Background

Anlotinib is a novel multikinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study investigated the potency of anlotinib in treating locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC).

Methods

This is a randomized, double-blind, placebo-controlled, multicenter phase II trial (NCT02586337). Eligible pts were 18-70 years age, ECOG PS of 0-1 and diagnosed as having pathologically confirmed locally advanced or metastatic RAIR-DTC with at least one measurable lesion. Previous anlotinib or other VEGFR-TKIs were not allowed. Pts were randomized (2:1) to receive anlotinib or placebo (12mg QD for 2 weeks every 3 weeks). The primary endpoint was PFS. The secondary endpoints included ORR, DCR, OS, Quality of life and safety. Pts in placebo arm could receive open-label anlotinib after disease progression.

Results

Between September 2015 and August 2018, 113 pts (76 in anlotinib arm, 37 in placebo arm) were enrolled. The data cutoff date for primary endpoint was January 1, 2020. The research met its endpoint that the median PFS was 40.54 months (95% CI 28.29, NE) in anlotinib arm and 8.38 months (95% CI 5.59, 13.80) in placebo arm (p < 0.0001). The HR was 0.21 (95% CI 0.12, 0.37). OS data was immature while a trend of OS benefit could be observed (Not reached vs. 52.83 months; HR = 0.57 [95% CI 0.29, 1.12]; p = 0.0976). This prolongation in OS became significant (HR = 0.36 [95%CI 0.18, 0.73], P = 0.0033) when a potential bias from crossover (24 pts received open-label anlotinib) was adjusted with a two-stage estimation method. ORR was 59.21% in anlotinib arm and no response was observed in placebo arm (p < 0.0001). DCR was 97.37% versus 78.38% (p = 0.0019). 26 pts in anlotinib arm needed dose reduction. The incidence of treatment-related AEs (TRAEs) in anlotinib and placebo arms was 100.00% and 86.49%. Serious TRAEs occurred in 15.79% pts received anlotinib. The most common TRAEs in anlotinib arm were hypertension (84.21%) and hand-foot syndrome (73.68%).

Conclusions

This study demonstrates the efficacy and safety of anlotinib and supports its use as a new option in the treatment of locally advanced or metastatic RAIR-DTC.

Clinical trial identification

NCT02586337.

Legal entity responsible for the study

Chia Tai TianQing Pharmaceutical Group Co., Ltd.

Funding

Chia Tai TianQing Pharmaceutical Group Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Apatinib, an oral inhibitor of vascular endothelial growth factor receptor 2, showed clinical activity in preliminary studies involving patients (pts) with differentiated thyroid cancer refractory to radioactive iodine (RAIR-DTC).

Methods

In this phase III, randomized, double-blind, multicenter trial involving pts with progressive RAIR-DTC, eligible pts were randomized (1:1) to either 500 mg apatinib orally once daily or placebo. The primary endpoint was progression-free survival (PFS), secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. The planned sample size was 118 pts, with 90% power to detect a 6.2-month improvement in PFS at a two-sided alpha level of 0.05. A planned interim analysis would be performed when 60% of expected events occurred.

Results

Between February 2017 to March 2020, 92 pts from 20 sites were randomized to apatinib (n=46) or placebo (n=46) arms. The pre-planned interim analysis was performed by the independent Data Monitoring Committee (IDMC) in March 2020 upon the occurrence of 61.45% (51/83) PFS events. The median PFS was 22.21 months (95% CI 10.91-Not Reached) in apatinib group, and 4.47 months (95% CI 1.94-9.17) in the placebo group (HR=0.26, 95% CI 0.14-0.47, p<0.0001), and the p-value was less than the prespecified interim efficacy margin (α=0.0085). ORR was 55.56% vs. 2.27%. The median OS was 29.9 months (95% CI 18.96-Not reached) in the placebo arm, and not reached in apatinib arm (HR=0.42, 95% CI 0.18-0.97, p=0.0356). The most frequent treatment-emergent ≥ grade 3 adverse events in two arms were hypertension (34.8% vs 0%), hand-foot syndrome (17.4% vs 0%) and proteinuria (17.4% vs 2.2%). Table: LBA89

Table: LBA89 Summary of efficacy

Conclusions

Apatinib significantly prolonged the PFS, OS, and improved ORR in pts with locally advanced or metastatic RAIR-DTC. The toxic effects of apatinib were well tolerated by the management of adverse events.

Clinical trial identification

NCT03048877.

