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- Halfdan Sorbye (Bergen, Norway)
- Marcia S. Brose (Philadelphia, United States of America)
LBA45 - Randomized open label phase III study comparing the efficacy and safety of everolimus followed by chemotherapy (CT) with streptozotocin (STZ)-5FU upon progression or the reverse sequence, in advanced progressive panNETs: The SEQTOR study (GETNE 1206)
- Ramon Salazar (Hospitalet de Llobregat, Spain)
Abstract
Background
STZ-5FU and everolimus are frontline treatments in patients (pts) with advanced and progressive pancreatic panNETs. Switching between both upon progression is a common strategy, but the best sequence is not yet well established.
Methods
SEQTOR trial aims to compare the progression-free survival rate to 1st treatment (PFS1) at 12 months (m) in STZ-based CT vs Everolimus. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), median PFS1 (mPFS1) and PFS to 2nd treatment (PFS2), safety and correlatives studies. Pts with advanced WHO grade 1/2 panNETs, ECOG 0-2, were randomized 1:1 to everolimus 10 mg/day followed by STZ-5FU upon progression (arm A), or the reverse sequence (arm B). STZ-5FU was given as per Moertel or Uppsala regimens. Initial results of 12m PFS1, ORR and safety are presented.
Results
A total of 141 pts were randomized (71 vs 70 for arm A/B). Median age was 58 years (range: 33-83), and 85 (60%) were male. Overall, 20 (14%) pts were WHO G1, 113 (80%) G2, and 8 (5.7%) unknown. ORR to 1st treatment assigned was 11% vs 30% in arms A/B, respectively (p=0.014). Stable Disease was the most common outcome to the 1st treatment with a CBR of 92% and 80% for arms A/B, respectively (p=0.07). The estimated Kaplan Meier 12m PFS1 rate was 69% and 64% in arms A/B, respectively; mPFS1 was 21.5 m (95% CI: 16.9-31.3) and 23.8 m (95% CI: 13.6-30.8) in arms A/B, respectively (p=0.351). The most frequent grade 3-4 adverse events were fatigue (10%), diarrhea (7%) and abdominal pain (7%) in arm A, and fatigue (13%), neutropenia (9%) and abdominal pain (8%) in arm B. Grade 3-4 pneumonitis was 1.5% in both arms. Arm A resulted in a significant increase of any-grade rash (27% vs 8%), infections (15% vs 5%) and lung infection (15% vs 5%).
Conclusions
Both sequential strategies showed similar efficacy, with no significant differences in PFS1. STZ-5FU assigned as the 1st treatment achieved a statistically significant higher ORR than everolimus, suggesting STZ-5FU should be the 1st option when tumor shrinkage is a priority. The differences in safety profile may also inform treatment choice for selected pts.
Clinical trial identification
EudraCT: 2013-000726-66; NCT02246127.
Editorial acknowledgement
We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.
Legal entity responsible for the study
Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE).
Funding
GETNE through industry partners Novartis Pharmaceuticals.
Disclosure
R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, Pharma Mar, Pierre Fabre, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. H.J. Klumpen: Financial Interests, Institutional, Invited Speaker, current treatments of cholangiocarcinoma: Medtalk; Financial Interests, Institutional, Invited Speaker, PODCAST on treatment of HCC: CCO; Financial Interests, Institutional, Advisory Board: Janssen, AstraZeneca; Financial Interests, Institutional, Invited Speaker, IMBRAVE 050: ROCHE; Financial Interests, Institutional, Invited Speaker, FIGHT 302: INCYTE; Financial Interests, Institutional, Invited Speaker, LEAP 012: MSD; Financial Interests, Institutional, Invited Speaker, TAS120: Taiho; Financial Interests, Institutional, Invited Speaker, COMPETE, COMPOSE: ITM Solucin GmbH; Financial Interests, Institutional, Invited Speaker, KEYNOTE 966: MSD; Financial Interests, Institutional, Invited Speaker, COSMIC 312: Exelixis; Other, Other, Subdomain leader G5.1: EURACAN; Other, In the Netherlands: Member National Guideline committee for biliary tract cancer; Other, in the Netherlands: Member of the National guideline committee for HCC. All other authors have declared no conflicts of interest.
