Background

Sorafenib has demonstrated a significant impact in progression free survival (PFS) in patients with advanced DTC in the DECISION trial. BRAF and RAS mutation status (MS) have not shown prognostic significance on PFS and overall survival (OS) in multivariate model. The aim of this study was to correlate different RNA expression profiles with PFS and OS in a multivariate model.

Methods

We previously identified 3 expression profiles, BRAF, RAS and non-BRAF/RAS-like based on RNA-seq analysis (77 million paired-end reads for each sample on HiSeq2000) of 125 tumour samples of patients included in the DECISION trial. RNAseq reads were mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. We used multivariate Cox proportional models to study the association between clinical variables (sex, age, thyroid cancer histology, Eastern Cooperative Oncology Group performance status), arm of treatment and biomarkers (EP and MS) with PFS and OS.

Results

The clinical variables in each expression profiles are shown in Table. Multivariable analysis indicated that only sorafenib treatment (HR: 0.39, 95% CI 0.23-0.66, p < 0.001), age (HR: 0.97, 95% IC 0.94-0.99, p = 0,002) and BRAF-like EP (HR = 0.41, 95% IC 0.17-0.99, p = 0.046) were independent prognostic factors for PFS. No significant prognostic factors we identified for OS. However, in papillary histology (PTC), only the BRAF-like EP was associated with outcome (HR = 0.32, 95% IC 0.118-0.876, p = 0.026).Table:

432PD Clinical variables in each expression profiles

Conclusions

RNA-seq analysis identifies 3 different expression profiles in DTC: BRAF-like, RAS-like and non-BRAF/RAS-like. BRAF-like EP includes almost all BRAF mutant tumors but also a 45% of tumors with no mutation in BRAF gene. In the multivariate analysis, BRAF-like EP has shown a better prognostic factor for PFS in DTC and for OS in PTC.

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology

Funding

Bayer HealthCare Pharmaceuticals, Inc.

Disclosure

C. Peña: Bayer employee. All other authors have declared no conflicts of interest.

Background

We queried whether CGP could differentiate the mTC subtypes of papillary (PTC), follicular (FTC), medullary (MTC) and anaplastic (ATC) carcinomas and their potential responses to targeted and immunotherapies.

Methods

CGP was performed on FFPE samples using hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 500X for up to 315 cancer-related genes. Total mutational burden (TMB) was determined on 1.1 megabases of sequenced DNA as previously described (PMID: 28420421).

Results

778 clinically advanced mTC were studied. Median age across the subtypes was similar with male patients slightly more frequent than females except for PTC. ATC had the highest median GA/sample at 4.34. BRAF was a target option for 73% of PTC and 39% of ATC, and RET for MTC in 81% of cases. Oncogenic rearrangements of RET, BRAF, ALK, and NTRK1 were detected in 8%, 3%, 1%, and 1% of PTC cases, respectively, and in 1%, 1%, 0%, and 1% of ATC cases, respectively, but not detected in any cases of FTC or MTC. At 66%, TP53 GA were most frequent in ATC. TERT GA were 58-67% in PTC, FTC and ATC and 0% in MTC. TMB was extremely low for all 4 mTC tumor types with only 3 mTC (<1%) having ≥ 20 mut/Mb. Examples of mTC with responses to targeted therapies will be presented.Table:

433PD

Conclusions

Refractory mTC patients are generally older than patients with classic localized primary PTC, and feature relatively more males. Advanced stage PTC, and to a lesser extent ATC, is frequently driven by BRAF GA or oncogenic rearrangements. Relapsed MTC is nearly universally driven by RET GA, whereas FTC has no dominant driver GA identified. TMB appears to be low for all subtypes of MTC, suggesting low potential for immunotherapies.

