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Basic and translational research

2P - Outcomes of patients with gynecological tumors harboring HER2 defects: a single center study based on Gustave Roussy cancer center’s molecular program

Presentation Number
2P
Speakers
  • Cyril Roussel-Simonin (Villejuif, France)
Presentation Topic
Basic and translational research

Abstract

Background

Human epidermal growth factor 2 (HER2) encoded by the ERBB2 gene. In serous endometrial carcinoma (SEC), HER2 is amplified in 17-30% cases. ERBB2 alterations are also present across other gynecological histologies. A randomized phase II study showed that the addition of trastuzumab to 1st line platinum chemotherapy increased PFS and OS in HER2 amplified SEC, yet there is currently no approval for those drugs in gynecological malignancies.

Methods

We retrospectively collected data from patients with gynecological cancers who were screened by next generation sequencing (NGS) on tumor and/or circulating tumor DNA (ctDNA) and discussed at Gustave Roussy’s molecular tumor board between March 2021 and June 2022. The objective of this study was to describe the outcomes of gynecological patients harboring HER2 amplifications or pathogenic mutations that were identified through Gustave Roussy’s molecular program.

Results

Between March 2021 and June 2022, 19 patients had a HER2 amplification and/or mutation. 11 patients (58%) exhibited an amplification, 6 (32%) a mutation and 2 (10%) both. All patients had metastatic disease at the time of screening. Regarding tumor types: 10 patients (53%) had endometrial carcinoma, 5 (26%) had ovarian carcinoma and 4 (21%) had cervix carcinoma. Only 9 patients (47%) received a HER2 directed therapy. All patient had ERBB2 amplification. 1 patient was treated within a trial and 8 were treated off label with a trastuzumab containing regimen. 2 patients (22%) had a complete response and 5 (55%) had a partial response. Median duration of response was 7,6 months and median progression free survival was 8.1 month [min : 2.6m; max:11.6m]. Overall survival was significantly longer in patients receiving HER2 targeted therapy compared to those harboring HER2 abnormalities who did not receive them (mOS: NR vs 15.06m, HR : 0.18, IC95% 0.037 - 0.89).

Conclusions

Gynecological cancer harboring HER2 amplification and/or mutation are rare but can benefit from HER2 targeted therapy. There is a need to to test patients for ERBB2 alteration and develop trials with HER2 targeted therapies including gynecological tumors in order to obtain approvals in routine care.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Basic and translational research

3P - NaPi2b Expression in High Grade Serous Ovarian Cancer: results from combined data sets

Presentation Number
3P
Speakers
  • Susana Banerjee (London, United Kingdom)
Presentation Topic
Basic and translational research

Abstract

Background

NaPi2b is a sodium-dependent phosphate transporter broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in normal tissues. Uptifitamab rilsodotin (UpRi) is a first-in-class NaPi2b-targeting antibody drug conjugate (ADC) with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a new target currently being studied in ovarian cancer; understanding its expression and prevalence across HGSOCs is key in developing a biomarker-driven therapy.

Methods

Multiple datasets were used to address the question of NaPi2b expression and prevalence. In all datasets, NaPi2b expression was assessed by IHC with NaPi2b positivity defined as a tumor proportion score ≥75. Sample sets included commercially procured HGSOC representing synchronous sampling of primary and metastatic lesions, matched metachronous samples (“archival” and “fresh”) from the Ph1b UpRi trial and HGSOC tissues sampled at multiple time points throughout the course of their disease.

Results

Our results suggest high prevalence of NaPi2b positive expression in HGSOC. In the UpRi Ph1b clinical trial, 64% (50/78; 95% CI 52.4 - 74.7) of patients were determined to be NaPi2b positive, as determined by the GLP (good laboratory practices) assay. When NaPi2b expression was examined from synchronous sampling of primary and metastatic lesions (N=18 pairs), as well as matched metachronous samples (N=56 pairs), there was high concordance rate ranging from 72-76% regardless of whether expression was evaluated over time or between anatomic locations.

Conclusions

NaPi2b is a stable biomarker that is highly expressed in the majority of HGSOC patients. Expression remains stable over time - regardless of biopsy sites or treatment history. These data are consistent with data previously published from an investigational companion diagnostic assay study from 398 unique HGSOC tissue samples suggesting a prevalence of 59% (Patel et al., USCAP 2022). These findings support early NaPi2b testing and the continued development of NaPi2b-directed agents for HGSOC. Further analyses from ongoing trials and data sets will provide additional information on NaPi2b expression.

