- Jean Emmanuel Kurtz (Strasbourg, France)
- Iain McNeish (london, United Kingdom)
- Liselore Loverix (Leuven, Belgium)
20MO - Time to deterioration in quality of life in patients (pts) with advanced endometrial cancer (aEC) treated with lenvatinib plus pembrolizumab (L+P) or treatment of physician’s choice (TPC)
- Domenica Lorusso (Rome, Italy)
Abstract
Background
In study 309/KEYNOTE-775, L+P showed significant OS and PFS benefits and improved ORR vs TPC in pts with aEC following prior platinum-based therapy. There were no substantial differences in health-related quality of life (HRQoL) scores between the 2 arms at 12 weeks. We describe a post-hoc analysis of time to first (TTfD) and time to definitive (TTdD) deterioration (by 10 points) of patient-reported outcomes (PROs).
Methods
Pts were randomized 1:1 to lenvatinib 20 mg QD PO + pembrolizumab 200 mg IV Q3W (n=411) or TPC (n=416; doxorubicin 60 mg/m2 IV Q3W or paclitaxel 80 mg/m2 IV QW, 3 wks on/1 wk off). PROs were assessed on day 1 of each treatment cycle (L+P and doxorubicin, 21 days; paclitaxel, 28 days) until the end of treatment visit using EORTC QLQ-C30, QLQ-EN24, and EQ-5D-5L in pts with ≥1 study dose and ≥1 postbaseline PRO. TTfD for the EORTC QLQ-C30 and QLQ-EN24 was defined as the time from treatment start to first onset of a ≥10-point increase (symptom score) or decrease (functional/global health status [GHS] score) from baseline. TTdD was defined as the time from treatment start to first onset of an increase (symptom score) or decrease (functional/GHS score) of ≥10 points from baseline without subsequent recovery.
Results
The mean observation period for PRO measures was longer for L+P vs TPC (eg, EORTC QLQ-C30: L+P, 9.3 mos; TPC, 4.3 mos). TTfD was generally similar between the 2 arms for most functional scales. Among the symptom scales, TTfD for dyspnea, poor body image, tingling/numbness, and hair loss favored L+P over TPC, whereas pain, appetite loss, diarrhea, and muscular pain favored TPC. TTdD favored L+P for most of the assessed scales.
Conclusions
Although TTfD did not demonstrably favor either arm, L+P was favored over TPC for almost all scales in the TTdD analysis. This may be due to longer follow-up and/or overall greater efficacy with L+P vs TPC. These data along with previously reported positive efficacy, safety, and overall HRQoL scores from Study 309/KEYNOTE-775 further support L+P for use in pts with aEC following prior platinum-based therapy.
Clinical trial identification
NCT03517449.
Editorial acknowledgement
Medical writing support was provided by Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: MSD; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: Clovis Oncology; Financial Interests, Personal, Other, Consultancy: PharmaMar; Financial Interests, Personal, Other, Consultancy: Amgen; Financial Interests, Personal, Other, Consultancy: AstraZeneca; Financial Interests, Personal, Other, Consultancy: Clovis Oncology; Financial Interests, Personal, Other, Consultancy: GSK; Financial Interests, Personal, Other, Consultancy: MSD; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Other, Consultancy: Immunogen; Financial Interests, Personal, Other, Consultancy: Genmab; Financial Interests, Personal, Other, Consultancy: Seagen; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Seagen; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Genmab; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Oncoinvest; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Corcept; Financial Interests, Personal, Advisory Board, Invited Member of Advisory Board: Sutro; Financial Interests, Institutional, Funding, Grant for Founding Academic Trial: MSD; Financial Interests, Institutional, Funding, Grant for Founding Academic Trial: Clovis Oncology; Financial Interests, Institutional, Funding, Grant for Founding Academic Trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT Trial with Institutional Support for Coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT Trial with Institutional Support for Coordination: Genmab; Financial Interests, Institutional, Funding, Grant for founding academic trial: PharmaMar; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca; Financial Interests, Institutional, Funding, Clinical trial/contracted research: Clovis Oncology; Financial Interests, Institutional, Funding, Clinical trial/contracted research: GSK; Financial Interests, Institutional, Funding, Clinical trial/contracted research: MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Immunogen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Incyte; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Novartis; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Roche; Financial Interests, Institutional, Invited Speaker, ENGOT Trial with Institutional Support for Coordination: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: Genmab; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: Immunogen; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: Clovis; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation receive: Roche; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: Incyte; Non-Financial Interests, Personal, Member, Board of Directors: GCIG. N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche; Financial Interests, Personal, Advisory Board, Various: PharmaMar; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, Various: AstraZeneca; Financial Interests, Personal, Advisory Board, Various: MSD/Merck; Financial