Legal entity responsible for the study

Jeffrey S. Ross

Funding

None

Disclosure

J.S. Ross: Employee, leader and stock owner in Foundation Medicine. L.M. Gay, P. Vanden Borre, N. Almog, A.B. Schrock, J-A. Vergilio, J. Suh, S. Ramkissoon, E. Severson, S. Daniel, S.M. Ali, J.A. Elvin: Employee and stock owner in Foundation Medicine. V.A. Miller, P.J. Stephens: Employee, leader stock ower in Foundation Medicine. All other authors have declared no conflicts of interest.

Background

LEN prolonged progression-free survival (PFS) in pts with RR-DTC in the SELECT trial, and efficacy was maintained in all subgroups. Toxicity was manageable with dose modifications, but whether a longer period of dose interruption might impact the efficacy of LEN was unclear.

Methods

In SELECT, pts were randomized 2:1 to receive LEN 24 mg/day or placebo. Pts assigned to LEN were divided into 2 groups: pts with duration of dose interruption <10% (A) and pts with duration of dose interruption ≥10% (B) of total treatment duration. A and B were not randomized groups. PFS, objective response rate (ORR), and safety were analyzed in both groups.

Results

Of 261 LEN-treated pts, there were 134 in group A and 127 in group B. Differences in pt characteristics between groups (A and B) were, respectively: age (>65 years, 33% and 49%), race (Asian, 10% and 25%), and ECOG performance status (0, 64% and 46%). Median duration of dose interruption was 19 days (range: 0–63) and 61 days (range: 2–266) in groups A and B, respectively. Median PFS was not reached (hazard ratio [HR] to placebo: 0.14; 95% CI: 0.09–0.20, P < 0.001) in group A and 12.8 months (HR to placebo: 0.31, 95% CI: 0.22–0.43) in group B. ORR was 76% for group A and 53% for B. Disease control rate was 88% and 87% in groups A and B, respectively. Common adverse events (AEs) were similar in both groups, but incidences were different for diarrhea (A: 74%; B: 58%), decreased appetite (A: 45%; B: 62%), decreased weight (A: 57%; B: 44%), palmar-plantar erythrodysesthesia (A: 27%; B: 38%), and proteinuria (A: 23%; B: 42%). Common AEs leading to dose interruption or reduction included diarrhea (A: 24%; B: 21%), hypertension (A: 16%; B: 24%), proteinuria (A: 11%; B: 27%), and decreased appetite (A: 10%; B: 27%).

Conclusions

Longer duration of dose interruption may negatively affect the potential efficacy of LEN. Management of toxicities is essential to avoid long dose interruption. Differences in pt characteristics might confound the results. However, in this analysis LEN achieved improved PFS and ORR compared to placebo, regardless of length of dose interruption.

Clinical trial identification

NCT01321554

Legal entity responsible for the study

Eisai Inc

Funding

Eisai Inc

Disclosure

M. Tahara: Grants and personal fees from Eisai during the conduct of the study and personal fees from Merck Serono, BMS, and Bayer outside the submitted work. M.S. Brose: Grants from Eisai during the conduct of the study. Grants and personal fees from Bayer HealthCare Pharmaceuticals, Exelixis, and Onyx. Grants from Novartis and Roche/Genentech outside the submitted work. L. Wirth: Personal fees from Eisai and Novartis outside the submitted work. T. Suzuki, K. Fujino: Employee of Eisai Co., Ltd. N. Batty, C. Dutcus: Employee of Eisai Inc. A. Gianoukakis: Grants and nonfinancial support from Eisai during the conduct of the study.

Background

Delta-like protein 3 (DLL3) is an atypical Notch receptor family ligand expressed in high-grade neuroendocrine carcinomas (NECs), but not in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3. A Phase 1 study of Rova-T in small cell lung cancer showed encouraging antitumor activity in patients (pts) with DLL3 expression, and was well-tolerated¹. Rova-T may also be active in other DLL3-expressing tumors.

