All times are listed in CEST (Central European Summer Time)
- Mauro Cives (Bari, Italy)
- Hans Gelderblom (Leiden, Netherlands)
- Maria E. Cabanillas (Houston, United States of America)
1646MO - Phase II ATLEP trial: Final results for lenvatinib/pembrolizumab in metastasized anaplastic and poorly differentiated thyroid carcinoma
- Christine Dierks (Halle (Saale), Germany)
Abstract
Background
Anaplastic thyroid carcinoma (ATC) patients without a BRAF mutation have a dismal prognosis despite extensive multimodal therapy. In a retrospective analysis we have previously shown the combination of lenvatinib/pembrolizumab to be effective for ATC/PDTC patients with elevated PD-L1 expression or high mutation frequency. Within the ATLEP trial, we therefore prospectively investigated the effect of the lenvatinib/pembrolizumab combination in ATC and PDTC patients.
Methods
The combination of lenvatinib/pembrolizumab was examined within a prospective phase II trial (ATLEP, Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab, EudraCT No. 2017-004570-3) involving 27 ATC pts and 8 PDTC pts. ATCs and PDTCs were all metastasized (Stage IV), mainly pretreated with chemotherapy/radiotherapy and surgery (>90%), and lacked a B-RAF V617F mutation. Lenvatinib was started with 20 mg per day, and pembrolizumab (200 mg) was given i.v. every 3 weeks for up to two years. The primary endpoint was defined as ORR of > 10% after 3 months of treatment. Tumors were genotyped by whole exome sequencing (WES) and analyzed for PD-L1 expression.
Results
Of 39 screened pts, 35 could be evaluated for treatment response at 3 mo of treatment. The primary endpoint ORR at 3 mo was achieved, and was 34.3% (12/35 PR) for all patients. For ATCs the BOR (best overall response) within two treatment years was 51.9% PR (14/27) and 44.4% SD (12/27). For PDTCs, BOR was 75% PR (6/8) and 25% SD (2/8). The Clinical Benefit Rate (CBR) was 96.3% for ATC (26/27) and 100% for PDTC (8/8). For ATCs, the median PFS was 9.5 mo and the OS 10.25 mo. 25.9% of the ATC patients survived more than 2 years (7/27). For PDTCs, the median PFS was 20 months, while median OS has not been reached. CTCAE grade III/IV toxicities included hemorrhage after fistula development, autoimmune hepatitis, pulmonary embolism and infectious complications including aspergillus pneumonias. Biomarker assessment (PD-L1 status, WES) will be available at presentation.
Conclusions
Our results implicate that a combination of lenvatinib and pembrolizumab is safe and effective in patients with ATC and PDTC, and induces high response rates including long-lasting remissions.
Clinical trial identification
EudraCT 2017-004570-3.
Legal entity responsible for the study
C. Dierks.
Funding
Eisai funded the drug Lenvatinib.
Disclosure
All authors have declared no conflicts of interest.
1647MO - BRAF mutated anaplastic thyroid carcinoma: Clinical characteristics and outcome under BRAF inhibitors and chemotherapy in real-life practice, a multicentric retrospective study of the French ENDOCAN TUTHYREF network
- Christelle De la Fouchardiere (Lyon, France)
Abstract
Background
Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with a very poor prognosis. The aim of the study was to analyze clinical and biological characteristics and outcome of ATC patients (pts) with
Methods
It is a multicentric retrospective study from the French ENDOCAN-TUTHYREF network. ATC pts diagnosed between 2010 and 2020 were identified in our national database. Overall survival (OS) and progression free survival after 1st line treatment (1L-PFS) were determined by the Kaplan-Meier method.
Results
Among the whole cohort of 360 ATCs, 212 had a molecular analysis and 53 pts (25%) had a
Conclusions
These results confirm the clinical benefit of BRAF inhibitors in
Legal entity responsible for the study
ENDOCAN TUTHYREF French network.
Funding
Has not received any funding.
Disclosure
C. de la Fouchardiere: Financial Interests, Personal, Advisory Board: Merck, Roche, Lilly, Bayer, Amgen, MSD, Servier, Pierre Fabre Oncologie, Bristol-Myers Squibb, Incyte, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Ipsen, Eisai; Financial Interests, Institutional, Invited Speaker: Pierre Fabre Oncologie, Servier. Y. Godbert: Financial Interests, Personal and Institutional, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: AztraZeneca; Financial Interests, Personal and Institutional, Advisory Board: esai; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Ipsen, Genzyme, Roche. F. Illouz: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Bayer. L. Lamartina: Financial Interests, Personal, Advisory Board: Bayer, Eisai, Lilly, Ipsen. E.-. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis - AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. J. Hadoux: Financial Interests, Personal, Advisory Board: Ipsen, Lilly, PharmaMar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer. All other authors have declared no conflicts of interest.