Legal entity responsible for the study

Mersana Therapeutics.

Funding

Mersana Therapeutics.

Disclosure

S. Banerjee: Financial Interests, Personal, Funding: AstraZeneca, GSK, Verastem; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, GSK, Immunogen, Merck & Co, Mersana Therapeutics, Novartis, OncXerna, Regeneron, Seagen, Shattuck; Financial Interests, Personal, Stocks/Shares: Perci Health; Financial Interests, Personal, Other, honoraria: Amgen, AstraZeneca, Clovis, GSK, Immunogen, Merck & Co, Mersana Therapeutics, Pfizer, Roche, Takeda. D.L. Richardson: Financial Interests, Personal, Advisory Role: Mersana Therapeutics, AstraZeneca, Genentech, GSK, Immunogen, Deciphera; Financial Interests, Personal, Funding: GSK, Celsion, Roche, Aravive, Shattuck, Mersana Therapeutics, Syros, Arch Oncology, Harpoon, Hookipa, Clovis, Karyopharm. N. Concin: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, Seattle Genetics, Mersana, eTheRNA immunotherapies, Seagen, AkesoBio, Eisai, NOGGO, Medscape Oncology; Financial Interests, Personal, Invited Speaker: Eickeler, Mediseminar, Medconcept, NSGO-CTU; Non-Financial Interests, Personal, Other, PI: different clinical trials with different companies; Non-Financial Interests, Personal, Other, president: ESGO; Non-Financial Interests, Personal, Other, Co-Chair Early Drug Development Network of ENGOT: ENGOT; Other, Personal, Other, travel expenses: Roche, Genmab, Amgen; Other, Personal, Other, compensation received for educational: MSD, Medscape Oncology; Other, Personal, Other, Compensation received for educational: TouchIME. B.J. Monk: Financial Interests, Personal, Other, Consultant: Agenus, Akeso Bio, Aravive, Elevar, GOG Foundation, Genmab/Seattle Genetics, Gradalis, Immunogen, Iovance, Karyopharm, McKesson, Mersana, Novocure, Pfizer, Puma, Sorrento, VBL; Financial Interests, Personal, Other, Consultant/Speaker: AstraZeneca, Clovis, Easai, Merck, Myriad, Roche/Genentech, TESARO/GSK; Financial Interests, Personal, Other, Honorarium Consultant: Regeneron, Verastem, Zentalis; Financial Interests, Personal, Other, Consultant and Investigator: US Oncology Research. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zailab; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK, Karyopharm; Financial Interests, Personal, Stocks/Shares: Karyopharm; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Ultimovacs, Apexigen; Financial Interests, Institutional, Invited Speaker: Deciphera; Non-Financial Interests, Personal, Advisory Role: Ultimovacs, Apexigen. R.L. Coleman: Financial Interests, Personal, Research Grant: AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Janssen, Roche/Genentech; Financial Interests, Personal, Advisory Role: Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Mersana Therapeutics, Genmab, GSK, Immunogen, Janssen, OncoQuest, Onxeo, Onxerna, Regeneron, Roche/Genentech, Novocure, Merck, AbbVie; Financial Interests, Personal, Other, Participation in Data Safety Monitoring Board: VBL Therapeutics. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. B. Pothuri: Financial Interests, Personal, Advisory Board, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board, Advisory board: AstraZeneca; Financial Interests, Personal, Advisory Board: Clovis Oncology, GlaxoSmithKline, Merck, Tesaro, Sutro, Mersana, Lily, Seattle Genetics; Financial Interests, Personal, Other, consulting: Toray, Arquer Diagnostics, Atossa, Elevar, Deciphera, Imab; Financial Interests, Institutional, Invited Speaker: Tesaro, Clovis Oncology, Roche Genentech, Takeda, Celsion, Celgene, AstraZeneca, Immunogen, Merck, GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker, clinical trial: Incyte, Toray, Karyopharm, Sutro, Eisai, VBL Therapeutics, Mersana, Seattle Genetics; Non-Financial Interests, Personal, Other, Member of GOG Partners group: GOG Foundation; Non-Financial Interests, Personal, Invited Speaker: Society of Gynecologic Oncology. C. Marth: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche Austria, Novartis, MSD, PharmaMar, GlaxoSmithKline, Amgen, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, GlaxoSmithKline, Novartis, Amgen, MSD, PharmaMar, Seagen. L. Demars: Other, Personal, Full or part-time Employment: Mersana Therapeutics. C. Bradshaw: Other, Personal, Full or part-time Employment: Mersana Therapeutics. C. Dicristo: Other, Personal, Full or part-time Employment: Mersana Therapeutics. R. Mosher: Other, Personal, Full or part-time Employment: Mersana Therapeutics. R. Drapkin: Other, Personal, Advisory Board: Repare Therapeutics, VOC Health Inc.

