1764P - Role of PIK3CA as a predictive biomarker in metastatic, imatinib-resistant GIST: A ct-DNA substudy of the VOYAGER trial

Background

The VOYAGER-trial compared avapritinib (ava) with regorafenib (rego) in patients (pts) with advanced gastrointestinal stromal tumors (GIST) in a 3^rd-line setting. Liquid biopsies at baseline identified clonal composition of secondary KIT mutations as predictive markers of avapritinib activity. We sought to investigate prevalence and potential clinical relevance of pathogenic mutations in KIT-dependent signaling intermediates as determined by circulating tumor (ct) DNA.

Methods

KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline was assessed using the 74-gene Guardant360® assay. Genomic variants were functionally validated using Cas9-based gene editing in GIST-T1 cells and pathogenic variants were correlated with clinical data.

Results

386/476 pts with KIT/PDGFRA-mutant tumors underwent baseline ctDNA analysis (ava: n=196; rego: n=190). PIK3CA represented the most frequently mutated gene within KIT-downstream signaling pathways found in 18/386 pts. Variants included 12 known gain-of-function mutations (mAF: 11.5%) and 6 VUS (mAF: 7.4%). Expression of activating variants conferred imatinib-resistance in vitro. Notably, secondary KIT mutations were frequently found in samples harboring pathogenic PIK3CA variants (9/12). Clinical data was available in 9/18 pts. Of those, only 1 pt with a PIK3CA H1047L variant (AF: 21.9%) showed immediate progression on ava but this pt was also found to have concurrent KIT T670I and A829P secondary mutations (AF: 7.4% and 6.4%). The time to progression in individual pts with a PIK3CA mutation who received ava was 1.6, 11 and 14.6 months (mo) and 6.3, 7.1, 9.7, 11.2, and 15.5 mo for those treated with rego. One pt discontinued treatment with rego after 5.6 mo due to an adverse event.

Conclusions

In a 3^rd-line setting, pathogenic PIK3CA mutations represent the most common genomic event in an oncogenic KIT signaling intermediate but were found in only 4.7% of pts using ctDNA sequencing. The presence of PIK3CA mutations in plasma did not preclude prolonged disease control to ava or rego. Limitations of this analysis are the small sample size and the possibility of clonal hematopoiesis of indeterminate potential (CHIP) as PIK3CA mutations were not confirmed in tumor samples.

Clinical trial identification

NCT03465722 Other Study ID: BLU-285-1303.

Editorial acknowledgement

Legal entity responsible for the study

Blueprint Medicines.

Funding

Bluprint Medicines.

Disclosure

J.C. Trent: Financial Interests, Personal, Advisory Role: Novartis, Lilly, Janssen, Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer. K. Newberry: Financial Interests, Personal, Stocks or ownership: Blueprint Medicines; Financial Interests, Personal, Other, Employment: Blueprint Medicines. A. Grassian: Financial Interests, Personal, Stocks or ownership: Blueprint Medicines. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche, Liscure. P. Rutkowski: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, Merck; Financial Interests, Personal, Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Lilly; Financial Interests, Personal, Research Funding: Novartis, Roche, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel: Orphan Europe, Pierre Fabre. R.L. Jones: Financial Interests, Personal, Advisory Board, I worked as a consultant.: Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Lilly, Springworks, Tracon, Upto Date, PharmaMar, Astex, Immunicum, Karma Oncology, Merck, Mundipharma, Synox; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial.: MSD. M. Heinrich: Financial Interests, Personal, Stocks or ownership: MolecularMD; Financial Interests, Personal, Other, Honoraria: Novartis. W.D. Tap: Financial Interests, Personal, Leadership Role: Certis Oncology Solutions, Atropos, Innova Therapeutics; Financial Interests, Personal, Stocks or ownership: Certis Oncology Solutions, Atropos; Financial Interests, Personal, Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Blueprint Medicines, Agios, NanoCarrier, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, AbMaxBio; Financial Interests, Personal, Research Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, Deciphera; Financial Interests, Personal, Other, Patents: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition—SKI2016-021-03. M. von Mehren: Financial Interests, Personal, Advisory Role: Deciphera, Exelixis; Financial Interests, Personal, Research Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCO; Financial Interests, Personal, Other, Travel: Deciphera Pharmaceuticals, NCCN. S. George: Financial Interests, Personal, Stocks or ownership: Abbott Laboratories; Financial Interests, Personal, Advisory Role: Blueprint Medicines, Deciphera, Bayer, Lilly, UpToDate, Research to Practice, MORE Health, Daiichi Sankyo, Kayothera; Financial Interests, Personal, Research Funding: Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks Therapeutics; Financial Interests, Personal, Other, Patents: UptoDate; Financial Interests, Personal, Expert Testimony: Bayer; Financial Interests, Personal, Other, Other Relationship: Research to Practice, WCG. O. Mir: Financial Interests, Personal, Full or part-time Employment, Amgen employee since Feb 1st, 2022: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen, Astra Zeneca. S. Bauer: Financial Interests, Personal, Other, Honoraria: Novartis, Pfizer, Bayer, Pharmaka, GSK; Financial Interests, Personal, Advisory Role: Blueprint Medicine, Bayer, Lilly, Deciphera, Nanobiotix, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GSK; Financial Interests, Personal, Research Funding: Blueprint Medicines, Novartis, Incyte. All other authors have declared no conflicts of interest.