Invited Discussant 1646MO and 1647MO
- Maria E. Cabanillas (Houston, United States of America)
888MO - Emergence of clonal hematopoiesis after peptide receptor radionuclide therapy for neuroendocrine tumors
- Rachel El Ferkh (Villejuif, Cedex, France)
Abstract
Background
In the advanced/metastatic Neuroendocrine tumors (NETs), PRRT (Peptide Receptor Radionuclide Therapy), has shown efficacy but with significant hematologic toxicity, including therapy-related myeloid neoplasms (t-MN). Here, we assessed the effect of PRRT on the development of t-MN and clonal hematopoiesis (CH) known to be a risk factor for t-MN development.
Methods
Firstly, we retrospectively identified t-MNs occurring after PRRT at Gustave Roussy Cancer Center for the last 20 years and described their characteristics. Secondly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in blood samples of 58 patients with TNE, exposed or not to PRRT, without any hematological malignancies.
Results
Out of 190 NETs treated with PRRT, we described 6 cases of t-MNs comprising 2 AML and 4 MDS (3.16%). Median age at t-MN was 70 years; median time between PRRT and t-MNs was 2.8 years. Two had unfavorable karyotype, NGS was available for 3 patients including 1 with a TP53 mutation. Median OS from t-MN diagnosis was 9.1 months. Between August and December 2021, 58 patients with TNE were explored by NGS including 27 (46.5%) treated with PRRT and 27 with anthracyclines. 27 (46.5%) patients had CH, including 10 patients (37%) with DNMT3A mutation, 9 TET2 (33%), 4 PPM1D (15%) and 3 (11%) TP53. 12/27 (44%) had more than one mutation. Patient with CH were older compared to others with a median age of 66 years vs 55 (p >0.001), received more PRRT treatment (17/27, 63%) vs (10/31, 32%) (p=0.03) but no differences were seen in term of history of treatment with anthracyclines (14/27, 52% vs 13/31, 32%, p=0.6) and time between NGS and TNE diagnosis (7.7 years vs 6.4 years, p=0.7). Out of the 27 patients with PRRT, 17 had CH, median time between first PRRT cycle and NGS was 2 years. Incidence of TP53 and/or PPM1D mutations were more common in patients with PRRT exposure compared to others (6/27 [22%] vs 1/30 [3%], p=0.04), and had more clonal complexity (9/27 [33%] vs 3/31 [9.6%], p=0.05).
Conclusions
T-MNs after PRRT are not so rare and had an unfavorable outcome. Patients with NET have a very high incidence of CH. Patients exposed to PRRT seems to have more CH, especially
Legal entity responsible for the study
J. Baptiste Micol.
Funding
GTE-AAA Grant.
Disclosure
J. Hadoux: Financial Interests, Personal, Advisory Board: Ipsen, Lilly, PharmaMar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer. L. Lamartina: Financial Interests, Personal, Advisory Board: Eisai, Bayer; Financial Interests, Institutional, Invited Speaker: Exelixis, Eisai, Sanofi, Bayer. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen, Pierre Fabre, Merck Kga, Pfizer, Bayer, Lilly; Financial Interests, Personal, Advisory Board: Roche, Basilea, Sotio, Pierre Fabre, Bohringer, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly, GlaxoSmithKline; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of steptozotocin in NET: Keocyt; Financial Interests, Institutional, Invited Speaker: Rafael, Amgen; Financial Interests, Institutional, Funding: Bayer; My wife is Head of the Oncology Business Unit in the French Affiliate of Sandoz: Sandoz France. E. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis-AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. C. Marzac: Financial Interests, Personal, Invited Speaker: Astellas. J. Baptiste Micol: Financial Interests, Personal, Invited Speaker: Jazz Pharmaceuticals, Astellas; Financial Interests, Personal, Advisory Board: AbbVie. All other authors have declared no conflicts of interest.