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Basic and translational research

4P - Evaluation of Antitumor Activity and Immunogenic Cell Death (ICD) Induction by MORAb-202 (Farletuzumab Ecteribulin) in Human Ovarian Cancer (OV) Models

Presentation Number
4P
Speakers
  • Keiji Furuuchi (Exton, PA, United States of America)
Presentation Topic
Basic and translational research

Abstract

Background

MORAb-202 is an antibody–drug conjugate comprised of the humanized anti-folate receptor-alpha (FRα) monoclonal antibody, farletuzumab, conjugated to the cytotoxic microtubule inhibitor, eribulin. In a phase 1 study (NCT03386942), MORAb-202 showed antitumor activity across varying FRα-expression levels at doses of 0.9 mg/kg (cohort 1) and 1.2 mg/kg (cohort 2) in patients with platinum-resistant (PR) OV. The disease control rate was 66.7% in cohort 1 and 95.2% in cohort 2. To evaluate the antitumor activity of MORAb-202 against high-grade serous OV, we investigated its biological mechanism of action, focusing on its ability to induce ICD using in vitro and in vivo models.

Methods

In vitro induction of ICD was evaluated in human OV cell lines treated with either MORAb-202 or eribulin by measuring HMGB1, HSP70, HSP90, and calreticulin. Antitumor activity of MORAb-202 was examined in OV cell line derived xenografts (CDx), and platinum sensitive (Pt-S) and platinum refractory (Pt-R) OV patient-derived xenografts (PDx). Immunohistochemistry/immunofluorescence (IHC/IF) staining in an OV CDx model was used to assess target engagement (anti-eribulin) and in vivo ICD induction (anti-HMGB1, anti-HSP90).

Results

Both eribulin and MORAb-202 elicited in vitro ICD induction of HMGB1, calreticulin, HSP70, and HSP90. HMGB1 increased in a dose-dependent manner; a time-course study in multiple cell lines showed this release to occur 72 hrs post treatment. In OV CDx and PDx models, a single dose of MORAb-202 (5 mg/kg) showed notable tumor shrinkage which was superior to eribulin monotherapy at a dose of 3.2 mg/kg (32 times the molar equivalent of eribulin in a 5 mg/kg dose of MORAb-202). A higher dosage of MORAb-202 (12.5 mg/kg) was required for durable tumor shrinkage in the Pt-R OV PDx model. In an OV CDx model, target engagement of MORAb-202 was confirmed. Translocation of HMGB1 and enhanced HSP90 production as ICD biomarkers were observed in triplicate tumor samples treated with MORAb-202 and eribulin.

Conclusions

These preclinical data illustrate ICD as a notable mode of action of MORAb-202 and suggest potential for effective antitumor activity in the clinic.

Editorial acknowledgement

Editorial support was provided by Dolly Al Koborssy, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Nutley, NJ, USA.

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc., Nutley, NJ, USA.

Disclosure

K. Furuuchi: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. J. Fulmer: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. K. Rybinski: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. H. Liu: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. A. Soto: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. W. Halle: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. R. Jean-Toussaint: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. S. Smith: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. T. Uenaka: Financial Interests, Personal, Full or part-time Employment: Eisai Inc.

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Basic and translational research

5P - Physiologically relevant treatment models to investigate epigenetic mechanisms driving platinum resistance in ovarian High Grade Serous Carcinoma

Presentation Number
5P
Speakers
  • Raffaella Ergasti (Rome, Italy)
Presentation Topic
Basic and translational research

Abstract

Background

The prognosis for patients with platinum-resistant ovarian High Grade Serous Carcinoma (HGSC) remains poor. BriTROC-1 data indicate that genomic alterations alone cannot explain acquired platinum resistance. We investigate epigenetic changes that may drive platinum resistance in HGSC.