Interests, Personal, Advisory Board, Various: Clovis Oncology; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: Tesaro; Financial Interests, Personal, Advisory Board, Various: Tesaro; Financial Interests, Personal, Advisory Board, Various: GSK; Financial Interests, Personal, Invited Speaker, Lectures: Novartis; Financial Interests, Personal, Advisory Board, Various: Pfizer; Financial Interests, Personal, Advisory Board, Various: Takeda; Financial Interests, Personal, Advisory Board, Various: BIOCAD; Financial Interests, Personal, Advisory Board, Various: Immunogen; Financial Interests, Personal, Advisory Board, Various: Mersana; Financial Interests, Personal, Advisory Board, Lectures: Eisai; Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio; Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna; Financial Interests, Personal, Advisory Board, Advisory role: Pieris; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Personal, Other, Steering Committee Member Clinical Guidelines: ESMO; Non-Financial Interests, Personal, Leadership Role, Chair, Scientific Committee: ACTO (Alleanza Contro il Tumore Ovarico). A. Casado Herraez: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: PharmaMar; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Tesaro; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Lilly; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: PharmaMar; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche. A.D. Santin: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Tesaro; Financial Interests, Institutional, Funding: Tesaro; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: Gilead Sciences; Financial Interests, Institutional, Funding: Puma Biotechnology; Financial Interests, Institutional, Funding: Genentech/Roche; Financial Interests, Institutional, Funding: R-Pharm; Financial Interests, Institutional, Funding: Immunomedics. E. Colomba: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Travel. Accommodations, Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Ipsen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer. D.S. Miller: Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Other, Honoraria: Clovis Oncology; Financial Interests, Personal, Member, Honoraria: Genentech; Financial Interests, Personal, Research Grant: EMD Serono Research & Development Institute; Financial Interests, Institutional, Research Grant: US Biotest; Financial Interests, Institutional, Research Grant: Advenchen Laboratories; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Xenetic Biosciences; Financial Interests, Institutional, Research Grant: Advaxis; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Aeterna Zentaris; Financial Interests, Institutional, Research Grant: TRACON Pharma; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Immunogen; Financial Interests, Institutional, Research Grant: Mateon Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Millennium Pharmaceuticas; Financial Interests, Institutional, Research Grant: Aprea AB; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: NVision; Financial Interests, Institutional, Research Grant: Leap Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Karyopharm Therapeutics; Financial Interests, Institutional, Research Grant: Agenus and Akesobio; Financial Interests, Institutional, Research Grant: Merck Sharpe & Dohme; Financial Interests, Personal, Other, Consulting Fees: Genentech; Financial Interests, Personal, Other, Consulting Fees: Tesaro; Financial Interests, Personal, Other, Consulting Fees: Eisai; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: Guardant Health; Financial Interests, Personal, Other, Consulting Fees: Janssen Oncology; Financial Interests, Personal, Other, Consulting Fees: Alexion Pharmaceuticals; Financial Interests, Personal, Other, Consulting Fees: Karyopharm Therapeutics; Financial Interests, Personal, Other, Consulting Fees: Incyte; Financial Interests, Personal, Other, Consulting Fees: Guardant Health; Financial Interests, Personal, Other, Consulting Fees: Janssen; Financial Interests, Personal, Other, Consulting Fees: Clovis Oncology; Financial Interests, Personal, Other, Consulting Fees: Asymmetrics Therapeutics LLC; Financial Interests, Personal, Other, Consulting Fees: Boston Biomedical Research Institute; Financial Interests, Personal, Other, Consulting Fees: Tarveda Therapeutics; Financial Interests, Personal, Other, Consulting Fees: Myriad Genetic Laboratories Inc.; Financial Interests, Personal, Other, Consulting Fees: GlaxoSmithKline LLC; Financial Interests, Personal, Other, Consulting Fees: AbbVie Inc.; Financial Interests, Personal, Other, Consulting Fees: EMD Serono Inc.; Financial Interests, Personal, Other, Consulting Fees: Seager Inc.; Financial Interests, Institutional, Other, Consulting Fees: Merck Sharpe & Dohme. K. Fujiwara: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Advisory Board: Nano Carrier; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Institutional, Funding: Regenerone; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Zeria; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Personal, Invited Speaker: Regenerone; Financial Interests, Personal, Invited Speaker: Zeria; Non-Financial Interests, Personal, Leadership Role: GOTIC. S. Pignata: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AZ; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: PPharmaMar; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Az. S.E. Baron-Hay: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Merck Sharpe & Dohme; Financial Interests, Personal, Advisory Role: Novartis. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Institutional, Other, COLIBRI Translational Research: BMS; Financial Interests, Personal, Advisory Board: Oxnea; Financial Interests, Personal, Advisory Board: Merck Sereno; Financial Interests, Personal, Advisory Board: Agenus; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Macrogenics; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Financial Interests, Personal, Advisory Board: Clovis; Non-Financial Interests, Personal, Principal Investigator: PAOLA1. R. Shapira-Frommer: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Medison; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Neopharm; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, consultation: Msdison; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD. R. Massaad: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. A. Martin Nguyen: Financial Interests, Personal and Institutional, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal and Institutional, Full or part-time Employment: Merck & Co., Inc. Q. Zhao: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai Inc. J. McKenzie: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai Inc. V.S. Prabhu: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal and Institutional, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses: Merck & Co., Inc. V. Makker: Financial Interests, Institutional, Funding, Study funding: Merck; Financial Interests, Institutional, Funding, Study funding: Eisai; Financial Interests, Institutional, Funding, Study funding: Clovis; Financial Interests, Institutional, Funding, Study funding: Karyopharm; Financial Interests, Institutional, Funding, Study funding: AstraZeneca; Financial Interests, Institutional, Funding, Study support: Zymeworks; Non-Financial Interests, Personal, Principal Investigator: Merck; Non-Financial Interests, Personal, Advisory Role: Eisai; Non-Financial Interests, Personal, Advisory Role: Clovis; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Advisory Role: Lilly; Non-Financial Interests, Personal, Advisory Role: GSK; Non-Financial Interests, Personal, Advisory Role: Karyopharm; Non-Financial Interests, Personal, Advisory Role: Iteos; Non-Financial Interests, Personal, Advisory Role: Faeth. All other authors have declared no conflicts of interest.
Invited Discussant of abstract 20MO
- Jean Emmanuel Kurtz (Strasbourg, France)
21MO - Limited benefit of molecular profiling in patients with low-grade endometrial cancer
- Stephanie Vrede (Nijmegen, Netherlands)
Abstract
Background
Most patients present with low-grade (grade 1-2) early-stage (FIGO I-II) endometrioid EC (EEC), it is questioned whether these patients benefit from molecular profiling. We aim to investigate the prognostic relevance of molecular profiling within low-grade EEC.
Methods
A retrospective multicenter study within the European Network for Individualized Treatment (ENITEC) network. Patients with early-stage EC were excluded if lymph node status was unknown. Molecular profiling was conducted using single-molecule Molecular Inversion Probes based on Next Generation Sequencing. Subsequently, cases were classified as: polymerase epsilon (POLE) mutant, microsatellite instable (MSI), tumor protein (TP53) mutation and no-specific molecular profile (NSMP).
Results
Total of 393 EC patients were included, 75% had early-stage EC, and 54% low-grade EEC. Of all patients, 8.1% was classified as POLEmut, 16.8% as MSI, 21.4% as TP53-mutated and 53.7% as NSMP. Median follow-up was 5.3-years. Across all molecular subgroups, patients with low-grade EEC had superior disease-specific survival (DSS) compared to high-grade (grade 3) EC, respectively >89% vs. >43%. Equally, patients with low-grade EEC had improved recurrence-free survival (RFS) compared to high-grade EC within POLEmut, MSI and NSMP. Within TP53-mutated, only grade 1 EEC showed an excellent RFS (92%) when compared to grade 2 (54%) and grade 3 EC (44%). In multivariate analysis that included age, lymphovascular space invasion, grade, FIGO stage and the four molecular subgroups, TP53-mutated, high-grade and advanced-stage (FIGO III-IV) remained independent prognostic factors for reduced DSS and RFS (respectively, hazard ratio (HR) 9.20 (95%-CI 1.23-68.90) p=0.031, HR 5.91 (95%-CI 2.63-13.28) p<0.001, HR 3.02 (95%-CI 1.61-5.62) p<0.001 and respectively, HR 12.27 (95%-CI 1.66-90.78) p=0.014, HR 2.66 (95%-CI 1.54-4.57) p<0.001, HR 2.58 (95%-CI 1.56-4.24) p<0.001).
Conclusions
Patients with grade 1 EEC have an excellent prognostic outcome across all molecular subgroups. In patients with grade 2 EEC, TP53-mutated seems to be prognostic relevant. Based on current data, routine molecular profiling in patients with low-grade EEC has shown limited contributive value to prognostic outcome.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
27MO - Integrated digital pathology and single-cell analysis identify the spatial and temporal evolution of immune cells networks in epithelial ovarian cancer
- Eleonora Ghisoni (Epalinges, Switzerland)
Abstract
Background
Immune checkpoint blockade (ICB) failed to demonstrate activity in epithelial ovarian cancer (EOC) so far. What controls the complex spatial distribution of tumor-infiltrating lymphocytes (TILs) and immune cells in EOC is poorly understood and it remains challenging to systematically define tumor-immune phenotype due to its highly heterogeneous nature.