887O - First multicentric randomized phase II trial investigating the antitumor efficacy of peptide receptor radionucleide therapy with 177Lutetium-Octreotate (OCLU) in unresectable progressive neuroendocrine pancreatic tumor: Results of the OCLURANDOM trial
- Eric Baudin (Villejuif, France)
Abstract
Background
No randomized trial has investigated the role of peptide receptor radionucleide therapy (PRRT) in advanced PanNET patients. We report the results of the first multicentric randomized open-label phase II study assessing PRRT-177Lutetium-Octreotate antitumor efficacy.
Methods
Patients (pts) with somatostatin receptor scintigraphy positive progressive advanced PanNET within 1 year according to RECIST1.1 were randomized 1:1 to OCLU (7.4 GBqX4/8w) or sunitinib (SUN;37.5 mg/d ) and stratified for prognostic factors.Primary endpoint was: progression-free survival (PFS) rate at 12 months according to RECIST 1.1 real-time central review. Secondary endpoints were : tumour response, PFS, overall survival, safety (NCI CTCAE v.4). The sample size calculation of the OCLU arm assumed a 25% increase (from 35% to 60%) of the 12-m PFS rate. 40 pts had to be included in a single stage Fleming design with type I error = type II error = 5%. If 19 or more pts showed no progression or death at 12 months, OCLU would be considered effective (Fleming design conclusion). The SUN group served as an internal control to validate the hypothesis of the Fleming design with a 12 months PFS rate of 35%.
Results
84 pts were enrolled (41 OCLU arm , 43 SUN arm ;median age, 63 yrs,52% female). Main characteristics were:Ki67>10%, 37% pts; >25% liver involvement,42% pts; functioning syndrome, 20% pts ; ≥2 systemic lines, 43% , well balanced between each arm. The primary endpoint was met with a 12m-PFS rate at 80.5% (33/41 pts with 12m-PFS) in the OCLU arm (IC90%: 67.5-89.9) vs. 42 % in the SUN arm (n=18/43 pts with 12mPFS) (IC90%: 29.1-55.5,including 35%). Median PFS was 20.7 in the OCLU arm (90CI: 17.2-23.7) vs. 11 months in the SUN arm (90CI:8.8-12.4). 44% pts with OCLU vs. 60% with SUN experienced grade 3-4 adverse events, with fatigue (7% vs. 12%), decrease blood count (12% vs 24%) and hypertension (12% vs. 19%) among the most frequent. One death occurs in the SUN arm. Additional results will be presented (best response, updated adverse events and, subgroup analysis).
Conclusions
The OCLURANDOM trial met is primary endpoint.
Clinical trial identification
EudraCT 2013-004032-30.
Legal entity responsible for the study
Gustave Roussy.
Funding
French Academic Projet Hospitalier Recherche Clinique (PHRC) grant and AAA/Novartis Pharma.
Disclosure
E. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis - AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. T.A. Walter: Financial Interests, Personal, Advisory Role: Novartis-AAA, Keocyt; Non-Financial Interests, Personal, Funding: Ipsen; Non-Financial Interests, Institutional, Project Lead: ROCHE. J. Hadoux: Financial Interests, Personal, Advisory Board: Ipsen, Lilly, Pharma Mar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer. C. Lachachi: Financial Interests, Institutional, Advisory Board: Novartis-AAA. D. Taieb: Financial Interests, Personal, Advisory Board: Novartis-AAA; Financial Interests, Personal, Invited Speaker: Novartis-AAA; Financial Interests, Institutional, Principal Investigator: Ipsen, Novartis-AAA. C. Ansquer: Financial Interests, Personal, Advisory Board: Novartis-AAA; Financial Interests, Personal, Invited Speaker: Novartis-AAA. L. de Mestier du Bourg: Financial Interests, Personal, Advisory Role: AAA, Ipsen, Keocyt, SIRTex. E. Deshayes: Financial Interests, Personal, Invited Speaker: Novartis-AAA. L. Dahan: Financial Interests, Personal, Invited Speaker: Servier, Novartis-AAA, Pierre Fabre, Oseus. Y. Touchefeu: Financial Interests, Personal, Invited Speaker: Novartis-AAA. C. Lombard Bohas: Financial Interests, Personal, Advisory Board: Novartis-AAA; Financial Interests, Institutional, Principal Investigator: Ipsen. All other authors have declared no conflicts of interest.