Methods

Using in an in vitro two-dimensional model, we recreated multiple cycles of chemotherapy. We utilised both established cell lines and primary cultures derived from HGSC ascites. Following cell characterisation (p53, PAX8 IHC), carboplatin sensitivity was assessed (sulforhodamine B assay). Cells were then pulsed with four cycles of carboplatin (50μM for 6 hours) with a week of recovery between each cycle. Methylation (Illumina 850k array), transcriptomic (RNAseq) and chromatin accessibility (ATACseq) assays were performed. Cells were also imaged using Stochastic Optical Reconstruction Microscopy.

Results

Firstly, we focused on RNAseq analysis to evaluate genes (and related biological processes) that are consistently enriched following carboplatin cycles and the unique genes that are conversely enriched at cycle level. We attempted to identify uniformly up-/down-regulated pathways across the different cultures. These data were compared with the same results obtained from the OvCar4, an established HGSC cell line and IVR01, an in-vivo resistant OvCar4 derivative. The ATACseq and methylation analyses are still ongoing, aiming to identify possible concordant changes in the chromatin accessibility and the methylation patterns that will allow us to clarify the changes observed in transcriptomic. The preliminary data obtained from the RNAseq analysis show that the highest number of enriched genes seems to occur after the first Carboplatin cycle, with a lower number of progressively enriched genes across all other ones. No constant biological processes were identified for the moment, across the different primary cell cultures. Further comparisons will be certainly needed.

Conclusions

Understanding the epigenetic landscape of HGSC using physiologically relevant models will allow us to identify possible therapeutic targets that could eventually prevent platinum resistance.

Legal entity responsible for the study

The authors.

Funding

Charity.

Disclosure

All authors have declared no conflicts of interest.

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Basic and translational research

6P - Unveiling the impact of intra-tumor heterogeneity in treatment response to achieve personalized medicine for endometrial cancer patients

Presentation Number
6P
Speakers
  • Beatriz Villafranca Magdalena (Barcelona, Spain)
Presentation Topic
Basic and translational research

Abstract

Background

Mortality in patients with high-risk and recurrent endometrial cancer (EC) is high since treatment options are limited, and tumors are extremely chemoresistant. In this study, we unveil the possible impact of molecular ITH in treatment response in EC; and we incorporate the molecular ITH of the tumor in the definition of a personalized medicine for EC patients.

Methods

Patient-derived xenograft (PDX) models were generated from 32 different tumor areas of a total of 13 EC patients. PDX tumors and a patient counterpart were analyzed by whole exome sequencing (WES) to unveil single nucleotide variation (SNV) and copy number variation (CNV) alterations. A bioinformatic pipeline was conducted to find the best candidate’s drugs targeting the specific mutated genes of each tumor area. Viability assays were performed to assess the efficacy of the selected drugs in organoids derived from patient-derived xenograft (PDX) organoids and mice models representing ITH.

Results

All EC models presented molecular ITH. A subset of the most relevant altered tumor drivers and pathogenic genes were used to select drugs targeting specific ITH genes or homogenously altered genes in the primary tumor. Targeted drugs and standard chemotherapy were tested in deep and superficial areas of two EC patients using their PDXOs. A relevant difference between the IC50 of both areas (50 μM vs 12 μM) was encountered when assessing the efficacy of the Geldanamycin, which is a HSP90 inhibitor, targeting the ITH alteration of the deep area of one patient.

Conclusions

We have established a workflow for the identification of specific drugs targeting the molecular ITH in EC. Our preliminary results indicate that ITH might have an important role in treatment response.

Legal entity responsible for the study

Vall d’Hebron Institute of Research.

Funding

Instituto de Salud Carlos III (ISCIII).

Disclosure

All authors have declared no conflicts of interest.

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Basic and translational research

7P - Integration of whole genome sequencing (WGS) into NHS pathways for high-grade ovarian cancer (HGOC): a single-centre prospective experience

Presentation Number
7P
Speakers
  • Ionut G. Funingana (Cambridge, United Kingdom)
Presentation Topic
Basic and translational research

Abstract

Background

Current molecular testing of HGOC uses panel testing of fixed tumour tissue. Matched tumour-germline WGS is now in the NHS National Genomic Test Directory for fresh frozen (FF) samples. WGS offers significant advantages over panel tests, particularly for accurate measures of mutational processes (homologous recombination deficiency [HRD], tumour mutational burden [TMB]). We report the experience of integrating WGS into routine NHS pathways for women with HGOC between April and November 2022.

