Background

Selective RET inhibitors have showed promising activity in advanced thyroid cancers harbouring RET mutations or fusions. Initial heterogenous mechanisms of resistance at time of disease progression have been described. However, little is known about the mechanisms of persistent disease at the time of maximum response and the pathways activated at regrowth.

Methods

We generated patient-derived xenograft (PDX) models from two patients with advanced thyroid cancers: one from a papillary thyroid tumor with a NCOA4-RET fusion and one from a medullary thyroid carcinoma with a RETM918T mutation. In both cases, RET/MAPK pathway was constitutively activated conferring a hyperproliferative phenotype. We treated both mouse models with multikinase inhibitors (MKI) (cabozantinib, lenvatinib and axitinib) or with a selective RET inhibitor (BLU667). RNAseq analyses were performed in control vehicle-treated tumors and xenografts treated short (5 or 20 days) or long time exposure (20 or 170 days) with BLU667 and after treatment release.

Results

Both PDX models responded to MKI and BLU667 with significant deeper responses with BLU667. The RET-fused PDX showed a more acute and prolonged response to BLU667 than the RETM918T model. Only with selective RET inhibitor we observed a profound effect on the whole gene expression profile of human and mouse cells in all analysed xenograft tumors. Longer treatments revealed a distinctive profile resembling a residual disease. Proliferation genes were downregulated upon treatment, whereas antigen presentation, chemokines and immune response gene sets were positively enriched in both PDX models. Interestingly, such immune reaction to RET/MAPK pathway repression was sustained upon BLU667 treatment release. Such immune reaction affected the gene expression of both cancer (human) and stroma (mouse) cells.

Conclusions

These results pave the way for a rational combination of RET inhibitors and immunotherapy in the two scenarios, as primary therapy to reduce the minimal residual disease and at time of resistance to selective RET inhibition.

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (ISCIII).

Disclosure

A. Garcia Alvarez: Financial Interests, Personal, Advisory Board: ADACAP (Novartis); Other, Expenses (Travel, Congress inscription): Advanz, Eisai, Ipsen, ADACAP (Novartis). J. Hernando: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Novartis, AAA, Angelini, Pfizer, Roche. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, Incyte. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono, Esteve, ITM; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. All other authors have declared no conflicts of interest.

Background

Most rectal neuroendocrine tumors (NETs) are small indolent G1 tumors with good prognosis. However, a few develop distant metastasis, leading to unfavorable outcome, and its association with molecular features are unknown. This study aimed to identify genomic, transcriptomic, and epigenetic alterations that can contribute to more accurate prediction of prognosis of rectal NET.

Methods

This study was a multicenter, noninterventional cohort study, performing multiomics analysis including whole exome sequencing (WES), single nucleotide polymorphism (SNP) array-based profiling for copy number, gene expression and methylation. Patients were classified into 3 cohorts based on the prognoses (ie, cohort A [no recurrence, alive for ≥5 years from initial surgery], cohort B [alive for ≥3 years since recurrence and/or metastasis], cohort C [alive for <3 years from recurrence and/or metastasis to death]). The primary endpoint was to reveal unique molecular alterations in rectal NETs of cohorts B and C compared with cohort A.

Results

A total of 40 patients with rectal NETs were enrolled and 36 patients were analyzed (14 G1-NETs and 22 G2-NETs; 11 in cohort A, 19 in cohort B, and 6 in cohort C). WES revealed 17% (6 of 35) of recurrent somatic mutations in CDC27, which were only identified in cohorts B and C. Cancer genes were infrequently involved: only SF3B1 was mutated in two cases, with the rest of genes including TP53, SMAD4, and ATM mutated in one case. Copy number analysis revealed 56% (19 of 34) chromosomal gain of 19p13.3 and 29% (10 of 34) loss of 16p11.2, both of which cohorts B and C predominated over cohort A. Gene set enrichment analysis between cohorts A and B showed significant enrichments of oxidative phosphorylation and MYC target gene sets for up-regulated genes in cohort B. Unsupervised hierarchical clustering analysis of DNA methylation revealed 3 subgroups, of which cluster 1 mainly consisted of cohort A and cluster 2 of cohorts B and C.