Invited Discussant LBA45 and 887O
- Jonathan Strosberg (Tampa, United States of America)
Q&A
- All Speakers (Lugano, Switzerland)
1644O - Donafenib in locally advanced/metastatic, radioactive iodine-refractory, differentiated thyroid cancer: A randomized, double-blind, placebo-controlled, multi-center phase III clinical trial (DIRECTION)
- Yansong Lin (Beijing, China)
Abstract
Background
Donafenib, an oral multi-kinase inhibitor that targets Raf/MEK/ERK, VEGFR, PDGFR, has shown potent efficacy and well-tolerated safety profile in patients with progressive locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in a phase II study. The DIRECTION study aims to evaluate the efficacy and safety of donafenib and initiated when there was no available TKI for Chinese RAIR-DTC patients.
Methods
In this randomized, double-blind, placebo-controlled, multi-center phase III trial, eligible patients were randomized (2:1) to receive donafenib (300 mg) or placebo twice daily until intolerable toxicity or disease progression. The primary endpoint was PFS, the second endpoints including ORR, OS, safety, et al.
Results
From July 2018 to February 2021, a total of 191 patients were randomized (donafenib, 128; placebo, 63) which is the largest Chinese RAIR-DTC patients enrolled in trials so far. The primary end point was met upon pre-planned second interim analysis when 67% PFS events were observed. Donafenib significantly prolonged the median IRC-PFS than placebo (12.9
Conclusions
Donafenib well balanced the efficacy and safety, suggesting its potential to be an alternative for patients with progressive RAIR-DTC.
Clinical trial identification
NCT03602495.
Legal entity responsible for the study
The authors.
Funding
Zelgen Biopharmaceuticals Co., Ltd.
Disclosure
L. Wu, L. Liu: Financial Interests, Personal and Institutional, Full or part-time Employment: Suzhou Zelgen Biopharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.
1645O - Durvalumab (D) plus tremelimumab (T) for the treatment of patients with progressive, refractory advanced thyroid carcinoma: The DUTHY (GETNE-T1812) trial
- Jaume Capdevila Castillon (Barcelona, Spain)
Abstract
Background
Targeting PD-L1 has proven limited efficacy in advanced thyroid cancer patients (pts). Dual targeting of PD-L1 and CTLA-4 could improve the efficacy of immunotherapy.
Methods
Pts with advanced thyroid cancers were recruited in three cohorts (C1-3): differentiated thyroid cancer (DTC, C1), medullary thyroid cancer (MTC, C2), and anaplastic thyroid cancer (ATC, C3). Pts in C1 and C2 were included after disease progression on standard systemic therapy and C3 regardless of prior therapy. No prior immunotherapy was allowed. Pts received D 1500 mg and T 75 mg every 4 weeks, up to 4 cycles, followed by durvalumab monotherapy until confirmed disease progression, or unacceptable toxicity. Primary objective was 6-month (m) PFS rate for C1-2 and 6-m overall survival (OS) rate for C3. Secondary objectives included safety and efficacy in terms of Objective Response Rate (ORR), median PFS and OS. The expected accrual was 37/37/12 pts respectively for C1-3.