Methods

WGS of somatic (×80) and germline (×30) was performed by the NHS Genomics Medicine Sequencing Centre using Illumina chemistries. Processing of the sequence data and variant triage was performed by Genomics England WGS analysis pipeline. All patients (pts) gave written informed consent for germline and tumour testing.

Results

WGS was performed in 19 pts. After an initial 3 month run-in period using banked FF samples, prospective testing was integrated into routine care from July 22. The median time from consent to clinical reporting was 48 days (IQR 44-68). WGS results changed the diagnosis in 3 patients: 2 with image-guided biopsies were changed from HGOC to low grade subtype and 1 recurrent poorly differentiated gynaecological carcinoma had unusually high TMB and APOBEC signatures that was inconsistent with HGOC enabling compassionate use of pembrolizumab. Estimating HRD from WGS using the CHORD algorithm showed strong concordance with Myriad MyChoice (9/11; 82%). One clinically platinum-refractory case was proficient by CHORD and had a genomic instability score [GIS] of 42. The second pt had a germline deleterious BRIP1 variant with GIS 36 and was deficient by CHORD. CCNE1 amplification was only present in platinum resistant cases.

Median age at diagnosis (range) years 60 (36-79)
Carcinosarcoma, N 1
Clear cell, N 1
High grade serous, N 16
Poorly differentiated, N 1
Surgery
   Diagnosis, N 2
   Primary, N 6
   Recurrence, N 2
Radiology
   Diagnosis, N 6
   Recurrence, N 1

Conclusions

Biopsy pathways for FF and WGS are feasible for diagnostic pathways in the NHS. WGS offers clinically relevant measures of mutational processes in HGOC with diagnostic and predictive value.

Legal entity responsible for the study

The authors.

Funding

CRUK Cambridge Centre.

Disclosure

J.D. Brenton: Financial Interests, Personal and Institutional, Advisory Board: Tailor Bio. All other authors have declared no conflicts of interest.

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Basic and translational research

8P - NXP800 versus cisplatin in ARID1a-mutated Ovarian Clear Cell Carcinoma xenograft models

Presentation Number
8P
Speakers
  • James R. Stewart (London, United Kingdom)
Presentation Topic
Basic and translational research

Abstract

Background

NXP800 (CCT361814) is a Heat Shock Factor (HSF1) pathway inhibitor currently being studied in a phase 1 clinical trial (NCT05226507). NXP800 demonstrated substantial antitumor activity in cancer cell lines of different histologies, including ovarian clear cell and endometrioid carcinoma (OCCC and EOC), gastric carcinoma, and haematological cancers. Loss of function of ARID1A was identified as a predictive marker for response to NXP800 in OCCC and EOC. Here we describe an in vivo study of NXP800 versus cisplatin as an active control in cisplatin-resistant and cisplatin-sensitive ARID1A-mutated OCCC xenografts, supporting the clinical development of NXP800 in this indication.

Methods

In vivo studies were performed by generating subcutaneous tumors in Nude (nu/nu) mice using TOV-21G and SKOV3 cell lines. Loss of ARID1A was confirmed in western blot.

Results

Treatment with NXP800 resulted in substantial tumor growth inhibition (TGI) in both models. In the TOV-21G model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 201.71, 205.66 and 202.20 mm3, respectively; on Day 28, average tumor volumes were 399.84, 236.68 and 121.47 mm3, respectively, representing increases in tumor volume of 98% for the vehicle control group and 15% for the cisplatin group, and a decrease in tumor volume of 41% for the NXP800 group. In the SKOV3 model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 136.2, 138.5 and 134.7 mm3, respectively; on Day 28, average tumor volumes were 312.94, 253.71 and 53.33 mm3, respectively, representing increases in tumor volume of 130% for the vehicle control group and 80% for the cisplatin group, and a decrease in tumor volume of 60% for the NXP800 group.

Conclusions

NXP800 exhibits notable therapeutic activity in xenografts of OCCC – a condition of high unmet medical need with limited treatment options – including sustained tumour growth inhibition and regression both in cisplatin resistant (SKOV3) and sensitive (TOV-21G) OCCC models. Planned phase 1b expansion cohorts will include ovarian clear cell carcinoma and ovarian endometrioid carcinoma patients with ARID1A mutation.

