- Enrique Grande (Madrid, Spain)
- George Pentheroudakis (Ioannina, Greece)
LBA76 - Efficacy and safety of surufatinib in patients with well-differentiated advanced extrapancreatic neuroendocrine tumors (NETs): Results from the randomized phase III study (SANET-ep) (ID 4979)
- Jianming Xu (Beijing, China)
Abstract
Background
Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule kinase inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony stimulating factor 1 receptor, which demonstrated encouraging efficacy in previous Phase Ib/II study in patients with advanced NETs regardless of tumor origin.
Methods
This was a randomized, double-blind, multi-center phase III study to evaluate efficacy and safety of surufatinib in patients with well-differentiated, progressive, unresectable or metastatic extrapancreatic NETs (NCT02588170). Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Crossover at disease progression was allowed. The primary endpoint was disease progression-free survival (PFS) assessed by investigators.
Results
By the cutoff date on 31 March 2019 for the pre-planned interim analysis, 198 patients were randomized (surufatinib: N = 129, placebo N = 69) with 128 PFS events observed. The tumor origins included gastrointestinal tract (47.0%), lung (11.6%), other (27.8%) or unknown (13.6%). Most patients (83.8%) were with NETs of pathological grade 2. Investigator-assessed median PFS was 9.2 vs. 3.8 months in surufatinib and placebo arms (hazard ratio [HR] = 0.334 [95% confidence interval [CI] 0.223, 0.499]; p < 0.0001), respectively. A trend of PFS prolongation (HR = 0.657, 95% CI 0.442, 0.977) was observed by the independent radiology committee. Overall survival (OS) was immature at data cutoff (18.7% OS events). Most common (≥5%) grade 3 or worse treatment-emergent adverse events were hypertension (36.4% in surufatinib arm vs. 13.2% in placebo arm), proteinuria (19.4% vs. 0%) and anemia (7.0% vs. 2.9%).
Conclusions
Surufatinib significantly improved the PFS in patients with progressive, advanced NETs originating outside of pancreas. No new safety signals were identified. The study was terminated by the recommendation of the Independent Data Monitoring Committee based on the interim analysis. A parallel study of surufatinib in pancreatic NETs is ongoing.
Legal entity responsible for the study
Hutchison MediPharma Ltd.
Funding
Hutchison MediPharma Ltd.
Disclosure
J. Li: Full / Part-time employment: Hutchison MediPharma Ltd. S. Fan: Full / Part-time employment: Hutchison MediPharma Ltd. W. Su: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. All other authors have declared no conflicts of interest.
LBA93 - Registrational results of LOXO-292 in patients with RET-altered thyroid cancers (ID 2402)
- Lori J. Wirth (Boston, MA, United States of America)
Abstract
Background
To date, no targeted therapy is approved for patients with RET-altered cancers. LOXO-292 is a highly selective RET inhibitor with activity across known oncogenic RET fusions and mutations. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion+ non-small cell lung cancer (NSCLC), RET fusion+ thyroid cancer and RET-mutant medullary thyroid cancer (MTC).
Methods
The LIBRETTO-001 global phase I/II study (87 sites, 16 countries) enrolled patients with advanced RET fusion+ cancers and RET-mutant MTC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. Phase I established the RP2D. Phase II enrolled patients in one of six cohorts based on tumor type, RET alteration and prior therapy. The primary endpoint was ORR. Secondary endpoints included DoR, PFS and OS.
Results
As of 17-June 2019, 253 RET-altered thyroid cancer patients (n = 226 RET-mutant MTC, n = 27 RET fusion+ thyroid cancer) were treated. The primary analysis set (PAS) for LOXO-292 registration in MTC, defined with the US FDA, consisted of the first 55 consecutively enrolled RET-mutant MTC patients who received prior cabozantinib and/or vandetanib. Among these previously treated RET-mutant MTC PAS patients, the investigator-assessed ORR was 56% (95% CI 42-70%, n = 31/55, 2 PRs pending confirmation), including 3 patients with a RET V804M/L gatekeeper mutation (1 CR, 2 PR, all confirmed). Median DoR has not been reached (6 DoR events, 95% CI 11.1 months-NE) with median follow-up of 10.6 months. Biochemical response rates (≥50% decrease lasting ≥4 weeks) were 91% for calcitonin (n = 49/54) and 64% for CEA (n = 34/53). The ORR in evaluable RET fusion+ thyroid cancer patients was 62% (95% CI 41-80%, n = 16/26, 2 PRs pending confirmation). In the safety data set of 531 patients, 5 treatment-related AEs occurred in ≥ 15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.