Results
From April 2019, 68 pts were enrolled; 37/19/12 in C1-3. C1 and C3 completed accrual, C2 completed the 1st stage and 2nd stage is open. Median age was 66 years; 39 (57.4%) were female. Pts received a median of 2/2/0 previous treatment lines for C1-3 respectively. Surgery of the primary tumor was performed in 35 (94.6%) / 16 (84.2%) / 2 (16.7%) pts in C1-3 respectively. The median follow-up was 12.2 m (range: 0.2-34.5) / 16.8 m (range: 1.4-32.9) / 11.5 m (range: 1.5-29.9), with a 6-m PFS rate of 32.4% / 37.5% / 33.3%, and median PFS of 5.3 m (95% CI: 2.7-6.5) / 5.3 m (95% CI: 2.8-NR) / and 4 m (95% CI: 2.2-NR), for C1-3 respectively. The 6-m OS rate was 70.3% / 93.8% / 65.6%, with a median OS of 12.5 m (95% CI: 9.4-NR) / NR / 13.8 m (95% CI: 5.7-NR), for C1-3 respectively. The ORR according to RECIST 1.1 was 8.1% / 15.8% / 33.3% for C1-3 respectively. In C3, the ORR was 50% in PD-L1 positive pts. In total 47 (71.2%) pts experienced toxicities, with 10 (15.2%) pts experiencing grade ≥3 toxicities. The toxicity was similar to previous trials with DT.
Conclusions
D+T was tolerable and showed promising activity in heavily pretreated advanced DTC and MTC. In ATC cohort, D+T demonstrated significant and clinically meaningful efficacy with prolonged OS, granting further research.
Clinical trial identification
EudraCT 2018-001066-42; NCT03753919.
Editorial acknowledgement
We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.
Legal entity responsible for the study
Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE).
Funding
GETNE though industry partner AstraZeneca.
Disclosure
J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hudchinson Pharma, ITM, Advanz, Merck Serono, Esteve; Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hudchinson Pharma, ITM, Advanz, Merck Serono, Esteve; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Amgen, Bayer; Financial Interests, Institutional, Member, Chair of the Spanish Task Force for Neuroendocrine and Endocrine Tumors Group (GETNE): GETNE; Financial Interests, Institutional, Member, Executive Committee Member of the European Neuroendocrine Tumor Society (ENETS): ENETS; Financial Interests, Institutional, Member, Treasurer and Track Chair of the reactal cancer working group of the Spanish Multidisciplinary Group of Digestive Cancers (GEMCAD): GEMCAD. M. Plana: Financial Interests, Advisory Role: Nanobiotix; Financial Interests, Other: BMS, MSD. J. Hernando: Financial Interests, Personal, Speaker’s Bureau: Eisai, Ipsen, Novartis, Adacap, Bayer, Roche, Angelini. N. Baste: Non-Financial Interests, Advisory Role: BiNTech, BMS, Eisai, Exelixis, Merck Serono; Financial Interests, Advisory Role: MSD, Roche. E. Grande: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Jansen, Lilly, Merck KGA, Pfizer, Roche; Financial Interests, Personal, Advisory Role: Adacal, Bayer, Caris Life, MSD, Novartis, OncoDNA, Sanofy-Genzyme; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Ipsen, Lexicon, MTEM/Threshold, Nanostrig, Pfizer, Roche, Merck; Non-Financial Interests, Other, AD board member: ENETS. D. Lorente: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bayer, Bristol-Myers, Janssen, MSD, Sanofi; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Pfizer, Sanofi. G. Marquina: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Clovis Oncology, Eisai, GSK/Tesaro, Lilly, Medicamenta, Roche; Financial Interests, Personal, Advisory Board: Clovis Oncology, GSK/Tesaro, Lilly, PharmaMar, Pfizer. A. García-Alvarez: Financial Interests, Personal, Other, Speaker, consultancy or advisory role or similar activity: Angellini, ADACAP, Eisai, Ipsen, Pfizer. T. Alonso-Gordoa: Financial Interests, Personal, Advisory Board: Ipsen, Sanofi, Bayer, Eisai, Novartis, Lilly; Financial Interests, Personal, Invited Speaker: Pfizer, Roche, Janssen-Cilag; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Project Lead: Pfizer, Ipsen. All other authors have declared no conflicts of interest.
Invited Discussant 1644O and 1645O
- Marcia S. Brose (Philadelphia, United States of America)
Q&A
- All Speakers (Lugano, Switzerland)