Legal entity responsible for the study

The authors.

Funding

Nuvectis Pharma.

Disclosure

E. Poradosu: Financial Interests, Personal, Other, Employee: Nuvectis Pharma. A. Woods: Financial Interests, Personal, Other, Employee: Nuvectis Pharma. S. Shemesh: Financial Interests, Personal, Other, Employee: Nuvecitis Pharma. P. Workman: Financial Interests, Personal, Advisory Board: Nextech, Astex Pharmaceuticals, CV6 Therapeutics, Black Diamond Therapeutics, Vividion Therapeutics, Storm Therapeutics, Alterome Therapeutics, Epicombi Therapeutics, Nuvectis Pharma; Financial Interests, Personal, Stocks/Shares: Chroma Therapeutics, Storm Therapeutics, Nextech; Financial Interests, Personal, Member of the Board of Directors: Storm Therapeutics; Financial Interests, Institutional, Research Grant: Vernalis/Novartis, Merck KGaA, Cyclacel Pharmaceuticals, Piramed/Genentech/Roche, Astex/AstraZeneca, Sareum/Sierra Oncology, AstraZeneca; Financial Interests, Personal, Other, Former employee: AstraZeneca. S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Immunogen, Mersana, Merck Sereno, MSD, Roche, AstraZeneca, GSK, Oncxerna, Shattuck Labs, Novartis, Epsilogen, Seagen, Eisai; Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview; Financial Interests, Personal, Stocks/Shares: PerciHealth; Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Non-Financial Interests, Personal, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem; Non-Financial Interests, Personal, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Academic sponsored trial PI (MONITOR-UK): GSK; Non-Financial Interests, Personal, Other, Member of membership committee: ESGO; Non-Financial Interests, Personal, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity. All other authors have declared no conflicts of interest.

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Cervical cancer

9P - The Survival Effect And Prognost?c Factors Of Residual Tumor Conf?ned To The Uterus After Rad?cal Rad?o-Chemotherapy In Cerv?cal Cancer

Presentation Number
9P
Speakers
  • Bedriye Dogan (Istanbul, Turkey)
Presentation Topic
Cervical cancer

Abstract

Background

Detection of residual tumor after radio-chemotherapy (RCX) in patients with locally advanced cervical cancer creates problems in clinical management. The aim of study is to evaluate the survival effect and prognostic importance of the residual tumor limited to the uterus in patients with advanced cervical cancer who received primary RCX.

Methods

125 cases of inoperable cervix cancer applied to our clinic between June 2012 and December 2018. Patients undergo magnetic resonance imaging of the pelvis to evaluate residual tumor before brachytherapy treatment, and positron emulsion tomography (PET-CT) to evaluate treatment response at 6 months after radical treatment.

Results

The median age was 50 and 111 patients (88.8%) were diagnosed with squamous cell carcinoma and 14 (11.2%) with adenocarcinoma. Median tumor size was 5 cm and 71 patients were stage IIB (56.8%), and lymphnodes (LN) were detected in PET-CT before treatment in 70 patients. Residual tumor was found in 47 patients (37.6%) median follow-up after external RCX 45 months (7-91), and in 10 patients at 6 months. Three-year overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 86.9%, 89.1%, and 76.4%, respectively. In the univariate analysis, it was seen that the presence of residual tumor detected at 6 months was an unfavorable prognostic factor on LRFS (p=0.01), OS (p=0.001), and DMFS (p=0.01). Pre-treatment evaluation, presence of pelvic LN in PET-CT (p=0.05) and detection of residual tumor after external pelvic radiotherapy (p=0.015) were unfavorable prognostic factors on LRFS and DMFS. Local control (LC) was better in patients < 60 years (p=0.001), and distant metastases were more common in tumors > 5 cm (p=0.02). LC was better in <60 years (p=0.001), and distant metastases were more common in > 5 cm (p=0.02). Presence of residual tumor on PET-CT 6 months after treatment was determined in multivariate analysis as an important prognostic factor on OS and LRFS.

Conclusions

Treatment is controversial in patients with residual tumor after RCX. Survival is worse in patients with residual tumor at 6-month follow-ups after treatment. The need for adjuvant therapy should be considered in these patients.