Legal entity responsible for the study

The authors.

Funding

Jiangsu Hengrui Medicine, China.

Disclosure

All authors have declared no conflicts of interest.

Background

Anaplastic thyroid cancer (ATC) is a rare/aggressive cancer with no standard radiation-based local treatment. Achieving locoregional disease control in the neck is critical due to major concerns of airway and esophageal compromise. Based on data suggesting synergy between pazopanib (P) and paclitaxel (T) in ATC, NRG Oncology conducted a randomized phase II study comparing concurrent T and intensity modulated radiation therapy (IMRT) with either P or placebo (C).

Methods

The study arm evaluated 2-3 weeks of weekly T (80 mg/m2) and daily P suspension (PS) 400 mg followed by concurrent weekly T (50 mg/m2), daily PS (300 mg), and IMRT 66 Gy. The standard arm substituted C for PS. Inclusion criteria included pathologic diagnosis of M0/M1 ATC (central path review), Zubrod 0-2, no recent hemoptysis/bleeding, no brain metastases. Target accrual was 88 patients (pts) (79 eligible) to show a >37.5% reduction in the hazard rate for overall survival (OS) with addition of PS (1-sided alpha 0.15, beta 0.2). Final analysis, after accounting for 1 interim analysis, was 1-sided log-rank test at 0.1379 level in eligible pts.

Results

89 pts (71 eligible) were accrued from 6/23/14-12/30/16, completing accrual 14 months earlier than projected. Pts excluded per protocol in each arm - PS 6; C 12. Median age 65 years. Female 52.1%. Zubrod 0-1 91.5%. Total thyroidectomy 36.6%; partial thyroidectomy 21.1%. M0 disease 56.3%. OS was not significantly higher with PS compared to C (p=0.28); hazard ratio (PS/C) was 0.86 (95% CI 0.52 - 1.43). OS and adverse events (AE) rates are in the table. Table: 1914MO

Conclusions

NRG-RTOG 0912 is the largest randomized ATC study that completed accrual demonstrating feasibility in the cooperative group setting. Although a statistically significant improvement in OS was not seen with PS added to T and IMRT, the OS rates and feasibility data from this prospective clinical trial will be useful to help design future studies in this rare and aggressive disease.

Clinical trial identification

RTOG 0912.

Legal entity responsible for the study

NRG/RTOG Oncology.

Funding

This project was supported by grants UG1CA189867 (NRG Oncology NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), & U24CA180803 (IROC) from the National Cancer Institute (NCI) and Novartis.

Disclosure

E.J. Sherman: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly/Loxo; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Plexxicon. P. Xia: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Philips Healthcare; Research grant/Funding (institution): Advanced Oncotherapy. C.H. Chung: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: CUE Biopharma; Advisory/Consultancy, Research grant/Funding (institution): Ignyta; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Mirati Therapeutics; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): IRX Therapeutics; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Lion Biotechnologies; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Regeneron. R.L. Foote: Licensing/Royalties: Bionix; Travel/Accommodation/Expenses: Hitachi Chemical. S. Yom: Research grant/Funding (institution): BioMimetix; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Merck. S.J. Wong: Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis. S. Koyfman: Research grant/Funding (institution): Merck Sharp & Dohme. S. Khan: Honoraria (institution), Advisory/Consultancy: Ariad; Honoraria (self), Advisory/Consultancy: EMD Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Speaker Bureau/Expert testimony: Genzyme; Advisory/Consultancy, Research grant/Funding (institution): Bayer/Onyx; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy, Research grant/Funding (institution): Guardant Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): Formation Biologics; Research grant/Funding (institution): Gilead Sciences; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Merck; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Threshold Pharmaceuticals. Q-T. Le: Advisory/Consultancy: Merck; Shareholder/Stockholder/Stock options: Aldea; Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy: Grail. N. Lee: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Vertex. All other authors have declared no conflicts of interest.

Background

NETs are heterogeneous tumours that have the unique capacity to secrete bioactive molecules that can cause specific clinical syndromes in ∼20% of cases (“functioning tumours”). In this context, and given the relevance of dysregulated metabolism in cancer, the aim of our study was to assess the metabolomic profile of NET pts to better understand metabolic dysregulation in this tumors and identify novel biomarkers of potential clinical use.