Conclusions

Rectal NETs with unfavorable outcomes (cohorts B and C) had unique genomic and epigenetic alterations, which might be used as a prognostic marker for risk stratification of rectal NETs.

Editorial acknowledgement

Medical writing support was provided by Yutaka Nakagawa (Novartis Malaysia Sdn Bhd).

Legal entity responsible for the study

Novartis Pharma K.K.

Funding

Novartis Pharma K.K.

Disclosure

N. Mizuno: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, FUJIFILM Toyama Chemical, Novartis, Taiho Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Local PI: Incyte, MSD, Ono Pharmaceutical, Seagen; Financial Interests, Institutional, Coordinating PI: Novartis. N. Kobayashi: Financial Interests, Personal, Invited Speaker: PDRadiopharma Inc., Novartis Pharma K.K.. H. Hirano: Financial Interests, Personal, Writing Engagement: Nichi-Iko; Financial Interests, Personal, Invited Speaker: Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Phama; Non-Financial Interests, Institutional, Research Grant: Amgen, Astellas, BeiGene, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Insyte, Janssen Pharmaceutical, Merck Biopharma, MSD, Novartis, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical. T. Tsuchikawa: Non-Financial Interests, Personal, Expert Testimony: Hokkaido University Hospital. S. Matsumoto: Financial Interests, Personal and Institutional, Full or part-time Employment: Kyoto University Hospital. H. Okuyama: Financial Interests, Personal, Advisory Board: Teijin healthcare, Novartis; Financial Interests, Personal, Invited Speaker: Incyte, Novartis, Taiho Pharmaceutical, Chugai pharmaceutical; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical, Chugai pharmaceutical; Financial Interests, Institutional, Local PI: Hutchison Medipharma. K. Shinjo: Financial Interests, Institutional, Funding: NanoCarrier, Eiken Chemical. R. Yamaguchi: Financial Interests, Personal, Advisory Board: Novartis Pharma K.K.; Financial Interests, Personal, Invited Speaker: Novartis Pharma K.K.. T. Kawata: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma K.K.. W. Hosoda: Financial Interests, Personal, Expert Testimony: Novartis. All other authors have declared no conflicts of interest.

Background

Well-differentiated neuroendocrine tumors G3 (NET G3) represent a separate entity from poorly differentiated neuroendocrine carcinoma (NEC). While platinum-based 1^st- line chemotherapy is established in advanced NEC, there is limited efficacy of 2^nd- line chemotherapies, and therapy of NET G3 is still under investigation. Since the mTOR inhibitor everolimus mediates disease stabilization in patients with NET G1/G2, and data on targeted therapy in NEN G3 were lacking, we investigated EVE as 2^nd- line treatment in NEN G3.

Methods

EVINEC was a prospective, single-arm, phase 2 study planned to enroll 40 patients with histologically confirmed NET G3 or NEC G3 with progressive disease on or after platinum-based chemotherapy. Treatment was EVE at 10 mg/day. The primary endpoint was safety; efficacy measurements were secondary endpoints. Central pathology review was performed by a highly experienced pathologist.

Results

Thirty-nine patients were initially found eligible. For three of these, central review determined their tumors not to be NEN. Of the remaining 36, 13 were NET G3, 14 NEC, and 9 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN). MiNEN patients remained on study since NEN components were NEC G3. Most frequent EVE-related adverse events were stomatitis (39%), fatigue (31%), diarrhea (28%), nausea (25%), decreased appetite (22%), epistaxis (19%), rash (19%), decreased weight (17%), back pain (14%), dry mouth (14%), aphthous ulcer (11%), dermatitis acneiform (11%), and pyrexia (11%). Two patients (6%) were affected by pneumonitis, and treatment-related infections were reported for 5 patients (14%). Median PFS and OS for the Per Protocol (PP) population were 2.2 and 12.0 mo., in NET G3 5.2 (range 0.7-18.8) and 23.9 mo., in NEC 1.8 and 5.6 mo., and in MiNEN 2.2 and 7.0 mo., respectively. Six patients were excluded from the PP set due to short treatment duration or lack of efficacy assessment.