889MO - Comparative expression of driver transcription factors in extra-pulmonary small cell carcinoma
- Stephen Liu (Washington, United States of America)
Abstract
Background
Extra-pulmonary small cell carcinomas (EPSCC) are aggressive neuroendocrine tumors that are clinicopathologically distinct from small cell lung cancer (SCLC). Recent data suggest that transcriptionally-defined SCLC subtypes exhibit different underlying biology and therapeutic vulnerabilities. With limited data available on the EPSCC transcriptomic landscape, we analyzed gene expression profiles and its correlation with clinical outcomes across EPSCC anatomic sites.
Methods
DNA (592 genes/whole-exome) and RNA (whole transcriptome) sequencing were performed for 1070 small cell carcinoma (SCC) patient (pt) samples that underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Samples were stratified into 5 subtypes based on the relative expression of key transcription factors (TFs): ASCL1, NEUROD1, YAP1, POU2F3, and Mixed. Real-world survival information was available for 111 pts treated with etoposide+platinum (EP) therapy. Overall survival (OS) was obtained from insurance claims & Kaplan-Meier estimates. Statistical significance is determined by Chi-square & Wilcoxon rank sum tests.
Results
EPSCC comprised 28.8% (n=308) of SCCs evaluated; most common primary sites included gynecologic (GYN, 21.8%, n=67), prostate (16.6%, n=51), bladder (15.9%, n=49) and colorectal (10.1%, n=31). Each primary site had a unique distribution of molecular subtypes relative to SCLC. ASCL1 was less frequent in GYN and bladder SCC (13.4% and 16.3%) compared to SCLC (35.7%), with bladder SCC enriched in NEUROD1 and POU2F3 (30.6% and 22.4% vs SCLC 17.5% and 6.4%, P<0.05). YAP1 was most common in GYN SCC (35.8% vs SCLC 20.7%, P<0.05). For both SCLC and EPSCC, low YAP1 was associated with improved OS (SCLC HR 2.1, P=0.05; EPSCC HR 4.3, P=0.02), and high NEUROD1 trended towards improved OS (SCLC HR 0.6, P=0.12; EPSCC HR 0.4, P=0.10) from start of EP therapy.
Conclusions
Our analysis revealed differential expression of key lineage-defining TFs in EPSCCs from various anatomic sites that looked distinct from SCLC. EPSCC and SCLC OS was similarly associated with TF expression, suggesting the underlying biology of SCLC and EPSCC subtypes might predict comparable therapeutic vulnerabilities.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
S. Puri: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, G1 Therapeutics; Financial Interests, Personal and Institutional, Invited Speaker: Onclive; Financial Interests, Institutional, Research Grant: 5 for the fight. A. Elliott: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris. H.P. Soares: Financial Interests, Personal, Advisory Board, Consulting fees: Ipsen, TerSEra, AstraZeneca, Incyte. E. Lou: Financial Interests, Personal, Invited Speaker: GlaxoSmithKline, Daiichi Sankyo, Boston Scientific US; Financial Interests, Personal and Institutional, Invited Speaker: Novocure; Financial Interests, Personal and Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: American Association for Cancer Research (AACR-Novocure Tumor-Treating Fields Research Award, Grant Number 19-60-62-LOU, American Cancer Society, The Randy Shaver Cancer Research and Community Fund, Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; Non-Financial Interests, Personal, Advisory Board: Nomocan Pharmaceuticals, Minnetronix, LLC; Non-Financial Interests, Institutional, Principal Investigator: Celegene, Intima Biosciences. B. Halmos: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Merck , BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, BeiGene, Janssen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Veracyte, Janssen, Takeda, Merck, BMS, Genetech, Pfizer, Eli Lilly. C.J. Langer: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novocure, AstraZeneca, Takeda, Genetech/Roche, Merck, Gilead, GSK, Pfizer, Onclive, RTP, Regeneron, Sanofi-Aventis; Financial Interests, Institutional, Research Grant: Eli Lilly, Trizel, Merck, Takeda, Inovio, AstraZeneca, Oncocyte, Janssen, Amgen; Financial Interests, Institutional, Other, Medical Writing support: Novartis ; Financial Interests, Personal, Other, DSMC: Eli Lilly, Amgen, Oncocyte Dx. D. Uprety: Financial Interests, Personal, Advisory Board: Daiichi Sankyo Inc, AstraZeneca, Sanofi. S. Darabi: Financial Interests, Personal, Invited Speaker: Oncolense; Financial Interests, Personal, Advisory Board: Bayer. P. Walker: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris. W. El-Deiry: Financial Interests, Personal, Stocks/Shares: Oncoceutics, p53 Therapeutics, Chimerix; Financial Interests, Personal, Research Grant: D&D Pharmatech; Financial Interests, Personal, Other: Patent on TIC10. A. VanderWalde: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris; Financial Interests, Personal and Institutional, Research Grant: AACR stand up to Cancer Grant; Financial Interests, Personal, Advisory Board: BMS, George Clinical, Elsevier. S. Liu: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genetech Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Eli Lilly Merck, Novartis, Regeneron, Sanofi, Takeda, Turning point therapeutics; Financial Interests, Institutional, Research Grant: Alkermes, Bayer, Blueprint, BMS, Elevation Oncology, Genetech, Gilead, Merck, Merus, Nuvalent Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics. All other authors have declared no conflicts of interest.