Methods

Multiplatform untargeted metabolomic profiling was performed in plasma of 77 pts with advanced GI and lung NETs, and of 68 control pts, matched per age, gender and IMC. Samples were analyzed by GC, CE and LC, coupled to MS. Differences between NETs and controls were performed by Univariate (MATLAB, t-Student (p≤0.05)) and Multivariate analysis (SIMCA15.0). Related pathways were explored by MPA/MSEA using Metaboanalyst 4.0. ROC and OPLS-DA were used to select metabolites with biomarker potential (AUC>0.85 or VIP>1). Logistic regression models were built to identify confounding clinical covariables. AdjAUCs were calculated with model probabilities of each diagnostic metabolite.

Results

We identified 155 differential compounds between NETs and controls, 14 of them by several techniques. The main biochemical groups of identified metabolites were amino acids (27.7%), fatty acids (16.1%), glycerophopholipids (14.1%), steroids (9.6%) and carbohydrates (3.8%). Specifically, we detected an increase of dipeptides and oxidized lipids in NETs, a decrease of carnitine levels and a rise of oxidized compounds derived from arachidonic acid (HETE). Differential metabolites were related with classical cancer pathways (apoptosis, cell cycle) and NET signalling (tryptophan metabolism, angiogenesis, mTOR). MPA/MSEA showed 32 novel enriched metabolic pathways in NETs, related with TCA cycle and with arginine, pyruvate or glutathione metabolism. Finally, OPLS-DA, ROC and LRM models showed 46 metabolites of diagnostic potential.

Conclusions

This study provides, for the first time, a comprehensive metabolic profile of NET pts. The study identified a reduced set of metabolites of potential diagnostic utility and also reveals new enriched metabolic pathways that may open new avenues of clinical research, including novel targets of therapy.

Legal entity responsible for the study

Instituto de Investigación Sanitaria Hospital 12 de Octubre. Imas12.

Funding

Spanish National Taskforce on Neuroendocrine Tumors (GETNE), AECC (SPAIN). CAM (Progama de Empleo Juvenil (YEI), co-funded by European Union (ERDF/ESF, “Investing in your future). Instituto de Salud Carlos III and SEOM.

Disclosure

M.C. Riesco-Martinez: Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Bayer; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Servier; Non-remunerated activity/ies: Incyte Bioscience. P. Espinosa-Olarte: Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pfizer. R. Garcia-Carbonero: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AAA, Advanz Pharma, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Sanofi and Servier; Research grant/Funding (self): Pfizer, BMS; Research grant/Funding (institution): ARMO BioSciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics, Boston Biomedicals, Merck, MSD, Amgen, Sanofi, Bayer, Bristol-Myers-Squibb, Boerhringer, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, PharmaMar; Non-remunerated activity/ies: Member of the Executive Committee of the Spanish Neuroendocrine Tumor Cooperative Group (GETNE), Member of the Executive Committee of the European Society of Neuroendocrine Tumors (ENETS), Member of the Scientific Advisory Group for Oncology (SAG-O) of th; Non-remunerated activity/ies: Global PI of a clinical trial of Axitinib (Pfizer) in NETs; Global PI of a clinical trial of Nivolumab (BMS) and chemotherapy in NECs; Non-remunerated activity/ies: Member of the EORTC, ASCO, ESMO, SEOM, TTD, GEMCAD. All other authors have declared no conflicts of interest.

Background

G3 NEC represent the most aggressive spectrum of NENs and have limited treatment options. The aim of this study was to analyze the prognostic factors in a large cohort of G3 GEP-NEC from the Spanish Registry.

Methods

R-GETNE includes 4807 GEP-NENs diagnosed between 2004 and 2019. The study cohort included patients with poorly differentiated neuroendocrine carcinomas (NEC) with a Ki67 index >20%.

Results

Of 535 patients with G3 NEC, 29% were ≥70 years (median age 64), 40% women and 85% had ECOG 0-1. The most common primary sites were colorectum (30%), pancreas (24%), unknown (16%), stomach (13%), and small intestine (4%). Stage at diagnosis was I in 3%, II in 9%, III in 20% and IV in 68%. 87% of stage I-III NECs were resected and, of these, 54% received adjuvant chemotherapy. Platin and etoposide was administered to 73% of patients with advanced NECs with a response rate of 64% and a median progression-free survival of 6.1 months. With a median follow-up of 4 years, 353 patients (67%) had died and the median overall survival (OS) was 14 months. Median OS by stage was: stage I, 6.1 years (1.8-NA); II, 5.8 years (1.9-NA); III, 2.1 years (1.5-6.7); and IV, 9.7 months (6.7-12.9). In stage IV, OS by site was: small intestine, 14.0 (12.6-15.8); pancreas, 10.1 (9.5-11.8); rectum, 9.9 (8.2-11.2); stomach, 7.3 (5.2-9.3); colon, 4.7 (2.8-7.0) and unknown primary, 2.7 months (1.9-3.8). Multivariate analysis showed that stage (I-III vs IV, HR 0.43, 0.27–0.81); primary site (small intestine, pancreas and rectum vs others, HR 0.63, 0.44–0.92); ECOG (0-1 vs 2, HR 0.64, 0.37-0.77), and gender (women vs men, HR 0.89, 0.74-0.95) were independent prognostic factors for OS (p<0.05).