Conclusions

No clinically relevant safety signals for EVE after prior platinum-based therapy in NEN G3 were identified. The data support efficacy in NET G3 but insufficient activity in NEC or MANEC. More data are warranted from prospective trials in NET G3 to address EVE efficacy compared to other treatments.

Clinical trial identification

EudraCT 2012-004550-28.

Editorial acknowledgement

Medical writing support was provided by Frauke Meyer, CORBIN GmbH, Berlin. The support was funded by the study Sponsor AIO-Studien-gGmbH.

Legal entity responsible for the study

AIO-Studien-gGmbH, Berlin.

Funding

Novartis.

Disclosure

M.E. Pavel: Financial Interests, Personal, Invited Speaker: Ipsen, AAA, Boehringer Ingelheím, Lilly; Financial Interests, Personal, Advisory Board: AAA, Amgen, Riemser; Financial Interests, Institutional, Advisory Board: Crinetics; Financial Interests, Personal, Other, study analysis: Hutchmed; Financial Interests, Personal, Invited Speaker, Speaker at meetings: MSD; Financial Interests, Institutional, Local PI, fees for study conduct: Novartis; Financial Interests, Institutional, Local PI, Fees for study conduct: ITM; Financial Interests, Institutional, Coordinating PI, Fees for coordinating PI: Ipsen; Financial Interests, Institutional, Steering Committee Member: AAA; Financial Interests, Institutional, Local PI: AAA; Non-Financial Interests, Advisory Role, speaker at meetings, advisor for projects: Patient support group Netzwerk NET, Germany and INCA; Non-Financial Interests, Leadership Role, Past president, currenct vice president: European Neuroendocrine Tumor Society - ENETS; Non-Financial Interests, Other, Member of EMSO Education Group, Participation in PG course and other educational activities; member of the NET track steering committee group for ESMO Annual Meetings: ESMO. All other authors have declared no conflicts of interest.

Background

NEN G3 are rare tumors with poor prognosis and have no established 2^nd- line therapy. The role of immune checkpoint blockade in these aggressive tumors remains unclear.

Methods

We report the final analysis of the phase II AVENEC study on the effect of anti-PDL1 therapy with avelumab (AVE, 10 mg/kg iv Q2W) in 60 patients (pts) with highly proliferative neuroendocrine tumors (NET) G3 (N=22) or undifferentiated neuroendocrine carcinomas (NEC, N=38) of any origin, progressing after ≥ 1 chemotherapy (excluding Merkel cell and small cell lung cancer), and compare it with the interim analysis of 19 progressive NEN G3 pts treated with AVE (800 mg iv Q2W) in combination with cabozantinib (CAB, 40 mg/d po) from the ongoing phase II CABOAVENEC study.

Results

AVENEC: Best overall response (iRECIST) of AVE was a partial response (PR) in 3 (5%) and a stable disease (SD) in 9 (15%) pts, with a disease control rate (DCR) at 16 wks of 15 % (1 PR, 8 SD), and a median duration of response of 18.2 wks. 6 pts (10 %) achieved SD or PR for > 24 wks, and 2 pts for > 52 wks. Response was similar regardless of differentiation, Ki67 or primary localization. After a median follow up (mFU) of 27.9 wks, only 11 (18 %) pts were still alive with a median overall survival (mOS) of 21.3 wks (CI 15.0–nr), and a median progression free survival (mPFS) of 8.1 wks (CI 6.1-8.1). AVE was well tolerated with no drug related withdrawals and a stable quality of life (EORTC QLQ-C30). CABOAVENEC: preliminary data from 19 pts (12 NET G3, 7 NEC) treated with AVE + CAB show a PR in 4, SD in 5, and progress in 5 pts (5 not yet evaluable). mPFS was 48.1 wks (CI 15,9-nr) with a DCR at 16 wks of 42 % (5/12). After a mFU of 29.1 wks, 17 (85%) pts are alive, with 2 pts still on treatment for > 1 yr. Adverse events of the combination therapy were as expected and manageable.