890MO - Mutation spectrum in liquid versus solid biopsies from advanced digestive neuroendocrine carcinoma patients
- Halfdan Sorbye (Bergen, Norway)
Abstract
Background
Digestive neuroendocrine carcinoma (NEC) are currently defined by the presence of a poorly differentiated neuroendocrine phenotype and a high proliferation rate (Ki-67>20%). Most digestive NEC are diagnosed with metastatic disease with survival less than 1 year if medically treated. Frequently only minor biopsies are available for further molecular diagnostics. The molecular characteristics of digestive NEC has recently been described, but data on applicability of liquid biopsies in digestive NEC is very limited.
Methods
We performed massive parallel sequencing of 76 cancer related genes in plasma ctDNA from 50 patients with advanced digestive NEC and compared findings to previous analyses performed in matched FFPE tumour biopsies. Optimal filters were used, including data from WBC as filter for removal of SNPs.
Results
Among the 50 patients, 46 had metastatic disease and 4 locoregional disease at the time of plasma sampling. We detected a total of 178 somatic mutations in the liquid biopsies. Out of these, 127 (71%) were also detected in the solid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (SNVs) in the tumor biopsies. Thus, 64% (127 out of 199) of mutations in solid biopsies were also found in the liquid biopsies. The concordance was higher in patients with liver metastases (p= p=1.5x10-5), while it was similar between digestive NEC with different primary sites, except for a lower concordance in esophageal cases (p=0.001). Concordance was not associated with tumor mutational burden (TMB). Tumour tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumours (70%; p=7.8x10-4). Applying a predefined set of criteria, we identified potentially targetable mutations in plasma of 26 (52%) of digestive NEC patients; 9 patients (18%) had potentially targetable mutation detected only in liquid biopsies.
Conclusions
We found liquid biopsy analyses to be an applicable alternative to solid biopsies in digestive NEC patients. Liquid biopsies could be used for biomarker assessment in clinical trials for these patients.
Legal entity responsible for the study
Helse Bergen, Haukeland University Hospital, Bergen, Norway.
Funding
Helse Bergen, Haukeland University Hospital, Bergen, Norway.
Disclosure
T. Grob: Financial Interests, Personal and Institutional, Research Grant: Roche. All other authors have declared no conflicts of interest.
496MO - Final overall survival results from the NICE-NEC trial (GETNE-T1913): A phase II study of nivolumab and platinum-doublet chemotherapy (CT) in untreated advanced G3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or unknown (UK) origin
- Rocio Garcia-Carbonero (Madrid, Spain)
Abstract
Background
G3 NENs are aggressive tumors with a median overall survival (OS) of ∼11 months (m) with standard platinum-based front line CT. Their high mutational burden and PD-L1 overexpression position G3 NENs as potential candidates for immunotherapy. The aim of this study was to assess the efficacy of the combination of CT plus Nivolumab (Niv) in patients (pts) with advanced CT-naïve G3 NENs.
Methods
NICE-NEC is an open-label, non-randomized, phase II trial that recruited pts with metastatic or locally advanced unresectable G3 NENs of GEP/UK origin. Pts received Niv 360mg d1, Carboplatin AUC 5 d1, Etoposide 100mg/m2 d1-3 Q3W (up to 6 cycles) followed by Niv 480mg Q4W (up to 24 m). Primary endpoint was 12-m overall survival (OS) rate. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and safety.