Conclusions

This is to date one of the largest reported series of G3 GEP-NECs and provides relevant information to help stratify prognosis of patients for clinical decisions.

Legal entity responsible for the study

GETNE (Spanish Taskforce of Neuroendocrine Tumours).

Funding

Ipsen.

Disclosure

J. Capdevila: Speaker Bureau/Expert testimony: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi and Merck Serono; Research grant/Funding (self): Novartis, Ipsen, Pfizer, AstraZeneca, Advanced Accelerator Applications and Eisai; Research grant/Funding (institution), Investigator initiated studies supported: Eisai, AstraZeneca and Advanced Accelerator Applications. M. Benavent: Speaker Bureau/Expert testimony: Pfizer, Ipsen, Novartis. V. Alonso-Orduna: Advisory/Consultancy: Amgen, Roche, Servier, Bayer, Ipsen, Novartis; Speaker Bureau/Expert testimony: Merck, Sanofi. T. Alonso: Advisory/Consultancy: Roche, Astellas, Bayer, Ipsen, Pfizer, Sanofi, Janssen-Cilag, MSD, BMS, Eisai; Speaker Bureau/Expert testimony: Ipsen, Pfizer, BMS, Eisai; Leadership role, Clinical Trials: Roche, AstraZeneca, GSK-Novartis, Clovis, Astellas, Bayer, Ipsen, Pfizer, Janssen-Cilag, MSD, BMS, Eisai. M. Sanchez Canovas: Travel/Accommodation/Expenses: Sanofi, MSD, Esteve, Amgen, Servier, Angelini, Leo Pharma; Research grant/Funding (self): LeoPharma; Speaker Bureau/Expert testimony: KyowaKirin. M. Llanos: Advisory/Consultancy: Amgen; Speaker Bureau/Expert testimony: Merck, Roche, Eisai, Servier, Ipsen, Lilly, Bristol, Sanofi, Pfizer. G. Crespo: Advisory/Consultancy: Bristol-Myers Squibb, Ipsen, Roche, Eisai, Sanofi, Eusa Pharma; Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Ipsen, Roche, Eisai, Sanofi, Janssen, Eusa Pharma. A. Teule: Advisory/Consultancy: Novartis Ipsen AAA Pfizer AstraZeneca; Speaker Bureau/Expert testimony: Novartis Ipsen AAA Pfizer AstraZeneca. J. Gallego Plazas: Speaker Bureau/Expert testimony: Lilly, Amgen; Advisory/Consultancy: BMS, Ipsen, Roche, Servier, Merck; Travel/Accommodation/Expenses: Novartis, Amgen. C. López: Advisory/Consultancy: Ipsen, Novartis, Pfizer, AAA, Roche; Speaker Bureau/Expert testimony: Ipsen, Novartis, Pfizer, AAA, Roche; Research grant/Funding (self): Ipsen, AstraZeneca, BMS. All other authors have declared no conflicts of interest.

Background

MPP (malignant paragangliomas and pheochromocytomas) are rare neuroendocrine tumors that can be associated with succinate dehydrogenase subunits (SDHx) germline mutations. SDH encodes for a TCA enzyme that catalyzes the oxidation of succinate to fumarate. When mutated SDH losses its function, leading to succinate accumulation. We have evaluated serum succinate levels as a new biomarker in SDHx-mutated MPP patients.

Methods

Retrospective monocentric study of 88 MPP patients (43 sporadic: SDHxWT; 45 mutated SDHx, among which 35 where SDHB) and 17 tumor-free familial asymptomatic carriers (SDH-B: 13, SDH-C: 2, SDH-D: 2). Clinical and biological data were available in all. 18F-FDG-PET was available in 32 metastatic MPP (15 sporadic, 17 SDH-B). 18F-FDG-PET analyses were performed on an Advantage Workstation (GE Healthcare). A healthy control group (n=10) is included. Serum succinate levels (n=290) were quantified by LC-MS/MS (Waters). Statistical analyses were performed with GraphpadPrism®.

