Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms

Siren Morken; Seppo W Langer; Anna Sundlöv; Lene Weber Vestermark; Morten Ladekarl; Geir Olav Hjortland; Johanna B Svensson; Elizaveta Mitkina Tabaksblat; Torjan Magne Haslerud; Jörg Assmus; Sönke Detlefsen; Anne Couvelard; Aurel Perren; Halfdan Sorbye

doi:10.1038/s41416-023-02462-0

Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms

Siren Morken^*, Seppo W Langer, Anna Sundlöv, Lene Weber Vestermark, Morten Ladekarl, Geir Olav Hjortland, Johanna B Svensson, Elizaveta Mitkina Tabaksblat, Torjan Magne Haslerud, Jörg Assmus, Sönke Detlefsen, Anne Couvelard, Aurel Perren, Halfdan Sorbye

^*Corresponding author for this work

Department of Oncology

14 Citations (Scopus)

Abstract

BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients.

METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.

RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment.

CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).

Original language	English
Journal	British Journal of Cancer
Volume	129
Issue number	12
Pages (from-to)	1930-1939
Number of pages	10
ISSN	0007-0920
DOIs	https://doi.org/10.1038/s41416-023-02462-0
Publication status	Published - Dec 2023

Keywords

Everolimus/adverse effects
Humans
Neuroendocrine Tumors/pathology
Pancreatic Neoplasms/pathology
Prospective Studies
Quality of Life
Temozolomide

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10.1038/s41416-023-02462-0

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Morken, S., Langer, S. W., Sundlöv, A., Vestermark, L. W., Ladekarl, M., Hjortland, G. O., Svensson, J. B., Tabaksblat, E. M., Haslerud, T. M., Assmus, J., Detlefsen, S., Couvelard, A., Perren, A., & Sorbye, H. (2023). Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms. British Journal of Cancer, 129(12), 1930-1939. https://doi.org/10.1038/s41416-023-02462-0

Morken, S, Langer, SW, Sundlöv, A, Vestermark, LW, Ladekarl, M, Hjortland, GO, Svensson, JB, Tabaksblat, EM, Haslerud, TM, Assmus, J, Detlefsen, S, Couvelard, A, Perren, A & Sorbye, H 2023, 'Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms', British Journal of Cancer, vol. 129, no. 12, pp. 1930-1939. https://doi.org/10.1038/s41416-023-02462-0

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title = "Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms",

abstract = "BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55\% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients.METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.RESULTS: For 37 eligible patients, the primary endpoint with 65\% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30\%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77\% vs. 22\% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43\% and 38\%. QoL remained stable during treatment.CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).",

keywords = "Everolimus/adverse effects, Humans, Neuroendocrine Tumors/pathology, Pancreatic Neoplasms/pathology, Prospective Studies, Quality of Life, Temozolomide",

author = "Siren Morken and Langer, \{Seppo W\} and Anna Sundl{\"o}v and Vestermark, \{Lene Weber\} and Morten Ladekarl and Hjortland, \{Geir Olav\} and Svensson, \{Johanna B\} and Tabaksblat, \{Elizaveta Mitkina\} and Haslerud, \{Torjan Magne\} and J{\"o}rg Assmus and S{\"o}nke Detlefsen and Anne Couvelard and Aurel Perren and Halfdan Sorbye",

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year = "2023",

month = dec,

doi = "10.1038/s41416-023-02462-0",

language = "English",

volume = "129",

pages = "1930--1939",

journal = "British Journal of Cancer",

issn = "0007-0920",

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number = "12",

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TY - JOUR

T1 - Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms

AU - Morken, Siren

AU - Langer, Seppo W

AU - Sundlöv, Anna

AU - Vestermark, Lene Weber

AU - Ladekarl, Morten

AU - Hjortland, Geir Olav

AU - Svensson, Johanna B

AU - Tabaksblat, Elizaveta Mitkina

AU - Haslerud, Torjan Magne

AU - Assmus, Jörg

AU - Detlefsen, Sönke

AU - Couvelard, Anne

AU - Perren, Aurel

AU - Sorbye, Halfdan

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients.METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment.CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).

AB - BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients.METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment.CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).

KW - Everolimus/adverse effects

KW - Humans

KW - Neuroendocrine Tumors/pathology

KW - Pancreatic Neoplasms/pathology

KW - Prospective Studies

KW - Quality of Life

KW - Temozolomide

UR - https://www.scopus.com/pages/publications/85174609831

U2 - 10.1038/s41416-023-02462-0

DO - 10.1038/s41416-023-02462-0

M3 - Journal article

C2 - 37872405

SN - 0007-0920

VL - 129

SP - 1930

EP - 1939

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 12

ER -

Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms

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