Found 1 Presentation For Request "lucence"
709P - Serial circulating tumor (ct)-DNA alterations using amplicon-based next-generation sequencing (NGS) to identify resistance mechanisms to immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC)
- Praful Ravi (Boston, United States of America)
Abstract
Background
Most mUC patients (pts) develop resistance to ICI therapy. Study of serial ctDNA alterations during therapy may provide a non-invasive method of exploring mechanisms of resistance to ICI.
Methods
Pts with mUC at DFCI who had ≥2 ml plasma available pre- and post-ICI or cisplatin-based chemotherapy (chemo) were eligible. Paired pre and post samples underwent ctDNA evaluation with 7 to 30 ng of DNA using an 80-gene panel which employs an amplicon-based NGS assay, including fusions (Lucence LiquidHallmark). The primary objective was to evaluate ctDNA alterations pre- and post-ICI, and to correlate with objective response.
Results
39 pts with pre and post-ICI and 6 with pre and post-chemo samples were included. Median age was 68 years, 79% of pts were male, and 97% had urothelial histology. The majority (82%) received single-agent ICI (PD1/L1 inhibitor). Median duration between pre and post samples was 6.2 months. The most common variants pre- and post-ICI were in TP53 (54% and 49%), TERT (49% and 49%) and BRCA1/2 (36% and 33%). 9 pts were responding to ICI at time of post-ICI blood collection, with 7 (78%) showing clearance of ≥1 ctDNA variants, most commonly in TP53 (n=4), PI3KCA (n=2) and BRCA1/2 (n=2). 18 of 20 pts (90%) who were progressing at time of post-ICI collection had emergence of a new alteration, most commonly in BRCA1/2 (n=6), PI3KCA (n=4), CCND2/RB (n=4) and TP53 (n=3). BRCA1 and PIK3CA mutations emerged in only 1 and 0 chemo pts. Pts who cleared TP53 alterations during ICI had a higher likelihood of response compared to those who did not (50% vs. 17%, p=0.04). No responses were seen in pts who had emergence of a BRCA1/2 (n=9) or PIK3CA variants (n=4) on therapy, while none of 3 patients with a driver FGFR2/3 alteration responded to ICI.
Conclusions
ctDNA alterations were detected in 96% of pre/post-ICI samples overall. Clearance of TP53 alterations during ICI therapy was associated with response, while emergence of BRCA1/2 or PI3KCA variants appeared to be associated with resistance. Exploration of therapeutic combinations of ICI with PARP and PI3K/Akt inhibition in mUC may be warranted.
Legal entity responsible for the study
The authors.
Funding
Lucence.
Disclosure
B.A. McGregor: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: Nektar; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Calithera; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Research Grant: Seattle Genetics. M. Pek: Financial Interests, Personal, Other, Employee: Lucence. Y. Choudhury: Financial Interests, Personal, Other, Employee: Lucence. M. Tan: Financial Interests, Personal, Other, Employee: Lucence. G.P. Sonpavde: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca. All other authors have declared no conflicts of interest.