Results

Serum succinate levels were increased in the disease-free SDHx group (median: 7.3 μM) compared to the control group (median: 4.8 μM). Succinate levels >6.9 μM allowed to identify disease-free SDHx mutated cases compared to the healthy control group (100% specificity; 85% sensitivity). When tumor is detected, mutated SDH-B patients had a significantly increased median succinate level (13.5 μM) compared to sporadic patients (7.9 μM) (p<0.01). Metastatic SDH-B patients showed a higher median succinate level (14.9 μM). Extension of the metastatic disease evaluated by the total lesion glycolysis (TLG) activity (18F-FDG-PET) was correlated to the succinate levels (r=0.76). In the SDHB group, patients with the highest tumor burden (3^rd and 4^th TLG quartiles) showed significant increased succinate levels compared to the sporadic group (p<0.001).

Conclusions

Serum succinate is a metabolic biomarker that might be useful to identify SDHx mutated carriers (tumor-free familial asymptomatic carriers and metastatic MPP patients) and as a marker of metabolic tumor burden in patients with metastatic MPP.

Legal entity responsible for the study

The authors.

Funding

GTE (Groupe d’Études des Tumeurs Neuro-Endocrines).

Disclosure

S. Leboulleux: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Loxo; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Genzyme. S. Broutin: Research grant/Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background

LAN and TMZ are among the main therapies recommended for progressive TNETs but prospective data are lacking. We present safety and efficacy outcomes of this combination in progressive TNETs.

Methods

ATLANT was a 12-month, phase II, multicentre, single-arm, open-label study. Eligible patients had unresectable, locally advanced or metastatic, well-differentiated TNETs (bronchial or thymic, typical or atypical carcinoid) with baseline radiological progression (RECIST v1.1) in the previous 12 months. Patients received subcutaneous LAN 120 mg and oral TMZ 250 mg/day over 5 days, every 28 days. Primary endpoint: disease control rate (DCR) at 9 months (RECIST v1.1 complete response, partial response or stable disease [clinically relevant: ≥30%, unacceptable: ≤10%]). Data were analysed using exact binomial proportion tests for one-way tables.

Results

Patients (N=40; 60% male) had a mean (SD) age of 64.9 (11.8) years. The primary tumour site was: lung, 90%; thymus, 10% (typical, 20.0%; atypical, 52.5%; carcinoid, 27.5%). Mitotic count (mitoses/2 mm²): <2: 30%; ≥2–<10: 42.5%; ≥10: 2.5%; not done: 25%. Ki-67 expression (N=20): <4%: 10%; 4–<25%: 80%; ≥25%: 10%. TNM staging: primary tumour TX: 5.1%, T0: 46.2%, T1: 7.7%, T2: 12.8%, T3: 10.3%, T4: 17.9%; regional lymph node N0: 56.4%, N1: 2.6%, N2: 23.1%, N3: 17.9%; distant metastasis M0: 5.1%, M1: 94.9%. Locally assessed DCR at 9 months (ITT population; N=40) was 35.0% (95% CI: 20.63; 51.68) (significantly higher than 10% p<0.0001 but not superior to 30% p=0.297). Median progression-free survival was 37.1 (95% CI: 24.1; 52.9) weeks. In total, 97.5% of patients had treatment-emergent adverse events (TEAEs; >90% of TEAEs were Grade 1/2), 9 (22.5%) patients had serious TEAEs (of which 2 were treatment related), 2 TEAEs led to withdrawal of study treatment, and 2 led to death. The observed TEAEs were in line with the known individual drug profiles, and there were no new or unexpected AEs. Most common TEAEs included nausea (52.5%), vomiting (32.5%) and diarrhoea (30.0%).

Conclusions

These results suggest that the LAN and TMZ combination was generally well tolerated and could be an effective regimen for managing progressive TNETs.

Clinical trial identification

NCT02698410; EudraCT: 2014-005579-10.

Editorial acknowledgement

Cara Valvona, PhD, on behalf of Watermeadow Medical, an Ashfield company, provided medical writing support, which was funded by the study sponsor in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Ipsen.

Funding

Ipsen.