Conclusions

Only a minority of 10-15% of heavily pretreated NEN G3 pts benefit from AVE monotherapy, which is very well tolerated. However, preliminary data suggest that the combination of AVE + CAB might be more effective in a higher percentage of pts and could therefore be a promising option for 2^nd -line therapy for these aggressive tumors.

Clinical trial identification

NCT03352934 and NCT05289856.

Legal entity responsible for the study

University Medical Center of the Johannes Gutenberg-University Mainz, Germany.

Funding

Merck Healthcare KGaA and Ipsen.

Disclosure

M.M.M. Weber: Financial Interests, Personal, Invited Speaker: Ipsen, Novartis, Lilly; Financial Interests, Personal, Advisory Board: Ipsen, Novartis, Lilly; Financial Interests, Institutional, Funding, Funding for CaboAveNEC Study: Ipsen; Financial Interests, Institutional, Funding, Funding for AveNEC and CaboAveNEC Study: Merck; Financial Interests, Institutional, Funding: Fresenius. L. Apostolidis: Financial Interests, Personal, Speaker, Consultant, Advisor: Ipsen Novartis; Financial Interests, Institutional, Principal Investigator: Camurus. S. Krug: Financial Interests, Personal, Advisory Board: Ipsen, AAA and Advanz Pharma; Financial Interests, Personal, Invited Speaker: Ipsen, AAA and Advanz Pharma. A. Rinke: Financial Interests, Personal, Advisory Board: Novartis, Ipsen, Advanz, Esteve; Financial Interests, Personal, Invited Speaker: IPSEN, Novartis, Advanz, Falk; Financial Interests, Institutional, Research Funding: IPSEN, Novartis, itm solution. B. Gruen: Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Dr. Rönsberg GmbH ; Financial Interests, Personal, Other: Sanofi Genzyme. P. Michl: Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Institutional, Research Funding: Ipsen. D. Wagner: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, Janssen; Financial Interests, Institutional, Research Funding: Roche and BMS. P.R. Galle: Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen. C. Fottner: Financial Interests, Personal, Invited Speaker: Ipsen. All other authors have declared no conflicts of interest.

Background

DLL3 is highly expressed on small-cell lung cancer (SCLC) tumours and neuroendocrine carcinomas (NECs). BI 764532 is a DLL3/CD3 IgG-like T cell engager with potent preclinical activity. NCT04429087 is an ongoing phase I dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, extrapulmonary (ep) NEC or large cell neuroendocrine lung carcinoma. Here we focus on pts with epNEC.

Methods

BI 764532 was given intravenously in 4 regimens: Regimen A (RA; fixed dose q3w); RB1 (fixed dose qw); RB2 (step-in doses, then fixed dose); RB3 (step-in, followed by target dose). Treatment (Tx) continued until progressive disease, unacceptable toxicity, other withdrawal criteria or maximum Tx duration (36 months). Main objective: maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532. Other objectives: safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy based on investigator review (RECIST v1.1).

