1762P - Utility of circulating tumor DNA (ctDNA) as a molecular biomarker in the phase II trial of imatinib plus binimetinib in patients with treatment-naïve, advanced gastrointestinal stromal tumor (GIST)

Background

The molecular landscape informs therapeutic selection in GIST. Tumor tissue-based next-generation sequencing (NGS) is the standard approach to molecularly characterize GIST. CtDNA-based NGS offers a non-invasive, molecular diagnostic approach. This study reports the results of an analysis exploring the utility of ctDNA sequencing as a molecular biomarker and adjunct to standard response assessment in the phase II trial of imatinib and binimetinib in newly diagnosed advanced GIST, including patients (pts) who started imatinib within 4 weeks (NCT01991379).

Methods

Liquid and tumor tissue samples were collected at baseline, on-treatment (rx), and at progression. DNAs extracted from plasma and tumor tissue were analyzed using comprehensive genomic assays, MSK-ACCESS and MSK-IMPACT, respectively. Sequenced ctDNA detection of the primary oncogenic driver was determined and correlated with clinical characteristics.

Results

31 out of 42 pts enrolled had ctDNA collected and were included in this analysis. Pts had KIT mutant (n=29, 94%), metastatic disease (n=24, 77%), median tumor burden at baseline of 116cm per RECIST v 1.1 and achieved a best response of partial response (n=22, 71%), stable (n=8, 26%) or progressive disease (n=1, 3%). At baseline, ctDNA detection of the primary oncogenic driver was 39% (n=12/31) and significantly more likely in pts that were rx-naïve (n=15) or had <4.2 weeks of rx (n=8) than otherwise (48% versus 13%, p-value = 0.004). Baseline ctDNA detection did not correlate with tumor burden or stage. The concordance rate between sequenced ctDNA and IMPACT detection of the primary driver mutation at baseline was 100%. Serial ctDNA analysis generally correlated with RECIST response and often conveyed rx response earlier than radiologic assessment. CtDNA detected resistance mutations in KIT.

Conclusions

In newly diagnosed advanced GIST, ctDNA detection rate of the GIST genotype was low and inversely correlated with duration of rx exposure. However, ctDNA responses proceed radiographic responses, which may be further exploited for non-invasive monitoring of rx response and emerging therapeutic resistance mutations.

Clinical trial identification

NCT01991379 Start date - November 2013 Completion date - November 2024.

Editorial acknowledgement

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Funding

Array BioPharma/Pfizer Orphan Products Grants Program/US Food and Drug Administration (R01FD005731) National Institute of Health/National Cancer Institute (Cancer Center Support Grant P30CA008748 Cycle for Survival and Geoffrey Beene Research Fund Shuman Fund GIST Cancer Research Fund GIST Cancer Awareness Fund Conquer Cancer Foundation.

Disclosure

C.M. Kelly: Financial Interests, Institutional, Principal Investigator: Servier, Amgen, Merck, Curadev Pharma; Financial Interests, Institutional, Local PI: Regeneron, Inhibrx, IDRX; Financial Interests, Personal, Full or part-time Employment, Spouse: Daiichi Sankyo Inc; Financial Interests, Personal, Stocks/Shares, spouse: Daiichi Sankyo; Financial Interests, Personal, Speaker, Consultant, Advisor: Deciphera, Exicure, Chemocentryx; Financial Interests, Personal, Advisory Board: Servier, Immunicum; Financial Interests, Personal, Steering Committee Member: Kartos; Financial Interests, Personal, Writing Engagement: PER; Financial Interests, Personal, Invited Speaker: More Health. S.P. D'Angelo: Financial Interests, Personal, Speaker, Consultant, Advisor: EMD Serono, Amgen, Nektar, Immune Design, GSK, Incyte, Merck, Adaptimmune, Immunocore; Financial Interests, Institutional, Research Funding: EMD Serono, Amgen, Merck, Nektar, BMS, Deciphera; Financial Interests, Personal, Advisory Board: Adaptimmune. M. Dickson: Financial Interests, Institutional, Research Funding: Eli Lilly, Aadi; Financial Interests, Personal, Speaker, Consultant, Advisor: Celgene. M. Gounder: Financial Interests, Personal, Other, Honarium: Flatiron Health, Guidepoint GLobal, Touch IME, Med learning group, More Health; Financial Interests, Personal, Writing Engagement: PER, Medscape; Financial Interests, Personal, Speaker, Consultant, Advisor: Daiichi Sankyo Inc, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutic, Boeringer Ingelheim, TYME, Ayala; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Other, Patent/Royalties/Intellectual property: UpToDate, GODDESS PRO Desmoid Tumor (Inst); Financial Interests, Personal, Other, Travel reimbursement: Epizyme; Financial Interests, Personal, Non remunerated activity: Foundation Medicine, Athenex, Rain Therapeutics. S. Movva: Financial Interests, Personal, Speaker, Consultant, Advisor: Genmab; Financial Interests, Institutional, Research Funding: Hutchinson Medipharma. E. Rosenbaum: Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, PMV Pharmaceuticals; Financial Interests, Institutional, Local PI: Incyte Corporation, Arcus Biosciences, GSK. E.K. Bartlett: Financial Interests, Institutional, Local PI: SkylineDx; Financial Interests, Institutional, Coordinating PI: Qbiotics Group Inc. A. Crago: Financial Interests, Personal, Stocks/Shares: Gilead Sciences; Financial Interests, Personal, Writing Engagement: Wolters Kluwer, WebMD; Financial Interests, Personal, Speaker, Consultant, Advisor: Springworks Therapeutics; Financial Interests, Personal, Other: Patent - assigned to MSKCC. M. Berger: Financial Interests, Personal, Speaker, Consultant, Advisor: Lilly, PETDx; Financial Interests, Institutional, Research Funding: Grail; Financial Interests, Personal, Other: Systems and Methods for Detecting Cancer via cfDNA Screening. L. Qin: Financial Interests, Personal, Full or part-time Employment: Viela Bio, Sironex; Financial Interests, Personal, Stocks/Shares: Viela Bio, Sironax; Financial Interests, Personal, Leadership Role: Viela Bio, Sironax. 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, Speaker, Consultant, Advisor: EMD Serono, Lilly, Daiichi Sankyo Inc, Deciphera, C4 therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceuticals, Servier, Bayer, Epizyme, Cogent, Medpacto, Foghorn Therapeutics, Amgen; Financial Interests, Institutional, Research Funding: Novartis, Lilly, Daiichi Sankyo Inc, Tracon, Blueprint medicines, immunedesign, Bioatla, Deciphera; Financial Interests, Institutional, Research Funding, Daiichi Sankyo Inc: Plexxikon; 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. P. Chi: Financial Interests, Institutional, Research Funding: Deciphera, Pfizer; Financial Interests, Personal, Stocks or ownership: ORIC pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: Depheria, Merck, Exelixis; Financial Interests, Personal, Royalties: ORIC pharmaceuticals. All other authors have declared no conflicts of interest.