Disclosure

P. Ferolla: Advisory/Consultancy, Speaker Bureau/Expert testimony: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Serono. A. Berruti: Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer. F. Spada: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: AAA; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck. M.P. Brizzi: Advisory/Consultancy: Ipsen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Celgene. T. Ibrahim: Advisory/Consultancy: Eisai; Research grant/Funding (institution): Novartis. A. Colao: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ipsen. A. Faggiano: Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Novartis. D. Giuffrida: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Celgene; Advisory/Consultancy: Ipsen; Speaker Bureau/Expert testimony: Pfizer; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Roche. S. Ghizzoni: Full/Part-time employment: Ipsen. A. Houchard: Full/Part-time employment: Ipsen. N. Fazio: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Honoraria (self), Advisory/Consultancy: Advanced Accelerator Applications; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD. All other authors have declared no conflicts of interest.

Background

CLARINET FORTE assessed the efficacy and safety of increasing LAN 120 mg dose frequency from every (q) 28 days (standard) to q14 days in patients with a progressive pancreatic NET (panNET) or midgut NET.

Methods

A prospective, single-arm, open-label, exploratory, international phase II study in patients with a metastatic or locally advanced, unresectable, G1/2 panNET or midgut NET, with centrally assessed progression within the last 2 years while on a standard LAN regimen for ≥24 weeks. Planned recruitment was 50 patients per cohort. LAN 120 mg q14 days was administered for 48 (panNET) or 96 (midgut) weeks (or until centrally-assessed progressive disease, unacceptable toxicity/tolerability, or death), or longer if <25 events had occurred.

Results

In the panNET (N=48) and midgut NET (N=51) cohorts, respectively, median (95% confidence interval [CI]) progression-free survival (PFS, primary endpoint) was 5.6 (5.5; 8.3) and 8.3 (5.6; 11.1) months. Post-hoc subgroup analysis in the panNET cohort showed median (95% CI) PFS of 8.0 (5.6; 8.3) months in patients with Ki67 ≤10% (N=43), and 2.8 (2.8; 2.9) months in patients with Ki67 >10% (N=5). Disease control rate (DCR; proportion of patients with complete response, partial response or stable disease; 95% CI) in the panNET and midgut NET cohorts, respectively: Week 24, 43.8% (29.5; 58.8) and 58.8% (44.2; 72.4); Week 48, 22.9% (12.0; 37.3) and 33.3% (20.8; 47.9). Treatment-related adverse events (TRAEs) occurred in 37.5% and 51.0% of patients in the panNET and midgut NET cohorts, respectively; only one TRAE was G≥3 (panNET: fatigue [N=1], G3). The most common (≥10%) classes of TRAEs were gastrointestinal disorders (panNET, 25.0%; midgut NET, 37.3%) and general disorders/administration-site conditions (midgut NET, 13.7%). Of note, the following TRAEs occurred: hyperglycaemia (N=2), bile stones (N=1), steatorrhea (N=1).

Conclusions

LAN 120 mg q14 days in patients with panNETs or midgut NETs (progressive on standard LAN dose) produced promising PFS and DCR. In the pan-NET cohort, the outcome was more favourable in patients with Ki67 ≤10%. Safety was consistent with the known safety profile of LAN.

Clinical trial identification

NCT02651987.

Editorial acknowledgement

Jessica Woods, BMedSci (Hons), on behalf of Watermeadow Medical, an Ashfield company, provided medical writing support, which was funded by the study sponsor in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Ipsen.

Funding

Ipsen.

Disclosure

M.E. Pavel: Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: AAA; Honoraria (self), Advisory/Consultancy: Lexicon. J.B. Ćwikła: Honoraria (self): Ipsen. C. Lombard-Bohas: Advisory/Consultancy, Research grant/Funding (self): Ipsen; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (self): Novartis. I. Borbath: Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy, Research grant/Funding (self): Ipsen; Research grant/Funding (self): Bayer; Research grant/Funding (self): Celgene. T. Shah: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen. U-F. Pape: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Ipsen; Honoraria (self), Research grant/Funding (self): Novartis. X-M. Truong Thanh: Full/Part-time employment: Ipsen. A. Houchard: Full/Part-time employment: Ipsen. P. Ruszniewski: Advisory/Consultancy: Novartis; Advisory/Consultancy: Ipsen; Advisory/Consultancy: AAA; Advisory/Consultancy: ITM; Advisory/Consultancy: Keocyt.