Conclusions
LOXO-292 had marked antitumor activity in RET-altered thyroid cancer and was well tolerated. These data will form the basis of an FDA new drug application in late 2019.
Clinical trial identification
NCT03157128.
Legal entity responsible for the study
Loxo Oncology.
Funding
Loxo Oncology.
Disclosure
L.J. Wirth: Advisory / Consultancy: Eisai; Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck. E. Sherman: Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: COTA consulting; Advisory / Consultancy: Novartis; Advisory / Consultancy: Goldilocks; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bristol-Myers Squibb. A. Drilon: Advisory / Consultancy: Ignyta; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: TP therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Takeda/Ariad/Millenium; Advisory / Consultancy: Helsinn; Advisory / Consultancy: Beigene; Advisory / Consultancy: BergenBio; Advisory / Consultancy: Hengrui Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Tyra Biosciences; Advisory / Consultancy: Verastem; Advisory / Consultancy: MORE Health; Advisory / Consultancy: Lilly; Research grant / Funding (institution): GlaxoSmithKlein; Research grant / Funding (institution): Teva. B. Robinson: Speaker Bureau / Expert testimony: Loxo Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Leadership role, Shareholder / Stockholder / Stock options: MaynePharma; Leadership role, Shareholder / Stockholder / Stock options: Cochlear; Research grant / Funding (institution): National Health and Medical Reasearch Council. J. Lorch: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Genentech; Research grant / Funding (institution): Bristol-Myer Squibb. C. McCoach: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novaritis; Research grant / Funding (institution): Revolution Medicines; Honoraria (self): Guardant Health; Travel / Accommodation / Expenses: Loxo oncology; Honoraria (self): Takeda. J.D. Patel: Advisory / Consultancy: AbbVie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Takeda. S. Leboulleux: Speaker Bureau / Expert testimony: Loxo Oncology; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Sanofi. F. Worden: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Cue Pharmaceuticals; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Loxo Oncology; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Pfizer. T.K. Owonikoko: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Astellas Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Stem CentRx; Research grant / Funding (institution): Regeneron; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Bristol-Myers; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): United Therapeutics; Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Loxo/Lilly; Research grant / Funding (institution): Fujifilm; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Leadership role, Shareholder / Stockholder / Stock options: Cambium Oncology; Research grant / Funding (institution): Biotherapeutics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck . M.S. Brose: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Advisory / Consultancy: Progenics. M.H. Taylor: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai Inc; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Loxo oncology; Advisory / Consultancy: Novartis; Advisory / Consultancy: Arqule. A. Italiano: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Epizyme; Advisory / Consultancy: ImmuneDesign; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pharmamar. S..M. Rothenberg: Full / Part-time employment: Loxo Oncology. V. Subbiah: Research grant / Funding (institution): Loxo oncology; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Nanocarrier; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Northwest Biotherapeutics; Research grant / Funding (institution): Berghealth; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pharmamar; Research grant / Funding (institution): D3; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Astrazeneca; Travel / Accommodation / Expenses: Apollo Hospitals; Licensing / Royalties: Sathgen Biotech; Travel / Accommodation / Expenses: ASCO; Travel / Accommodation / Expenses: ESMO; Research grant / Funding (institution): Blueprint. M. Cabanillas: Speaker Bureau / Expert testimony: Loxo; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis. All other authors have declared no conflicts of interest.