Results

As of 26 July 2023, 129 pts received ≥1 dose (≥ 0.03 μg/kg) of BI 764532 (RA: n=24; RB1: n=10; RB2: n=79; RB3: n=16). Male: 59%; median age: 60 (range 32–81); ECOG PS 0/1: 28/71%; prior PD1/PD-L1 Tx: 49%; ≥2 prior lines of Tx: 70%. Dose limiting toxicities: 1 pt on RA (Grade [G]3 confusion) and 6 pts on RB2 (G5 immune effector cell-associated neurotoxicity syndrome [ICANS]; G4 cytokine release syndrome [CRS]; G3 CRS; G3 ICANS; G3 nervous system disorder and G2 infusion-related reaction). MTD has not been reached; dose escalation is ongoing. 53 pts with epNEC have been treated (ongoing in 14). TRAEs (any/G≥3): 92/17%. The most common TRAEs (any/G≥3) were: CRS (72/4%); pyrexia (26/0%); dysgeusia (19/0%) and fatigue (17/0%); there were no Tx discontinuations due to TRAEs.

In the efficacy population, there were 46 pts with epNEC (gastrointestinal: n=23; genitourinary: n=16; unknown origin: n=7). ORR/DCR was 22/41%. In pts who received clinically active doses of BI 764532 (n=36), ORR/DCR was 28/47%.

Conclusions

BI 764532 showed clinically manageable tolerability; MTD has not been reached. Promising efficacy was observed in pts with epNEC. The study is ongoing.

Clinical trial identification

NCT04429087.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Lynn Pritchard, of Ashfield MedComms, an Inizio company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono, Esteve, ITM; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. Y. Kuboki: Financial Interests, Personal, Advisory Board: Takeda, Boehringer Ingelheim, Amgen; Financial Interests, Personal, Other, Honoraria: Taiho Pharmaceutical, Bayer, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, Merck Serono; Financial Interests, Institutional, Research Funding: Taiho Pharmaceutical, Takeda, Incyte, Daiichi Sankyo, Ono Pharmaceutical, Boehringer Ingelheim, Amgen, Chugai Pharma, GSK, Astellas Pharma, Genmab, Janssen Oncology, AbbVie, Lilly. O. Alese: Financial Interests, Institutional, Research Grant: Taiho Oncology, Ipsen Pharmaceuticals, GSK, Bristol Myers Squibb, PCI Biotech AS, ASCO, Calithera Biosciences, Inc., SynCore Biotechnology Co. Ltd., Suzhou Transcenta Therapeutics Co., Ltd., Corcept Therapeutics Inc., Hutchison MediPharma, Boehringer Ingelheim, cor Inc., Cue Biopharma, Inc., Merck, Syros Pharmaceuticals Inc., Inhibitex Inc., Arcus Biosciences Inc., ImmunoGen; Financial Interests, Personal, Advisory Role: Ipsen Pharmaceuticals, Aadi Bioscience, Taiho, Pfizer, Seagen Inc., Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: AstraZeneca. D. Morgensztern: Financial Interests, Personal, Advisory Board: AbbVie, Eli Lilly, Arcus, Mirati; Non-Financial Interests, Personal, Principal Investigator: AbbVie, Arcus, Merk, Novartis, Pfizer, Bristol Myers Squibb, Incyte, Surface, Amgen, Genprex, Boehringer Ingelheim, NeoImmunotech, Apollomics; Financial Interests, Personal, Advisory Role: Arcus. C.M. Sayehli: Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Eli Lilly, Boehringer Ingelheim, Catalym. M.F. Sanmamed: Non-Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, BMS, Roche; Non-Financial Interests, Personal, Advisory Board: Numab, BMS; Non-Financial Interests, Institutional, Research Grant: Roche, BMS. E. Arriola: Financial Interests, Personal, Other, Honoraria: Takeda, Lilly, Roche, MSD, Boehringer, BMS, AstraZeneca; Financial Interests, Personal, Advisory Role: Takeda, Lilly, Roche, MSD, Boehringer, BMS, AstraZeneca; Financial Interests, Institutional, Research Funding: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Takeda, Roche, MSD, AstraZeneca. Z. Oum' Hamed, E. Song, M. Studeny: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Wermke: Financial Interests, Personal, Other, Honoraria: Lilly, Boehringer Ingelheim, Synlab, Janssen, Merck Serono, GWT, Amgen, Novartis; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck Therapeutics; Financial Interests, Institutional, Research Funding: Roche; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, Merck Serono.