Results
From 2019 to 2021, 38 pts were enrolled. Median age was 61 years, 68% male, 89.4% ECOG 0-1, 68.4% were poorly differentiated, 65.8% had Ki67 >55%, 94.7% stage IV at diagnosis, and 74% had ≥2 organs involved. With a median follow-up of 18.6 m (range: 2.2-24.6) for alive pts, ORR was 54.1%, DCR 83.8% and median PFS was 5.7 m (95%CI: 5.1-9). Throughout the study period, 21 (56.8%) pts died. Median OS was 13.9 m (95%CI: 8.3-NR) with an estimated cumulative survival ratio of 53.8% (95%CI: 39.8-72.6) / 44% (95%CI: 30.1-64.2) at 12/18 m. 12 (32.4%) pts were long survivors (OS >18 m). The 12-m OS rate was 46.7% vs 59.3% for Ki-67 ≤55 and >55, respectively (p=0.513); and 58.3% vs 54.7% for well and poorly differentiated, respectively (p=0.773). Median OS was 6.4 m for colorectal, 14.6 m for pancreatic, and not reached for esophago-gastric / small bowel NENs.
Conclusions
The combination of CT plus Niv shows promising activity and prolonged survival benefit in a subset of pts with GEP/UK primary G3 NENs. Randomized trials are warranted to confirm treatment benefit. Ongoing translational studies may help identify predictive/prognostic biomarkers to improve selection of pts most likely to benefit from this treatment strategy.
Clinical trial identification
EudraCT 2019-001546-18; NCT03980925.
Editorial acknowledgement
We acknowledge Mfar Clinical Research staff for their assistance in the development of this abstract.
Legal entity responsible for the study
Grupo Español en Tumores Neuroendocrinos y Endocrinos (GETNE).
Funding
Grupo Español en Tumores Neuroendocrinos y Endocrinos (GETNE) as Sponsor through industry partner Bristol-Myers Squibb (BMS).
Disclosure
J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hudchinson Pharma, ITM, Advanz, Merck Serono, Esteve; Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hudchinson Pharma, ITM, Advanz, Merck Serono, Esteve; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Aplications, Eisai, Amgen, Bayer; Non-Financial Interests, Institutional, Member, Chair of the Spanish Task Force for Neuroendocrine and Endocrine Tumors Group (GETNE); Non-Financial Interests, Institutional, Member, Executive Committee Member of the European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Institutional, Member, Treasurer and Track Chair of the rectal cancer working group of the Spanish Multidisciplinary Group of Digestive Cancers (GEMCAD). P. Jimenez-Fonseca: Financial Interests, Personal, Other, Travel grant: IPSEN; Financial Interests, Personal, Advisory Role: AAA; Financial Interests, Personal, Invited Speaker: Sanofi, LEOpharma, HRApharma; Non-Financial Interests, Institutional, Other, membership or affiliation: Seom, Getne, TTD, ENETS. E. Grande: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, IPSEN, Janssen, Lilly, Merck KGa, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, OncoDNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, Nanostring Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Invited Speaker, Independent research grant: Ipsen; Non-Financial Interests, Other, Ad Board member: ENETS. I. Sevilla: Financial Interests, Personal, Advisory Role: Ipsen, Pfizer, Amgen; Financial Interests, Personal, Invited Speaker: Novartis, PharmaMar, Bayer, AAA. T. Alonso-Gordoa: Financial Interests, Personal, Advisory Board: Ipsen, Sanofi, Bayer, Novartis advanced accelerator applications, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: Pfizer, Roche, Janssen-Cilag; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Project Lead: Pfizer, Ipsen. J. Hernando: Financial Interests, Personal, Expert Testimony: Eisai, Ipsen, Novartis, AAA, Angelini, Pfizer, Roche. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, HMP, Ipsen, Merck, Midatech, MSD, Novartis, Pierre Fabre, Roche, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (Axinet, Nicenec, Pembrola): BMS, MSD, Pfizer; Other, Honoraria received by spouse for advisory board or invited Speaker roles: Abbie, AstraZeneca, Bayer, Boehringer, BMS, Genomica Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. All other authors have declared no conflicts of interest.
LBA46 - Bevacizumab (B) plus FOLFIRI after failure of platinum-etoposide in patients (pts) with advanced neuroendocrine carcinoma (NEC): The PRODIGE 41-BEVANEC randomized phase II study
- Thomas A. Walter (Lyon, France)
Abstract
Background
Platinum-etoposide combination chemotherapy is the first-line standard-of-care for pts with advanced, poorly-differentiated, gastroenteropancreatic (GEP) NEC. However, nearly all pts will develop resistance and there is no standard second-line treatment.