Methods

This is a Phase 1/2, open-label, multicenter study (NCT02709889) to determine safety and tolerability of Rova-T in 8 cohorts: malignant melanoma, medullary thyroid cancer (MTC), glioblastoma (GBM), large cell NEC (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic NEC (GEP NEC), other NEC and other solid tumors. Eligible adults have a histologically confirmed, DLL3-expressing, advanced solid tumor relapsed/refractory to standard therapy, and no prior exposure to a pyrrolobenzodiazepine-based drug. A 3 + 3 dose escalation is used in each cohort, at doses 0.2-0.4 mg/kg of Rova-T administered intravenously on Day 1 of each 42-day cycle, and proceeding until a maximum tolerated dose (MTD) is determined. A 2-stage design will be used for disease-specific expansion cohorts.

Results

As of 3 April 2017, 31 pts (2 melanoma, 2 MTC, 3 GBM, 3 LCNEC, 3 NEPC, 3 GEP NEC, 10 other NEC, 5 other solid tumor) have been treated (26 pts at 0.2 mg/kg, 5 pts at 0.3 mg/kg Rova-T). The MTD has not been reached. Twenty-six pts (84%) had an adverse event (AE), and only 3/31 pts (10%) had a Grade 3+ AE deemed to be related to Rova-T. Common AEs were fatigue (32%), nausea (29%), and constipation (23%). Four pts had serosal effusions, 2 (6%) of which were assessed to be drug-related, and 3 pts (10%) had adverse skin reactions. Ten pts (32%) discontinued treatment, 5 for progressive disease and 4 due to AEs. Eleven pts have had post-baseline tumor assessments, and anti-tumor activity has been observed in multiple disease cohorts.

Conclusions

Preliminary safety and efficacy data of Rova-T warrant continued study in these disease populations, and will be updated at time of presentation. 1. Rudin et al., Lancet Oncol 2016.

Clinical trial identification

NCT02709889

Legal entity responsible for the study

AbbVie Stemcentrx

Funding

AbbVie Stemcentrx

Disclosure

A. Mansfield: Consulting to Genentech, BMS and Trovagene with honoraria provided to institution. H. Beltran, K. Lewis: Research funding from AbbVie Stemcentrx. A.F. Farago: Consulting or advisory role for AbbVie, Pharmamar, Merrimack Pharmaceuticals, Takeda, Intervention Insights. Honorarium from Foundation Medicine. C.L. Hann: Advisory board for AbbVie Stemcentrx and BMS. Research funding from GlaxoSmithKline and Merrimack Pharmaceuticals. S. Richey: Employee of Texas Oncology. Consulting or advisory role for Exelixis, Pfizer, Prometheus and Sanofi. Research funding from Novartis, BMS, Eisai, Genentech/Roche, GSK, and AbbVie. D. Smith: Research funding from US Oncology. H.P. Soares: Advisory board for Cornerstone Pharmaceuticals. Research funding from Novartis. Consultant fees/honoraria for Ipsen. A. Spira: Consultant for AbbVie. Research funding from AbbVie (to institution). S. Lally, M. Rossi, L. Saunders, S.J. Dylla, E. Kavalerchik: Employee of AbbVie Stemcentrx and may own stock. L. Anthony: Research funding from AbbVie Stemcentrx, Lexicon Pharmaceuticals, Novartis, Markey Cancer Center Foundation. All other authors have declared no conflicts of interest.

Background

Several attempts to improve the knowledge about the molecular biology of EP-NETS. However, the majority of these studies rely on alterations or pattern descriptions rather than integrative analysis of the findings derived from different platforms. We aim to identify new potential biomarkers integrating the differential expression of miRNAs and DNA methylated regions.

Methods

From a series of 115 EP-NETS formalin-fixed and paraffin embedded samples, we selected 8 cases of small intestine (SI) NETS and 8 pancreatic (P) NETS based on relapse (yes vs no) trying to identify the most phenotypically different cases within these groups in our series. DNA and RNA were extracted. The methylome EPIC array was used to determine differentially methylated regions (DMRs) and a transcriptomic array was used to analyse miRNA expression. Quality check (QC) of data was ran prior to analysis. False discovery rate (FDR) was applied to correct for multiple comparisons. Chromosomal regions with differentially expressed miRNAs and DMRs were plotted to perform an integrative analysis.