Background

Surgical resection of Nonfunctioning Pancreatic Neuroendocrine Tumor (NF-PanNET) is curative in most of the cases. Neoadjuvant treatments in patients with resectable NF-PanNET at high-risk of recurrence have never been investigated. Aim of this study was to test the safety and efficacy of neoadjuvant PRRT with ¹⁷⁷Lu-DOTATATE followed by surgery in patients with resectable high-risk NF-PanNET.

Methods

This was a multi-center single-arm phase 2 trial. Treatment was PRRT with ¹⁷⁷Lu-DOTATATE (Lutathera) followed by surgery in patients with high-risk of recurrence resectable NF-PanNET. “High-risk NF-PanNET” was defined by the presence of at least one of the following: tumor size > 4 cm, nearby organ/s invasion, Ki67 >10%, vascular invasion, single liver metastasis, nodal involvement. Primary endpoints were postoperative morbidity and mortality. Secondary endpoint was the rate of objective radiological response.

Results

Thirty-one patients were enrolled in the study. Twenty-six (84%) tolerated 4 cycles of ¹⁷⁷Lu-DOTATATE whereas 4 patients did not complete 4 cycles for adverse events. One patient voluntary interrupted treatment after 2 cycles. A partial radiological response was observed in 17 patients (59%) whereas no disease progression occurred. Two patients refused to undergo surgery after ¹⁷⁷Lu-DOTATATE. Eventually, 29 patients underwent surgery after a median period of 281 days (261.5–309 days) from the enrollment. Resection of NF-PanNET was achieved in 28 patients (96.5%) whereas one patient underwent exploratory laparotomy. Pancreaticoduodenectomy (n= 11) and distal pancreatectomy (n= 11) were the most frequent operations. At final histology, the majority of patients had a NF-PanNET G2 (n= 16) and a nodal involvement (N1) was present in the 52% of cases. There was no postoperative mortality. Severe postoperative complications occurred in the 24% of patients and postoperative pancreatic fistula was the most frequent complication after surgery (34%).

Conclusions

Neoadjuvant PRRT with ¹⁷⁷Lu-DOTATATE followed by surgery for NF-PanNET is safe and effective demonstrating evidence of a high rate-of radiological response.

Clinical trial identification

NCT04385992.

Legal entity responsible for the study

Massimo Falconi.

Funding

Advanced Accelerator Applications (a Novartis company).

Disclosure

All authors have declared no conflicts of interest.

Background

IoN is one of only 2 large definitive RCTs to examine whether upfront radioiodine ablation (RAI) after surgery is needed for low-risk patients with well-differentiated thyroid cancer (DTC). The IoN primary endpoint is recurrence: structural loco-regional recurrence/residual disease by imaging, confirmed by tissue diagnosis. ‘No RAI’ was successfully shown to be noninferior to standard RAI (World Congress on Thyroid Cancer 2023 ). 3-year recurrence-free rates were 98.4% (no RAI) vs. 96.2% (RAI), risk difference +0.6% with lower 95%CI limit -3.3% (within the -5% allowable margin); noninferiority p-value=0.03.

Methods

500 patients with newly diagnosed histologically-confirmed DTC classified as low risk were recruited from 33 UK centres (2012-2020). All had total thyroidectomy and TSH suppression, and randomised (1:1) to have RAI (1.1GBq, with/without rhTSH) or no RAI. Patients were assessed at baseline, 2 months after either RAI or stimulated thyroglobulin in the no RAI group, then 6-monthly thereafter. We report adverse events (AEs), EORTC QLQ-C30 quality of life (QoL) and hospitalisation in radiation protective rooms.

