39MO - Clinical evaluation of a low-coverage whole-genome test for homologous recombination deficiency detection in ovarian cancer

Background

The PAOLA-1/ENGOT-ov25 phase 3 trial is a first line treatment study for advanced ovarian cancer which showed that the maximum benefit of the PARP inhibitor olaparib plus bevacizumab maintenance is observed in patients with Homologous Recombination Deficient (HRD) tumors. Using PAOLA-1 data, we report a retrospective clinical evaluation of SeqOne HRD solution based on low-coverage and cost-effective whole genome sequencing (WGS).

Methods

SeqOne HRD solution combines genomic instability and CCNE1 gene amplification features extracted from WGS, as well as pathogenic mutations in BRCA 1/2 genes. We conducted a dilution experiment to evaluate the lower limit for sequencing coverage and tumoral content. The clinical evaluation on 364 patients from the PAOLA-1 trial included Progression-Free Survival (PFS) data and comparisons with the MyChoice® CDx test (Myriad genetics). All samples were prepared using Agilent’s SureSelect reagents and sequenced on Illumina’s NextSeq or NovaSeq platforms.

Results

The dilution experiment shows that the test provides consistent HRD status for a sequencing coverage of at least 0.3X and a percentage of tumoral content of at least 20%. A concordance above 90% was found between MyChoice® CDx test and SeqOne HRD solution with WGS data. The ability to detect patients who benefit from olaparib maintenance was similar for SeqOne HRD solution or MyChoice test. In HRD positive patients treated with olaparib, the PFS Hazard Ratio (HR) was 0.38 (0.27-0.55) and 0.33 (0.23-0.48) with the SeqOne solution or MyChoice test and was 0.98 (0.68-1.41) and 0.99 (0.67-1.46) respectively in HRD negative patients. In patients with BRCA wild type tumors, both SeqOne and MyChoice positive patients benefit from Olaparib maintenance with HR respectively of 0.50 (0.30-0.81) and 0.46 (0.27-0.76).

Conclusions

The SeqOne HRD solution brings a cost-effective and clinically validated Whole Genome Sequencing approach to detect HRD and to select advanced ovarian cancer patients to be treated in first-line with olaparib plus bevacizumab maintenance. This solution is efficient with a low tumoral content while being flexible by accommodating different lab configurations.

Legal entity responsible for the study

SeqOne Genomics.

Funding

SeqOne Genomics.

Disclosure

R. Boidot: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, GSK, Myriad Genetics, Takeda; Financial Interests, Personal, Other: Oxford Nanopore technologies, New England Biolabs, Agilent Technologies; Financial Interests, Institutional, Funding: Boehringer Ingelheim, Takeda, Oxford Nanopore Technologies Oxford Nanopore Technologies. M.G.B. Blum: Financial Interests, Institutional, Full or part-time Employment: SeqOne. M. Wissler: Financial Interests, Personal, Invited Speaker: MSD, Roche, Servier, Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca. C. Gottin: Financial Interests, Institutional, Full or part-time Employment: SeqOne. J. Ruzicka: Financial Interests, Institutional, Full or part-time Employment: SeqOne. N. Duforet-Frebourg: Financial Interests, Institutional, Full or part-time Employment: SeqOne. A. Jeanniard: Financial Interests, Institutional, Full or part-time Employment: Agilent. P. Just: Financial Interests, Personal, Advisory Role: GSK, Roche. P. Harter: Financial Interests, Personal, Advisory Board, Value includes honoraria for lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, includes honoraria for lectures: GSK, Roche, MSD; Financial Interests, Personal, Invited Speaker: Amgen, Stryker, Zailab, Eisai; Financial Interests, Personal, Advisory Board: Clovis, Immunogen, Novartis, Mersana; Financial Interests, Personal, Other, IDMC member: Sotio; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, GSK, Genmab, Immunogen; Financial Interests, Institutional, Funding: Seagen, Clovis; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Clovis, GSK, PharmaMar; Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AstraZeneca. A.J. Gonzalez Martin: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Clovis, GSK, Genmab, Alkermes, Sutro, Roche, SOTIO, PharmaMar, Oncoinvent, Novartis, Mersana, MSD, Macrogenics, Eisai, Immunogen, Regeneron, HederaDx, Illumina; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis, Roche, Novocure, MSD, Takeda, Zaylab; Financial Interests, Institutional, Invited Speaker, PI of ANITA trial: GSK, Roche; Financial Interests, Personal, Invited Speaker, Member of ENGOT ov43-SC: MSD; Financial Interests, Institutional, Invited Speaker, ENGOT PI of EPIK-O trial: Novartis; Financial Interests, Institutional, Invited Speaker, ENGOT PI of AVB-500 phase III trial: Aravive. 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. J. Mäenpää: Financial Interests, Personal, Advisory Role: AstraZeneca, GSK. N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche, PharmaMar, AstraZeneca, MSD/Merck, Clovis Oncology, GSK, Pfizer, Immunogen, Mersana; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca; Financial Interests, Personal, Invited Speaker, Lectures: Novartis; Financial Interests, Personal, Advisory Board, Lectures: Eisai; Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio, Pieris; Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna; Financial Interests, Institutional, Research Grant: AstraZeneca, PharmaMar, Roche; Non-Financial Interests, Personal, Other, Sterring committee member Clinical Guidelines: ESMO; Non-Financial Interests, Personal, Leadership Role, Chair, Scientific Committee: ACTO (Alleanza contro il tumore ovarico). I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021), Aksebio China (2021), AstraZeneca (2021-2022), Bristol Myers Squibb (2021), Deciphera Pharmaceuticals (2021), Eisai (2021), F. Hoffmann-La Roche Ltd (2021), Genmab (2021), GSK (2021), Immunogen Inc. (2021-2022), Jazzpharma (2021-2022), Karyopharm (2021), MSD (2021-2022), Novocure (2020-2022), Novartis (2021), Oncoinvent AS (2021-2022), Seagen (2021), Sotio a.s. (2021-2022); Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), Deciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Oncoinvent AS (2019-2020); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019); Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). K. Fujiwara: Financial Interests, Personal, Advisory Role: Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, Takeda, Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, NanoCarrier; Financial Interests, Personal, Research Grant: Immunogen, Oncotherapy, Regeneron. D. Bertrand: Financial Interests, Institutional, Full or part-time Employment: SeqOne. N. Philippe: Financial Interests, Personal, Stocks/Shares: SeqOne. 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. E. Pujade-Lauraine: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca; Financial Interests, Personal, Other, IDMC board: Agenus, Incyte; Financial Interests, Personal, Full or part-time Employment: ARCAGY research.