1380O - 177Lu-DOTATATE plus 166Ho-radioembolization in patients with neuroendocrine tumours: A single center, prospective, interventional, non-comparative, open label, phase II study (HEPAR PLUS study) (ID 3974)
- Sander Ebbers (Utrecht, Netherlands)
Abstract
Background
The liver is the most commonly affected organ in metastatic neuroendocrine disease and is the most incriminating factor for patient survival. Additional treatment of liver disease with radioembolization may improve outcome in NET patients with bulky residual liver disease after PRRT. To investigate this hypothesis, a phase II study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE.
Methods
The HEPAR PLUS study was a single center, prospective, interventional, non-comparative, open label study. Thirty patients with >3 measurable residual liver metastases according to RECIST 1.1 received 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives: objective response rate (ORR = complete plus partial response) after three months according to RECIST 1.1 (treatment volume, liver and patient-based analysis). Secondary endpoints included toxicity profile according to CTCAE v4.03 and quality of life assessments according to EORTC QLQ-C30 and GI.NET21 questionnaires.
Results
Three months after PRRT plus 166Ho-RE, liver ORR was 43% according to RECIST 1.1. In patient-based analysis, ORR was 40% according to RECIST 1.1, stable disaese in 50% and three patient (10%) experienced progressive disease (due to progressive lesions or development of new lesions outside the treatment volume). CTCAE grade 3-4 toxicities were limited to abdominal pain (10%), nausea (3%) and fatigue (3%). One related serious adverse event occurred in one patient (3%), fatal radiation induced liver disease. Quality of life assessments showed a temporary non-significant decrease in most scales at three weeks post-treatment and complete resolution three months after treatment.
Conclusions
This was the first prospective study to combine PRRT and 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE leads to a high objective response rate without significant additional short-term side-effects, and a temporary non-significant decrease in quality of life in well-selected patients.
Clinical trial identification
NCT02067988.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A.J.A.T. Braat: Non-remunerated activity/ies: Terumo; Non-remunerated activity/ies: BTG; Non-remunerated activity/ies: Sirtex Medical. M.G.E.H. Lam: Honoraria (institution), Non-remunerated activity/ies: Terumo; Advisory / Consultancy, Non-remunerated activity/ies: BTG; Advisory / Consultancy, Non-remunerated activity/ies: Sirtex Medical; Non-remunerated activity/ies: Mirada. All other authors have declared no conflicts of interest.
Invited Discussant LBA76, LBA93 and 1380O (ID 6816)
- Enrique Grande (Madrid, Spain)
512O - Malignant non-adrenal paraganglioma (mPara) and adrenal pheochromocytoma (mPheo) a comparative comprehensive genomic profiling (CGP) study (ID 1796)
- Gennady Bratslavsky (Syracuse, NY, United States of America)
Abstract
Background
We used CGP to compare the genomic alterations (GA) in mPara and mPheo to enable the search for potential therapy targets.
Methods
FFPE sections of 84 mPara and 44 mPheo underwent hybrid-capture based CGP. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (DAKO 22C3 antibody).
Results
All patients had recurrent and/or metastatic disease. Patient ages were similar, but mPara featured significantly more male patients (Table). The GA/tumor frequency was low for both tumor types. The most frequent un-targetable GA were in SDHB, ATRX and TERT in mPara and ATRX, TP53 and SDHB in mPheo. The most frequent potentially targetable GA in mPara were in FGFR1 (7%, primarily amplifications) and NF1, PTEN, NF2 and CDK4 (all 2%) and for mPheo were in RET (9%, primarily fusions), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in only in 1% of mPara and 2% of mPheo. Germline mutations in known cancer predisposition genes were predicted in 38 (45%) mPara and 8 (18%) mPheo cases, predominantly involving the SDHA/B genes. The TMB and PD-L1 expression levels were similar in both tumor types and 0% of cases were associated with MSI High status.mPara mPheo Number of Cases 84 44 Age in years (range) 48 (10-80) 52 (7-78) Males/Females 51/33 23/21 GA per tumor[AS1] 1.9 2.3 Most common Untargetable GA SDHB (27%) ATRX (21%) TERT (18%) TP53 (7%) SDHA (7%) ATRX (25%) TP53 (21%) SDHB (13%) CTNNB1 (7%) VHL (7%) CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%) Most common Targetable GA FGFR1 (7%) NF1 (2%) PTEN (2%) NF2 (2%) CDK4 (2%) RET (9%) NF1 (9%) FGFR1 (5%) CD274 amplification 0% 0% PBRM1 GA 1% 2% MSI 0% 0% Median TMB mut/Mb 1.3 2.4 TMB > 10/20 mut/Mb 6%/2% 5%/0% PD-L1 Expression low/high 14%/0% 0%/0%
Conclusions
mPara and mPheo feature similar GA with mPara more often associated with germline GA. Although the GA/tumor is relatively low for mPara and mPheo, CGP can reveal important potential therapy targets in both tumor types including RET, NF1 and FGFR1. Based on biomarker assessments, mPara and mPheo do not appear to have strong potential for responsiveness to immunotherapies.