Results

Median age was 47; 77% female; 78% papillary, 18% follicular, 4% oncocytic; 47% pT1, 44% pT2, 9% pT3; and 63% multifocal. At 2 months, grade 2+ events for 15 AEs of special interest were uncommon (<5% for any type, and similar between the trial arms); overall 9.6% (no RAI) vs. 8.0% (RAI), p=0.55. Mean differences (no RAI vs. RAI) in 28 QoL factors were all small, ranging -2.0 to +2.8 (scale 0-100), all p-values>0.12. Similar findings were seen at other timepoints. Hospital isolation for RAI patients only was 18% (same day outpatient), or 46, 23, 10 and 2% for 1,2,3 and 4 overnight stays respectively. For every 100 patients avoiding upfront RAI the healthcare cost saving is £204K (UK NHS costs of RAI, rhTSH and hospital stay).

Conclusions

Among low-risk DTC patients who did not have RAI, AEs and QoL were similar to those who did have RAI; as were the recurrence rates. Clinical guidelines can be updated to routinely offer selected patients the option of avoiding upfront RAI, to prevent overtreatment and unnecessary hospital isolation, with lower healthcare costs.

Clinical trial identification

ISRCTN80416929; NCT01398085; EudraCT 2011-000144-21; CTA 23151/0006/001-0001

Legal entity responsible for the study

University College London.

Funding

Cancer Research UK.

Disclosure

All authors have declared no conflicts of interest.

Background

Adrenocortical carcinoma (ACC) belongs to the family of rare cancers (annual rate of 0.72-1.3 cases/million people). The French national network « ENDOCAN-COMETE », was set up in 2009 to structure care and research on ACC patients across the country. The aim of this study was to look for the survival impact of this national network organization.

Methods

ACC diagnosed between 2010 and 2017 were, first, identified from 13 cancer registries of the French network FRANCIM covering 18% of the French population. This population was described in term of characteristics, systemic managements and treatment delays. Secondly, ACC patients identified by FRANCIM were categorized as 1/ referred to one of the 11 centres of the French ENDOCAN-COMETE network at diagnosis (ACC-R) or, 2/ ACC patients lately or not referred (ACC-nR). The survival rate at 2, 3 and 5 years (2-yrs OS, 3yrs OS and 5yrs-OS) were compared, according to ENSAT stage classified as localized (stage I-II) or advanced (stage III-IV).

Results

Between 2010 and 2017, 134 ACC were diagnosed in this population (mean estimated incidence of 0.14/100000 pers-yrs): 12 (9%) were stage I, 44 (33%) stage II, 17 (13%) stage III and 48 (36%) stage IV (13 patients ENSAT stage was unknown). Among them, 124 patients were analyzed (10 patients were excluded). Eighty-seven out 124 patients (70%) were referred to an ENDOCAN-COMETE network at diagnosis (ACC-R). Mean age at diagnosis was 51.5 yrs (ACC-R) vs. 58.6 (ACC-nR). Overall Survival (OS) rates of localized ACC (ENSAT stage I-II) was significantly higher in ACC-R compared to ACC-nR : 2-yrs OS was 94% vs 65%, 3-yrs OS was 90% vs 65% and 5-yrs OS was 79% vs 51%, p=0.025 (mean OS : 6.6 vs 3.15 yrs). OS rates were similar in advanced ACC (ENSAT stage III-IV) between ACC-R vs ACC-nR. In localized ACC: 39% were ACC-R vs. 54% ACC-nR. By comparing localized ACC-R vs localized ACC-nR, we found that complete resection was found in 76% vs 68%, Weiss score median was 5 vs 5, median Ki67 was 6% vs 15%, presence of endocrine syndrome was 47% vs 35% and age was 47 vs 58 yrs, respectively. Moreover 81% of ACC-R patients received mitotane treatment vs 65% of ACC-nR.

Conclusions

Our study shows a better survival of stage I-II ACC patients treated in the French ENDOCAN COMETE network.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.