Methods
PRODIGE 41 – BEVANEC (NCT02820857) is an academic, non-comparative, phase 2 trial. Main inclusion criteria were histologically proven, grade 3, locally advanced or metastatic GEP-NEC or NEC of unknown primary, and documented progressive disease during or after first-line therapy. Pts were randomized 1:1 to receive 5 mg/kg Bevacizumab (B) with FOLFIRI, or FOLFIRI alone, every 14 days until progression or unacceptable toxicity. The primary objective was to demonstrate a 6-month overall survival (OS) rate of ≥50% in the experimental arm (efficacy: if at least 26 of 52pts alive at 6 months), power, 85%; one-sided alpha risk, 10%). Other endpoints included progression-free survival (PFS), objective response rate (ORR), response duration, biochemical response and safety.
Results
From Sep 2017 to Feb 2022, 133 pts were randomized in 26 centers; 126 pts received at least one course of chemotherapy and were evaluable for the primary endpoint. Median age was 67 years (range 26–85), 66% males, 90% with ECOG PS 0-1. The primary tumor was mainly colorectal (n=38), pancreas (n=33), oesogastric (n=22) and unknown (=23). The primary objective was met (30 pts alive at 6 months ± 5 pts still in follow-up less than 6 months) with Folfiri-B. Median PFS and OS were 3.7 months (95%CI [1.9-5.6]) and 7.0 months (95%CI [4.6-11.5]) with Folfiri-B, and 3.5 months (95%CI [1.9-5.1]) and 8.9 months (95%CI [5.7-10.7]) with Folfiri. Biochemical response, ORR (25.5% vs 18.3%) and response duration were numerically higher in Folfiri-B vs Folfiri. Three patients stopped B because of toxicity; one treatment-related death occurred in Folfiri-B and most frequent grade ≥ 3 AEs were neutropenia (12%), asthenia (10%) and diarrhoea (10%).
Conclusions
Folfiri-B reached the primary endpoint in 2nd line NECs pts.
Clinical trial identification
NCT02820857.
Legal entity responsible for the study
Thomas Walter.
Funding
ROCHE has furnished the bevacizumab for the experimental arm.
Disclosure
T.A. Walter: Non-Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Invited Speaker: Novartis-AAA, Ipsen. R. Coriat: Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Institutional, Funding: Ipsen. D. Malka: Financial Interests, Personal, Invited Speaker: Roche. F. Di Fiore: Financial Interests, Personal, Invited Speaker: Merck, Roche, Pierre Fabre, Ipsen, Novartis, Sanofi, Bayer, Servier. V. Hautefeuille: Financial Interests, Personal, Invited Speaker: Novartis-AAA; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Principal Investigator: Ipsen. V. granger: Financial Interests, Personal, Invited Speaker: AAA-Novartis; Financial Interests, Personal, Advisory Board: Mylan. L. Mineur: Financial Interests, Personal and Institutional, Invited Speaker: Amgen, Servier; Financial Interests, Institutional, Research Grant: haliodx; Non-Financial Interests, Personal, Other, Congress travel: Merck, Ipsen. C. Lepage: Financial Interests, Personal, Invited Speaker: Ipsen, Amgen; Financial Interests, Personal, Advisory Board: Novartis. All other authors have declared no conflicts of interest.
Invited Discussant 888MO, 889MO, 890MO, 496MO and LBA46
- Mauro Cives (Bari, Italy)
1MO - An open-label, phase II trial of cabozantinib for advanced adrenocortical carcinoma
- Matthew T. Campbell (Houston, United States of America)
Abstract
Background
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options. This study aims to explore the role of carbozantinib in ACC management.
Methods
This is an investigator initiated, phase II study to evaluate the efficacy and safety of cabozantinib in patients with advanced ACC. Response to therapy was assessed objectively using The Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. The primary end point was progression free survival (PFS) at 4 months (mo) (PFS4). Secondary endpoints included median PFS, overall response rate (ORR), median overall survival (OS), pharmacokinetic studies, and safety. Correlative tissue-based studies were performed.
Results
The study has fully accrued enrolling 18 patients with advanced ACC (8 females (44%). The median follow-up was 19.4 mo (range 2.9-45.6). The PFS4 was 72% (13/18), median PFS was 7.2 mo (95%CI: 3.3,9.2 mo). Of 18 patients, 16 had restaging with ORR including 2 partial response, 12 stable disease, and 2 progressive disease as best response; disease control rate was 78% (95% CI, 52% to 94%). The median PFS was 7.2 mo (95% CI, 3.3 mo to 9.2 mo), and the median OS was 23.9 mo (95% CI, 12.9, not reached). 13 patients (72.2%) had at least possible treatment-related grade 3 or 4 adverse events. Median day 29 pre-dose level of cabozantinib was 505mg/mL (range 279-1810). Correlative study analysis will be presented.