Results

Sample-wise and chip-wise QC were performed. DMRs were analyzed comparing patients with or without relapse (R) in SI-NETS and PNETS. The most significant differentially methylated regions for R vs non-R in PNETS were found in chromosome (chr) 2, and in chr 1 and 2 for SI-NETS. A gene set analysis of the DMRs was performed using a FDR < 0.1. Gene sets commonly represented in SI-NETS and PNETS are within CD8 TCR pathway and endothelin pathway. None of the miRNAs maintain significance using a FDR <0.2. However, one of the top10 differentially expressed miRNAs for PNETS, hsa-miR-149-5p (uncorrected p = 0,014) is found in the same region of the chr 2 were the most significant DMRs and differentially methylated promoters are located. Has-miR-9-1-5p (uncorrected p = 0.017) was also differentially expressed in PNETs and located close to one of significant DMRs in chr 1.

Conclusions

It is feasible to integrate the analysis of DMRs and miRNAs in EP-NETS. Certain areas of chr1 and 2 concentrated regions with different epigenetic regulation when compare R vs non-R. Validation of the findings is ongoing.

Legal entity responsible for the study

IdIPAZ - Hospital Universitario La Paz

Funding

Fundación Eugenio Rodriguez Pascual Fundación Eugenio Rodríguez Pascual; Sociedad Española de Oncología Medica

Disclosure

All authors have declared no conflicts of interest.

Background

Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of ¹⁷⁷Lu-DOTATATE treatment on the time to clinically relevant change (deterioration) in health-related QoL (HRQoL). The NETTER-1 trial is an international phase III study in patients with progressive, somatostatin receptor positive midgut NET. Patients were randomized to receive treatment with ¹⁷⁷Lu-DOTATATE versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires QLQC-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on HRQoL.

Methods

231 patients completed EORTC QLQC-30 and G.I.NET-21 questionnaires at baseline and every 12 weeks thereafter until tumor progression centrally confirmed. QoL scores were converted to a 100-point scale according to EORTC instructions and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from randomization to the first QoL deterioration ≥10 points for each patient in the corresponding domain scale. This magnitude of variation was considered clinically relevant. All analyses were conducted on the ITT population.

Results

TTD was significantly longer in the ¹⁷⁷Lu-DOTATATE arm (N = 117) vs the control arm (N = 114) for the following domains: global health status (hazard ratio (HR) 0.406; p = 0.0006), physical functioning (HR 0.518; p = 0.0147), role functioning (HR 0.580; p = 0.0298), fatigue (HR 0.621; p = 0.0297), pain (HR 0.566; p = 0.0247), diarrhea (HR 0.473; p = 0.0107), disease related worries (HR 0.572; p = 0.0176) and body image (HR 0.425; p = 0.0058). In the other domains TTD did not reach statistical significance between the arms. Differences in median TTD were clinically significant in several domains: 28.8 months vs. 6.1 months for global health status, and 25.2 months vs. 11.5 months for physical functioning.

Conclusions

This analysis from the NETTER-1 Phase III study demonstrates that ¹⁷⁷Lu-DOTATATE provides a significant quality of life benefit for patients with progressive midgut NETs compared to high-dose octreotide, in addition to the meaningful increase in progression-free survival already reported.

Clinical trial identification

NCT01578239

Legal entity responsible for the study

NETTER-1 study group and Advanced Accelerator Applications

Funding

Advanced Accelerator Applications

Disclosure

M. Lopera Sierra: Advanced Accelerator Applications Chief Medical Officer E. Krenning: Stock ownership. All other authors have declared no conflicts of interest.

Background

Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing gastroenteropancreatic neuroendcrine neoplasms (NEN) has shown promising results in a recently published clinical trial (NETTER-1, NEJM, Jan 2017). In this study, we performed an intention to treat analysis in over 1000 patients with NEN (pancreas, mid-gut, lung and others) treated at our center.

