ana Custodio9, Isabel Sevilla10, Jorge Hernando7, Pablo Gajate5, Javier Molina-Cerrillo5, Juan José Díez11, María Santos2, Javier Lanillos2, Rocío García-Carbonero12. 1. Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain. 2. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. 3. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain. 4. Medical Oncology, Hospital Universitario Marqués de Valdecilla, Instituto de investigación sanitaria Valdecilla (IDIVAL), Santander, Spain. 5. Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain. 6. Medical Oncology Department, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain. 7. Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology, Barcelona, Spain. 8. Institut Català d'Oncologia (ICO)-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Spain. 9. Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain. 10. Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Málaga (IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain. 11. Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro Segovia de Arana, Madrid, Spain. 12. Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Abstract
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/m2 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.
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/m2 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.
Authors: G Delle Fave; D O'Toole; A Sundin; B Taal; P Ferolla; J K Ramage; D Ferone; T Ito; W Weber; Z Zheng-Pei; W W De Herder; A Pascher; P Ruszniewski Journal: Neuroendocrinology Date: 2016-01-19 Impact factor: 4.914
Authors: Aldo Scarpa; David K Chang; Katia Nones; Vincenzo Corbo; Ann-Marie Patch; Peter Bailey; Rita T Lawlor; Amber L Johns; David K Miller; Andrea Mafficini; Borislav Rusev; Maria Scardoni; Davide Antonello; Stefano Barbi; Katarzyna O Sikora; Sara Cingarlini; Caterina Vicentini; Skye McKay; Michael C J Quinn; Timothy J C Bruxner; Angelika N Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne McLean; Craig Nourse; Ehsan Nourbakhsh; Peter J Wilson; Matthew J Anderson; J Lynn Fink; Felicity Newell; Nick Waddell; Oliver Holmes; Stephen H Kazakoff; Conrad Leonard; Scott Wood; Qinying Xu; Shivashankar Hiriyur Nagaraj; Eliana Amato; Irene Dalai; Samantha Bersani; Ivana Cataldo; Angelo P Dei Tos; Paola Capelli; Maria Vittoria Davì; Luca Landoni; Anna Malpaga; Marco Miotto; Vicki L J Whitehall; Barbara A Leggett; Janelle L Harris; Jonathan Harris; Marc D Jones; Jeremy Humphris; Lorraine A Chantrill; Venessa Chin; Adnan M Nagrial; Marina Pajic; Christopher J Scarlett; Andreia Pinho; Ilse Rooman; Christopher Toon; Jianmin Wu; Mark Pinese; Mark Cowley; Andrew Barbour; Amanda Mawson; Emily S Humphrey; Emily K Colvin; Angela Chou; Jessica A Lovell; Nigel B Jamieson; Fraser Duthie; Marie-Claude Gingras; William E Fisher; Rebecca A Dagg; Loretta M S Lau; Michael Lee; Hilda A Pickett; Roger R Reddel; Jaswinder S Samra; James G Kench; Neil D Merrett; Krishna Epari; Nam Q Nguyen; Nikolajs Zeps; Massimo Falconi; Michele Simbolo; Giovanni Butturini; George Van Buren; Stefano Partelli; Matteo Fassan; Kum Kum Khanna; Anthony J Gill; David A Wheeler; Richard A Gibbs; Elizabeth A Musgrove; Claudio Bassi; Giampaolo Tortora; Paolo Pederzoli; John V Pearson; Nicola Waddell; Andrew V Biankin; Sean M Grimmond Journal: Nature Date: 2017-02-15 Impact factor: 49.962
Authors: Aatur D Singhi; Ta-Chiang Liu; Justin L Roncaioli; Dengfeng Cao; Herbert J Zeh; Amer H Zureikat; Allan Tsung; J Wallis Marsh; Kenneth K Lee; Melissa E Hogg; Nathan Bahary; Randall E Brand; Kevin M McGrath; Adam Slivka; Kristi L Cressman; Kimberly Fuhrer; Roderick J O'Sullivan Journal: Clin Cancer Res Date: 2016-07-12 Impact factor: 12.531
Authors: Yuchen Jiao; Chanjuan Shi; Barish H Edil; Roeland F de Wilde; David S Klimstra; Anirban Maitra; Richard D Schulick; Laura H Tang; Christopher L Wolfgang; Michael A Choti; Victor E Velculescu; Luis A Diaz; Bert Vogelstein; Kenneth W Kinzler; Ralph H Hruban; Nickolas Papadopoulos Journal: Science Date: 2011-01-20 Impact factor: 47.728
Authors: Eric Raymond; Laetitia Dahan; Jean-Luc Raoul; Yung-Jue Bang; Ivan Borbath; Catherine Lombard-Bohas; Juan Valle; Peter Metrakos; Denis Smith; Aaron Vinik; Jen-Shi Chen; Dieter Hörsch; Pascal Hammel; Bertram Wiedenmann; Eric Van Cutsem; Shem Patyna; Dongrui Ray Lu; Carolyn Blanckmeister; Richard Chao; Philippe Ruszniewski Journal: N Engl J Med Date: 2011-02-10 Impact factor: 91.245