Legal entity responsible for the study

B. Dogan.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Cervical cancer

10P - Neoadjuvant chemotherapy with bevacizumab for IIb stage cervical cancer, is it time to rethink standard of care

Presentation Number
10P
Speakers
  • Farrukh M. Djuraev (Tashkent, Uzbekistan)
Presentation Topic
Cervical cancer

Abstract

Background

Cervical cancer is the second most frequent cancer among women in Uzbekistan. Due to poor accessibility of radiation therapy, especially in remote regions, addition of bevacizumab to platinum containing chemotherapy leads to improvement in overall survival in advanced cervical cancer. We therefore studied addition of bevacizumab to chemotherapy in a group of cervical cancer patients.

Methods

The prospective study enrolled 54 patients with cervical cancer FIGO IIB stage, who underwent neoadjuvant chemotherapy: paclitaxel 175mg/m2 + carboplatin AUC6 + bevacizumab 15 mg/kg every 21 days. The control arm included 55 patients with the same stage cervical cancer, who underwent platinum containing chemotherapy in the same dosage, but without bevacizumab. The response rates were determined by means of preoperative clinical examination, diagnostic imaging (RECIST), changes in tumour markers (SCC) and by histopathology.

Results

Clinical response rate after addition of bevacizumab was found in 88,8% of patients, and 74,5 % of patients who were treated without bevacizumab (p = 0.025), Addition of bevacizumab to platinum containing therapy led to higher rate of clinical complete remission (44.9 vs. 15.5%; p = 0.072). Significant reduction of tumor size was observed in all patients 100% who were treated chemotherapy + bevacizumab, and in 75% cases in patients only chemotherapy, this fact led to higher operability rates in both. The rate of pathological complete response (pCR) was altered significantly 28.6% bevacizumab free therapy vs. 44.5% chemotherapy + bevacizumab (p ≤ 0.005).

Conclusions

Addition of bevacizumab led to avoiding radiation therapy, better clinical response, higher operability and PCR rates. Further validation of angiogenesis Inhibitors in neoadjuvant treatment of cervical cancer needs larger multicentric randomized clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Cervical cancer

11P - Conization before radical hysterectomy in early cervical cancer: A Korean multi-center study

Presentation Number
11P
Speakers
  • Maria Lee (Seoul, Korea, Republic of)
Presentation Topic
Cervical cancer

Abstract

Background

To identify a specific population who might benefit from cervical conization prior to radical hysterectomy (RH).

Methods

From six institutions in Korea, we identified patients with node-negative, margin-negative, parametria-negative, 2009 FIGO stage IB1 cervical cancer who received primary Type C RH between January 2006 and December 2021. Patients were divided into multiple groups by cervical tumor size, surgical approach, and histology. We conducted a series of independent 1:1 propensity score matching and compared survival outcomes between the conization and control groups.

Results

In total, 1254 patients were included in this analysis: conization (n=355) and control (n=899). After matching, the conization group showed significantly better DFS (P=0.001) and OS (P=0.019) than the control group. Among the matched patients with squamous cell carcinoma (SCC) and cervical tumor >2 cm, the conization group showed significantly better DFS than the control group when MIS RH was conducted (3-year DFS rate, 96.3% vs. 87.4%; P=0.007 and aHR, 0.271; 95% CI, 0.100–0.736; P=0.010), but not open RH. Among the matched patients with non-SCC and cervical tumor >2 cm, the conization group showed significantly better DFS than the control group when MIS RH was conducted (3-year DFS rate, 97.0% vs. 74.8%; P=0.021 and aHR, 0.198; 95% CI, 0.043–0.916; P=0.038), but not open RH. However, no difference in DFS was observed between the conization and control groups among the matched patients with cervical tumor ≤2 cm, regardless of the surgical approach. In patients who underwent open RH, DFS did not differ by uterine residual tumor size. In contrast, DFS was significantly worsened as the size of the uterine residual tumor increased from >0 and ≤1 cm to >3 and ≤4 cm in patients who underwent MIS RH.

Conclusions

Patients with 2009 FIGO stage IB1 cervical cancer having a cervical tumor >2 cm who are scheduled to undergo primary MIS RH might benefit from cervical conization, as conization was associated with a lower recurrence rate. Although there was no survival benefit from cervical conization in patients with cervical tumor ≤2 cm, cervical conization purporting to minimize the uterine residual tumor may be worth considering before MIS RH.