Methods

From 2004, 1048 patients received at least one cycle of Yttrium-90 or Lutetium-177 based PRRT, and were included in an intention to treat analysis. Ga-68 somatostatin receptor (SSR) PET/CT was used for restaging and response to therapy assessment (EORTC criteria). Accordingly, overall survival (OS) and progression free survival (PFS) were calculated. Adverse events (hematotoxicity and nephrotoxicity) were determined by CTCAE (v4.03).

Results

Overall survival (95% CI) was 51 months (47.0-54.9) and differed according to tumor grade, location of primary tumor, functionality, previous therapies, and the radioisotope used for PRRT. PFS was 19 months (16.9-21.0), which was influenced by tumor grade, location of primary tumor, and the radioisotope used for PRRT. PFS after initial progression and first and second resumption of PRRT, following therapy-free intervals of > 6 months, was 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 2.1% patients. No grade 4 nephrotoxicity was observed with Lu-177. Few patients with severe renal dysfunction before PRRT, progressed to end-stage renal disease. No patient with normal renal function before PRRT developed G3 (or higher) nephrotoxicity.

Conclusions

PRRT is effective as it favorably prolongs the OS and PFS in patients with metastatic neuroendocrine neoplasms. However, this depends on the tumor grade, location of primary tumor, and the radionuclide used for therapy. Low rate of severe hematotoxicity were observed. There was no therapy associated severe nephrotoxicity in patients with normal renal function prior to commencement of PRRT.

Clinical trial identification

Not applicable

Legal entity responsible for the study

Richard P. Baum

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The phase III, placebo-controlled, randomized TELESTAR study evaluated efficacy and safety of telotristat ethyl (TE) in patients (pts) with diarrhea (≥4 bowel movements [BMs]/day) due to carcinoid syndrome (CS) inadequately controlled by somatostatin analogs (SSAs). TE, a tryptophan hydroxylase inhibitor, decreases peripheral serotonin levels. As add-on treatment to SSAs, TE 250 mg 3x/day (tid) and TE 500 mg tid significantly reduced BM frequency (p < 0.001) compared with placebo over the 12-week Double-blind Treatment (DBT) period. After Week 12, pts crossed over to a 36-week Open-label Extension (OLE) period with TE 500 mg tid; data from the full 48 weeks are presented.

Methods

Changes from baseline in BM frequency (monitored weekly), urinary 5-hydroxyindoleacetic acid (u5-HIAA; Weeks 18, 24, and 48), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) score (Weeks 24 and 48), and safety during the OLE period were evaluated.

Results

Of the 135 pts randomly assigned, 118 completed the DBT period; 115 pts subsequently entered (and 79 completed) the OLE period. Of the 36 pts who discontinued the OLE period, the most frequent reasons were adverse event (AE; 15 pts) and withdrawal of consent (9 pts). Treatment-emergent AEs led 18 pts to discontinue TE; gastrointestinal disorder was the most commonly reported reason (6 pts). Reductions from baseline in BM frequency (∼2 BMs/day) and u5-HIAA levels (range –20.0 mg to –49.5 mg/24 hours) during the OLE were consistent with results of the DBT period and persisted through Week 48. Improvement in EORTC QLQ-C30 diarrhea subscale scores relative to baseline (range –18.8 to –30.6 points) was notable and persisted through Week 48. Crossover into the OLE period was well tolerated. Treatment-emergent AEs were mainly mild to moderate and occurred at a similar rate as in the DBT period.

Conclusions

Patients benefitted from TE throughout the OLE period. TE was well tolerated over 48 weeks and its efficacy was consistent with previously reported data.

Clinical trial identification

NCT01677910

Legal entity responsible for the study

Lexicon Pharmaceuticals, Inc.

Funding

Lexicon Pharmaceuticals, Inc.

