1157O - A multi-cohort phase II study of durvalumab plus tremelimumab for the treatment of patients (pts) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic or lung origin: The DUNE trial (GETNE 1601)

Background

Immune checkpoint blockade (ICB) has demonstrated limited activity in advanced NENs mainly due to the background biology of these “cold” neoplasms, with low tumor mutational burden, expression of PD-L1 and lymphocyte infiltration. Targeting both PD-L1 and CTLA-4 may increase the efficacy of ICB in NENs and revert the intrinsic resistance to this therapeutic approach.

Methods

Pts were recruited in four cohorts (C1-4): typical/atypical lung carcinoids (C1), G1/2 gastrointestinal (C2), G1/2 pancreatic (C3) and G3 NENs of gastroenteropancreatic origin (C4). All pts were included after progression to standard therapies for each C. Pts received durvalumab (D) 1500 mg up to 13 cycles and tremelimumab (T) 75 mg up to 4 cycles, every 4 weeks. Primary objective was 9-month (m) clinical benefit rate (CBR) for C1-3 and 9-m overall survival rate (OS) for C4. Assuming a 9mCBR P0/1 of 30%/50% for C1-3, and 9mOS P0/1 of 13%/23% for C4, (α=0,05 and 80% power) 28 pts in C1-3 and 30 pts in C4 were needed.

Results

123 pts were included. Median age 62-y, 59% male, 43% ECOG 0. With a median follow-up of 10.8 m, CBR at 9-m was 7.4%/32.3%/25% for C1/2/3 respectively. OS rate at 9-m for C4 was 36.1%. The irRECIST overall response rates (irORR) for C1-4 were 7.4%/0%/6.3%/9.1%, respectively. PD-L1 expression did not enrich for efficacy in either primary or secondary endpoints except for C1 group, where irORR was 16% in pts with PD-L1-positive tumors vs. 0% in pts with PD-L1 negative (p=0.033). Most common treatment-related AEs were fatigue (43%), diarrhea (31.7%), pruritus (23.6%), nausea (13.8%), and hypothyroidism (9.8%). Most frequent grade ≥3 treatment-related AEs were liver toxicity (9.7%), diarrhea (6.5%), fatigue and vomiting (2.4% each).

Conclusions

D+T combination showed modest activity in this heavily pretreated population. In high grade NENs, D+T reached the primary endpoint of increasing OS rate and deserves further evaluation. Objective radiological responses were infrequent. No new safety concerns have been observed in this large population of advanced NENs.

Clinical trial identification

EudraCT: 2016-002858-20; NCT03095274.

Editorial acknowledgement

Legal entity responsible for the study

Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE).

Funding

AstraZeneca.

Disclosure

J. Capdevila: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution), Research grant/Funding (institution): Principal investigator: Investigator initiated studies: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution), Research grant/Funding (institution): Principal investigator: Investigator initiated studies: Advanced Accelerator Applications; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Serono; Research grant/Funding (self), Research grant/Funding (institution), Research grant/Funding (institution): Principal investigator: Investigator initiated studies: AstraZeneca. A. Teule: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AAA; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca. C. López: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Research grant/funding (self): PI in clinical trials: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): AAA; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Research grant/funding (self): PI in clinical trials: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Research grant/funding (self): PI in clinical trials: AstraZeneca. R. García-Carbonero: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AAA; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Advanz Pharma; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: HMP; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ipsen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Midatech Pharma; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): PharmaMar; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Sanofi; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Servier; Research grant/Funding (institution): ARMO Sciences; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Boston Biomedicals; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Sysmex; Research grant/Funding (institution): Gilead Sciences; Research grant/Funding (institution): Adacap; Research grant/Funding (institution): VCN; Research grant/Funding (institution): Lilly; Non-remunerated activity/ies: Spanish Neuroendocrine Tumour Cooperative Group (GETNE); Non-remunerated activity/ies, Member of the Executive Committee: European Society of Neuroendocrine Tumours (ENETS); Non-remunerated activity/ies, Member of the Executive Committee: European Medicines Agency (EMA); Research grant/Funding (institution), Member of the Scientific Advisory Group for Oncology (2008-2017): AstraZeneca. M. Benavent: Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Novartis. A. Custodio: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: AAA; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Non-remunerated activity/ies, Senior leadership role: Grupo Español de Tumores Neuroendocrinos (GETNE); Non-remunerated activity/ies, Senior leadership role: European Society of Neuroendocrine Tumours (ENETS). V. Alonso: Advisory/Consultancy: Amgen; Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy: Roche; Speaker Bureau/Expert testimony: Sanofi Genzyme; Advisory/Consultancy: Servier; Advisory/Consultancy: Bayer; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Novartis. T. Alonso Gordoa: Advisory/Consultancy, Speaker Bureau/Expert testimony, Leadership role, Research grant/Funding (institution), Project lead in neuroendocrine tumours: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Leadership role, Research grant/Funding (institution), Project lead in kidney cancer: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Janssen-Cilag; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GSK-Novartis; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Nektar Therapeutics; Non-remunerated activity/ies, Member of the Spanish Germ Cell Tumors Board: Spanish Germ Cell Tumors; Non-remunerated activity/ies, Scientific advisor: Spanish Society of Medical Oncology (SEOM). G. Crespo: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eusa Pharma. M. Blanco-Codesido: Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Roche; Research grant/Funding (self), Clinical Trial, PI: Beigene; Research grant/Funding (self), Clinical Trial, PI: Bristol-Myers Squibb; Research grant/Funding (self), Clinical Trial, PI: AAA; Research grant/Funding (self), Clinical Trial, PI: Five Prime Therapeutics. P. Jimenez-Fonseca: Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy: AAA; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Leo Pharma; Speaker Bureau/Expert testimony: HR Pharmaceuticals; Non-remunerated activity/ies: Sociedad Española de Oncología Médica (SEOM); Non-remunerated activity/ies: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE); Non-remunerated activity/ies: TTD; Non-remunerated activity/ies: European Neuroendocrine Tumor Society (ENETS). I. Sevilla: Advisory/Consultancy: Ipsen; Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: PharmaMar; Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy: Bayer; Speaker Bureau/Expert testimony: AAA. M. Llanos: Advisory/Consultancy: Amgen; Speaker Bureau/Expert testimony: Merck; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Writing: Shire. J. Hernando-Cubero: Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: AAA; Speaker Bureau/Expert testimony: Angelini; Speaker Bureau/Expert testimony: Sanofi. J.L. Manzano: Advisory/Consultancy, Melanoma and Colo-Rectal Cancer (Advisory Role): Bristol-Myers Squibb; Advisory/Consultancy, Melanoma: Novartis; Advisory/Consultancy, Melanoma (Advisory Role): Pierre Fabre; Advisory/Consultancy, Melanoma: Roche; Advisory/Consultancy, Melanoma (Consultancy): MSD; Advisory/Consultancy, Colo-Rectal Cancer (Advisory Role): Amgen; Advisory/Consultancy, Colo-Rectal Cancer (Advisory Role): Merck. All other authors have declared no conflicts of interest.