Conclusions
Cabozantinib use in patients with advanced ACC can provide sustained disease control with manageable safety profile in the majority of ACC patients.
Clinical trial identification
NCT03370718.
Legal entity responsible for the study
University of Texas MD Anderson Cancer Center.
Funding
Exelixis.
Disclosure
M.T. Campbell: Financial Interests, Personal, Research Grant: Exelixis. C. Jimenez: Non-Financial Interests, Personal, Other, Research Support: Exelixis; Non-Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Progenics, Lantheus, Pfizer, HRA Pharma. A. Shah: Non-Financial Interests, Personal, Advisory Board: Pfizer, Exelixis, BMS; Non-Financial Interests, Personal, Other, Research Support: 4D Pharma, Eisai, EMD Serono. All other authors have declared no conflicts of interest.
2MO - EO2401 (EO) therapeutic vaccine for patients (pts) with adrenocortical carcinoma (ACC) and malignant pheochromocytoma/paraganglioma (MPP): Phase I/II SPENCER study
- Eric Baudin (Villejuif, France)
Abstract
Background
EO was designed to activate memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived synthetically produced HLA-A2 restricted peptides with mimicry to TAAs (IL13Rα2, BIRC5 and FOXM1) upregulated in ACC/MPP and CD4 peptide UCP2.
Methods
Cohort (C) 1 established safety of EO + nivolumab (N); pts analyzed in C2a/3a. Pts with non-resectable ACC (C2) and MPP (C3), with (C2a/3a), or without (C2b/3b), prior systemic therapy for advanced disease received EO (300 μg/peptide, Q2 weeks (w) x4 then Q4 w) + N (240mg/dose x3, then 480mg/dose, following EO) = EN. NCT04187404.
Results
33 pts with ACC (C2a 26, C2b 7), 13 pts with MPP (C3a 9, C3b 4) started EN. EN well tolerated and safety profile consistent with N mono except for local administration site reactions after EO (35% of pts; grades 1-3). In ACC (n=33, median follow-up [mFU] 10.5 months [mo]), objective response rate (ORR) 12%, disease control rate (DCR; ORR + SD) 36%, median progression-free survival (mPFS) 1.9 mo (12% ongoing 38-50 w). No influence of prior therapy on ORR/PFS observed. Median survival (mOS) C2a 11.3 mo (46% alive 35-76 w) and C2b NA (86% alive 29-49 w). In MPP (n=13, mFU 9.6 mo), ORR 7%, DCR 77%, mPFS 4.7 mo (38% ongoing 9-40 w) and mOS 11.4 mo (62% alive 14-57 w). Currently no influence of prior therapy. CD8 T cell ELISPOT responses against the EO peptides (19/20 pts) and cross-reactivity with targeted TAAs (15/16 evaluable pts) shown. Max level of immune response correlate with clinical outcome. Post-hoc analyses identified clinical factors (no mitotane, ECOG > 1, ACC 1st diagnosis ≤9 mo, max lesion size >125 mm, >3 organs involved, reduced lymphocytes >grade 1) excluding majority of pts in C2a without benefit. In post-hoc favorably selected group (n=14, mFU 12.4 mo) ORR 29%, DCR 64%, mPFS 3.8 mo and mOS 13.0 mo. Pts with favorable outcome had low mutational burden/PDL1 expression. Cytokines/chemokines did not correlate with clinical benefit.
Conclusions
EO2401 was well tolerated and generated immune responses correlating with efficacy. Efficacy seen in ACC group defined post-hoc by clinical parameters; a randomized study is starting. Expansion of MPP group ongoing, update will be presented.
Clinical trial identification
NCT04187404.
Legal entity responsible for the study
Enterome.
Funding
Enterome.