Methods
We profiled two large cohorts of primary-recurrent EOCs FFPE samples (N=180) by multi-immunofluorescence (mIF). We used a targeted gene panel for homologous recombination deficiency (HRD) to link genomic determinants with immune phenotypes. We established syngeneic mouse models to characterize TIL infiltration and single-cell T-cell and TME states based on BRCA mutational status and in response to chemotherapy (ChT).
Results
Applying digital pathology imaging we established a new algorithm to quantify the quantity and spatial distribution of CD8+ TILs while taking into consideration intra-tumoral heterogeneity. We defined four CD8+ immune-categories in our cohorts: purely-inflamed, mixed-inflamed, excluded and desert EOCs. Overall survival (OS) was significantly longer in inflamed EOCs compared to excluded and desert ones (p=0.021). Results were validated in a third independent cohort (N=62, p=0.001). By interrogating cellular neighborhoods and leukocytes networks on a whole-tissue basis we captured immune homotypic niches (T-cell to T-cell and macrophages to antigen-presenting cells [APC]) and heterotypic ones. TILs-APC niches were significantly enriched in purely inflamed tumors at baseline and were maintained at recurrence. Single-cell RNAseq analysis of mouse models confirmed higher CD8+ and TILs-APC infiltration in recurrent Brca1mut tumors concomitant with enhanced TILs exhaustion program characterized by PD1, TIM3, TIGIT and cytotoxic signatures.
Conclusions
We provide a new immune-classification for EOC which is relevant for OS and demonstrate the key role of TIL-APC niches to drive TILs inflammation at recurrence. Our findings suggest that next-generation tissue-based biomarkers for ICB should include the simultaneous analysis of multiple immune cell type and their spatial interactions.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
G. Coukos: Financial Interests, Personal, Research Grant: Celgene; Financial Interests, Personal, Research Grant: Boehringer-Ingelheim; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Iovance Therapeutics; Financial Interests, Personal, Research Grant: Kite Pharma. All other authors have declared no conflicts of interest.
Invited Discussant of abstracts 21MO and 27MO
- Iain McNeish (london, United Kingdom)
28MO - Real-world whole sequencing data of ovarian cancer patients
- James D. Brenton (Cambridge, United Kingdom)
Abstract
Background
Poly(ADP-ribose)-polymerase (PARP) inhibitor therapy has dramatically changed outcomes for women with high-grade serous ovarian carcinoma. Germline or somatic pathogenic variants in BRCA1 or BRCA2 are strong predictive biomarkers for PARP therapy, but patients with other causes of homologous recombination deficiency (HRD) also strongly benefit. NHS patients have commercial testing for HRD using the Myriad MyChoice assay, but using WGS through the GLH could provide a more cost-effective and universally accessible assay for NHS patients.
Methods
We compared the performance of 3 bioinformatics algorithms for HRD detection (CHORD, HRDetect, Dragen) for ovarian cancer patients included in the 100K dataset to perform real-world response and survival analysis.
Results
HRD was associated with better overall survival outcome across all 3 algorithms in patients treated with platinum-based therapy (CHORD: n=259, HR=0.32 [95% CI 0.19–0.52], Wald test=20.94, p«0.001; Dragen: n=268, HR=0.38 [95% CI 0.23–0.62], Wald test=14.9, p<0.001; HRDetect: n=239, HR=0.28 [95% CI 0.16–0.48], Wald test=21.24, p«0.001). The results of the analysis showed substantial concordance, both in between each bioinformatics algorithm and in correlation with the BRCA1/2 status. However, for accurate correlation of the WGS-based HRD scores with the measures of response, there is a prerequisite of high-quality clinical data.
Conclusions
Clinically relevant HRD prediction is feasible using WGS data and supports further development of these algorithms for NHS use in the Genomics Medicine Service. Future improvements will use a multimodal machine-learning (ML) model to define separate weights for classes of clinical data or genomic data (HRD) and subclasses of data points. We will also include multimodal data as additional covariates in the models, including radiomic and pathology image analysis data. Incorporating multi-dimensional data, in particular pathology and radiological imaging parameters, into an ML model is fundamental for improved integrative biomarkers of HRD.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J.D. Brenton: Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Tailor Bio; Financial Interests, Personal, Stocks/Shares: Tailor Bio; Financial Interests, Institutional, Invited Speaker: Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Aprea AB; Non-Financial Interests, Personal, Member: Association of Cancer Physicians. All other authors have declared no conflicts of interest.
Invited Discussant of abstract 28MO
- Liselore Loverix (Leuven, Belgium)
Q&A and discussion
- Jean Emmanuel Kurtz (Strasbourg, France)