Legal entity responsible for the study

S.I. Kim.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Cervical cancer

12P - Tisotumab vedotin in recurrent or metastatic cervical cancer

Presentation Number
12P
Speakers
  • Marta Bini (Milan, Italy)
Presentation Topic
Cervical cancer

Abstract

Background

Tisotumab vedotin (TV) is an antibody-drug conjugate used for the treatment of adult patients with recurrent or metastatic cervical cancer. TV comprised of a monoclonal antibody against tissue factor and monomethyl auristatin E (MMAE), a potent inhibitor of cell division.

Methods

This is a systematic review of data about the safety and antitumor activity of TV in cervical cancer patients.

Results

The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable anti-tumor activity in pre-treated patients with recurrent or metastatic cervical cancer. The innovaTV-204 trial showed that TV monotherapy resulted in an objective response rate of 24% (including 7% and 17% complete and partial responses, respectively). In September 2021, the US Food and Drugs Administration (FDA) granted accelerated approval to TV for the treatment of recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy. The ongoing randomized, open-label Phase 3 innovaTV-301/ENGOTcx12/GOG-30xx trial will assess the effect of TV alone vs. the investigator’s choice of chemotherapy in second- or third-line recurrent or metastatic cervical cancer. Meanwhile, the multicohort phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing the combination with TV alone and in combination with (i) bevacizumab, (ii) carboplatin, (iii) pembrolizumab, and (iv) pembrolizumab plus carboplatin with or without bevacizumab. The preliminary data highlighted the feasibility of the combination due to a good toxicity profile and suggest good clinical activity. In the first line, TV in combination with carboplatin or pembrolizumab provides an ORR of 55% and 41%, respectively. The effect of adding TV to the current standard of care in first-line (pembrolizumab plus carboplatin with or without bevacizumab) is still under evaluation.

Conclusions

Several trials tested the role of TV monotherapy for pre-treated recurrent or metastatic cervical cancer. Although the phase III randomized controlled trial (ENGOT-cx12/GOG-3057/innovaTV-301) is still enrolling, the available evidence from phase II studies supports the adoption of TV in pre-treated recurrent or metastatic cervical cancer patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Cervical cancer

13P - Cervical cancer screening in a Basic Health Unit in South of Brazil: impact of the COVID-19 pandemic

Presentation Number
13P
Speakers
  • Isabella F. Michelon (Pelotas, Brazil)
Presentation Topic
Cervical cancer

Abstract

Background

About 90% of the estimated cervical cancer deaths occur in low and middle-income countries. In Brazil, cervical cytology (i.e Pap smear) is a widely used strategy for its early detection. Considering the crucial role of the primary care in women’s health in Brazil and the COVID-19 pandemic related health crisis, this cross-sectional study aimed to analyze the repercussions of the COVID-19 pandemic in cervical cancer screening in a teaching Basic Health Unit (BHU) from South of Brazil, in the city of Pelotas.

Methods

This study was approved by the institutional ethics committee (5.706.229). We analyzed records of Pap smears performed between February 2019 to February 2020 and March 2020 to April 2022, referred to as pre-pandemic and pandemic period. The statistical analysis was performed using the Statistical Package for the Social Sciences program.

Results

The sample mean age was 43.6 years and they were mostly residents of the area covered by the BHU (94.35%). During the pre-pandemic and pandemic period 339 and 653 exams were collected, respectively. A 42% reduction in tests performed in 2020 compared to 2019 was observed as well as an increase of 107% in 2021 compared to 2020. An increase was assessed in the rate of non-residents (of the area of responsibility of the BHU) performing Pap tests in the Unit during the pandemic period (p = 0.001). Most of the results were negative for intraepithelial lesion or malignancy (NILM). A significant difference in abnormal results in the pre-pandemic and pandemic period, respectively, was seen (p = 0.012).

Association between the pre-pandemic and COVID-19 pandemic period and Pap smears results

Pre-pandemic period N (%) Pandemic period N (%) P value
Residents of the area covered by the BHU*
Yes 328 (97) 608 (95) 0.001
No 10 (3) 30 (5)
Cervical cytology*
NILM 306 (95.6) 567 (91.0) 0.012
Abnormal 14 (4.4) 56 (9.0) 0.012

*Variables with data missing

Conclusions

The crisis brought on by the COVID-19 pandemic may have exacerbated pre-existing health disparities in cervical cancer already present in Brazil in pre-pandemic periods. Recovery strategies in primary care are needed to prioritize high-risk patients and lessen the burden of cervical cancer in the future.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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