Disclosure

D. Hörsch: Grants and personal fees from Lexicon Pharmaceuticals, Inc., Ipsen Bioscience, Novartis Pharmaceuticals and Pfizer, Inc. M.H. Kulke: Relationships with Lexicon Pharmaceuticals, Inc., Ipsen Bioscience, and Novartis Pharmaceuticals. M. Caplin: Advisory board, speaker honoraria and/or research funding from Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals and Ipsen Biopharmaceuticals. L. Anthony: Grants from Lexicon Pharmaceuticals, Inc. E. Bergsland: Advisory boards for Ipsen Bioscience, Lexicon Pharmaceuticals, Inc., and Novartis Pharmaceuticals. Research support from Lexicon Pharmaceuticals, Inc., and Novartis Pharmaceuticals. P. Kunz: Research funding Merck & Co., Genetech, Advanced Accelerator Applications, Lexicon Pharmaceuticals, Inc., Oxygen, Esanex, Dicerna Pharmaceuticals, & Ipsen. Advisory boards Novartis Pharmaceuticals, Ipsen, & Lexicon Pharmaceuticals, Inc E. Grande Pulido: Research funding from Astellas, Pfizer and AstraZeneca. J.S. Dillon: Received grants from Lexicon Pharmaceuticals, Inc. P. Lapuerta, P. Banks, S. Jackson: Employee of Lexicon Pharmaceuticals, Inc. M. Pavel: Grants and personal fees from Ipsen Bioscience and Novartis Parhmaceuticals. Personal fees from Lexicon Pharmaceuticals, Inc., and Pfizer, inc. All other authors have declared no conflicts of interest.

Background

NETs are uncommon, and there is no consensus regarding the optimal follow-up frequency or modality after resection. Current follow-up guidelines for resected GEP-NETs are based on limited evidence and our large, international practice survey showed poor compliance by NET expert clinicians. A need for clear and practical guidelines was identified.

Methods

A RAND/UCLA appropriateness process was employed given the lack of published data. A systematic review was undertaken as well as a multi-national practice survey to understand current follow-up patterns. Results from two large retrospective reviews (Ontario, Canada and Tampa, Florida) examining outcome following curative surgery were obtained. An 18-member multidisciplinary international panel scored 193 clinical scenarios for appropriateness of timing of consultations and investigations for detecting recurrence on a 1-9 scale. At a face-to-face consensus conference, the final follow-up recommendations were developed.

Results

Twelve studies were identified describing follow-up strategies post-resection, with only one comparing follow-up strategies. Data from our practice survey (n = 163) and our population-based study (n = 936) are separately reported. Based on the scenario scoring, the panel resolved 14 summary statements, with the major themes of (1) less frequent follow up visits and investigations within the first five years (2) longer follow up even beyond 10 years (3) different recommendations for pancreatic versus gastrointestinal NETs (4) identification of low risk subgroups where no routine follow-up was recommended (5) no role for any serum or urine biomarkers, or chest imaging (6) the need to evaluate functional imaging in follow-up.

Conclusions

Streamlined, practical guidelines were developed for the follow-up of patients with resected GEP-NETs. These guidelines differ significantly from other current guidelines. The expert consensus was informed by previously unavailable large outcome datasets. Compliance, cost-effectiveness and patient acceptability will be evaluated in future studies.

Legal entity responsible for the study

Sunnybrook Research Institute

Funding

AGITG

Disclosure

S. Singh: Honoraria and travel funding from Ipsen, Pfizer and Novartis. D. Chan: Travel support from Novartis and honoraria from Ipsen. D. Metz: Vice Chair at NANETS, consultant for Novartis and Ipsen. Commercial research grant from Lexicon and AAA. Consultant/advisory board for AAA. J. Strosberg: Consultation for Novartis and Ipsen. E. Segelov: Honoraria from Roche, Bayer, Ipsen and Pfzier; research funding from Merck Serono and Ipsen; travel support from Roche and Ipsen. All other authors have declared no conflicts of interest.