Legal entity responsible for the study
Foundation Medicine.
Funding
Foundation Medicine.
Disclosure
E.S. Sokol: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.A. Elvin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Vergilio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J..K. Killian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. N. Ngo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. D. Lin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. E. Severson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Chung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. P. Reddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. V.A. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest.
1381O - RNA expression profiles and splicing alterations in grade 1/2 neuroendocrine neoplasms from small intestine origin (siNENs). Final results of the GETNE-NETSEQ study (ID 2442)
- Jaume Capdevila (Barcelona, Spain)
Abstract
Background
Despite favorable clinical and pathological prognostic factors, some patients (pts) with siNENs have impaired survival. In this study, we aimed to identify distinct RNA expression and splicing profiles (EP and SP, respectively) to correlate with prognosis.
Methods
Paraffin-embedded tumor samples of 48 pts with metastatic grade 1/2 siNENs were analyzed for RNAseq. We generated on average 66 million paired-end reads for each sample on HiSeq2500 (Illumina). RNAseq reads were mapped against the human reference genome (hg19) with Tophat (v2.0.14) and quantified using Cufflinks tools suite for expression analysis. As for splicing, SUPPA2 software was used to detect and quantify the splicing isoforms. 41 samples had sufficient quality to be included in the analysis. We used multivariate Cox proportional models to study the association between clinical variables and EP, SP and overall survival (OS). Poor outcome was defined as death within the first 3 years from advanced stage diagnosis.
Results
9348 transcripts for unique genes were quantified and over 160000 splicing isoforms were examined. A gene signature of 329 transcripts was defined by a two-way statistical analysis between short- and long-term survivors. A pathway enrichment analysis showed a dysregulation in the poor prognosis group on the mTOR and the Toll-like pathways. The EP signature was shown to be an independent prognostic variable for OS (HR 0.05, 95% CI 0.005-0.51, p = 0.011 in multivariate analysis). The analysis of splicing revealed that 90 isoforms were differentially expressed, including those from ELOA and C14orf178 genes, which were associated with aggressiveness.
Conclusions
Different RNA-clusters, different deregulated pathways, and selective splicing alterations were identified for those pts with advanced siNENs with poor prognosis. To our knowledge, this is the first time that Toll-like pathway is involved in the pathogenesis of siNENs and that variants of ELOA and C14orf178 are linked to this pathology. These results may open the future option for a better management and new actionable pathways in this setting.
Legal entity responsible for the study
GETNE (Spanish Taskforce for Neuroendocrine and Endocrine Tumors).
Funding
GETNE.
Disclosure
J. Capdevila: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer, Sanofi, Eisai, Ipsen, Pfizer, Novartis, Advanced Accelerator Applications, Merck; Leadership role, Research grant / Funding (institution): Astrazeneca, Eisai; Travel / Accommodation / Expenses: Ipsen, Eisai. J. Hernando: Speaker Bureau / Expert testimony: Eisai, Ipsen, Angelini, Roche; Travel / Accommodation / Expenses: Adacap, Novartis, Ipsen, Roche, Astrazeneca, Eisai. All other authors have declared no conflicts of interest.
Invited Discussant 1381O and 512O (ID 6818)
- George Pentheroudakis (Ioannina, Greece)