Disclosure
E. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis - AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. S. Grisanti: Financial Interests, Personal, Advisory Role: Boehringer-Ingelheim, BMS Foundation, Sanofi-Aventis. M. Fassnacht: Financial Interests, Institutional, Invited Speaker, Clinical trial on adrenocortical carcinoma and malignant pheochromocytoma: Enterome Bioscience; Financial Interests, Institutional, Invited Speaker, Clinical trial in Cushing's syndrome: HRA Pharma, Corcept; Non-Financial Interests, Leadership Role: European Network for the Study of Adrenal Tumor; Data safety board for a clinical trial (compensation is paid to the Institution): Bayer Pharma. C.W. Menke-van der Houven van Oordt: Financial Interests, Institutional, Research Grant: BMS/Celgene, Pfizer, Cristal Therapeutics; Financial Interests, Institutional, Advisory Role: Novartis, Pfizer, Daiichi DSankyo/AstraZeneca. C. de la Fouchardiere: Financial Interests, Personal, Advisory Role: Lilly, Bayer, BMS, Amgen, Servier, Roche, Pierre Fabre, Incyte, Eisai, MSD Oncology, Ipsen; Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Other, Travel, accomodation, expenses: Roche, Celgene, Amgen, BMS, Servier; Financial Interests, Personal, Other: Incyte, MSD; Financial Interests, Personal, Other, Honoraria: Merck Serono, Roche; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Pierre Fabre, Servier. V. Subbiah: Financial Interests, Personal, Advisory Role: MedImmune, Helsinn Therapeutics, Loxo, R-Pharm, QED Therapeutics; Financial Interests, Personal, Other, Travel, accomodation, expenses: PharmaMar, Bayer, Novartis, Helsinn Therapeutics; Financial Interests, Personal, Other: Medscape; Financial Interests, Institutional, Research Grant: Novartis, GSK, NanoCarrier, Northwest Biotherapeutics, Genentech/Roche, Berg, Bayer, Incyte, Fujifilm, PharmaMar, D3 ONcology Solutions, Pfizer, Amgen, AbbVie, Multivir, Blueprint Medicines, Loxo, Vegenics, Takeda, Alfasigma, Agenesys, Idera, Boston Biomedicall, Inhibrx, Exelixis, Amgen, Turning Point Therapeutics. C. Jimenez: Financial Interests, Personal, Other, Honoraria: MSD, Pfizer; Financial Interests, Personal, Advisory Role: MSD, Pfizer, Progenics, Lantheus, HRA Pharma; Financial Interests, Personal, Research Grant: MSD, Exelixis, Progenics, Lantheus. J. Capdevila Castillon: Financial Interests, Personal, Advisory Role: Amgen, Bayer, AAA, AstraZeneca, Eisai, Exelixis, Ipsen, ITM, Lilly, Sanofi, Merck, Novartis, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Amgen, Bayer, AAA, AstraZeneca, Eisai, Exelixis, ITM, Lilly, Sanofi, Merck, Novaris, Pfizer; Financial Interests, Personal, Invited Speaker: Ipsen. D. Granberg: Financial Interests, Institutional, Research Grant: Enterome, MSD. K.G. Daugaard: Financial Interests, Personal, Advisory Role: Bayer Pharma, Astellas, MSD, Janssen; Financial Interests, Grant: Lilly, MSD, Janssen, BMS. M. Kroiss: Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Advisory Role: Loxo Oncology, Lilly, Ipsen, Bayer , Eisai, Ipsen; Financial Interests, Personal, R esearch Grant: Enterome, Lilly, Loxo Oncology; Financial Interests, Personal, Other, Travel, accomodation expenses: Lilly. O. Kimpel: Financial Interests, Personal, Other, Honoraria: HRA Pharma. L. Lamartina: Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Advisory Role: Bayer, Eisai, Ipsen; Financial Interests, Personal, Other, Travel, accomodatioon, expenses: AAA (Novartis). J. Hadoux: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Advisory Role: Ipsen, AAA, Roche, PharmaMar, Lilly. J. Paillarse: Financial Interests, Personal, Member, employee and shareholder: Enterome. L. Chêne: Financial Interests, Personal, Leadership Role: Enterome. J. Fagerberg: Financial Interests, Personal, Leadership Role: Enterome. A. Berruti: Financial Interests, Personal, Advisory Role: Janssen-Cilag, Astellas Pharma, Amgen; Financial Interests, Personal, Speaker’s Bureau: Janssen-Cilag, Astellas Pharma; Financial Interests, Institutional, Research Grant: Janssen-Cilag, Astellas Pharma; Financial Interests, Personal, Other, Travel, Accomodation expenses: Janssen-Cilag, Sanofi. All other authors have declared no conflicts of interest.
Invited Discussant 1MO and 2MO
- Hans Gelderblom (Leiden, Netherlands)