PO.BCS01.11 · 生物信息与计算

Clinical utility of landmark ctDNA molecular response as an early indicator of immunotherapy outcomes in lung cancer

编号 110 展板 17 时间 4/19 02:00–05:00 区域 Section 5 主讲 Jaime Wehr, MS

分会场 Liquid Biopsy: Multi-Analyte and Multi-Omic

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作者与单位

Jaime Wehr¹, Noushin Niknafs¹, Lavanya Sivapalan¹, Archana Balan¹, Gavin Pereira¹, Samira Hosseini-Nami¹, Iiasha Beadles¹, Aliyah Pabani¹, Kristen Marrone¹, Qing K. Li¹, Joseph Christopher Murray¹, Mark Sausen², Bryan Chesnick³, Lorenzo Rinaldi³, Christine L. Hann¹, Susan Combs Scott¹, Josephine Feliciano¹, Vincent K. Lam¹, Benjamin Levy¹, Patrick M. Forde¹, Julie R. Brahmer¹, Valsamo (Elsa) Anagnostou¹

¹Johns Hopkins University, Baltimore, MD,²LabCorp, Baltimore, MD,³Delfi Diagnostics, Inc., Baltimore, MD

摘要 Abstract

Background: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC), however the clinical role of ctDNA molecular response requires further validation. Methods: As part of a prospective clinical protocol (NCT05995821), we performed ctDNA (n=328) and matched white blood cell DNA (WBC; n=109) targeted 521 fixed gene panel next-generation sequencing (Elio Plasma Complete) from 109 patients with advanced/metastatic NSCLC who received anti-PD-(L)1 as monotherapy or in combination with chemotherapy. Following variant cellular origin resolution, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. For a subset of patients (n=34), whole-exome sequencing of baseline tumors was performed and used in benchmarking ctDNA detection and therapy response assessment. Results: Among 2,818 plasma variants, 23% were clonal haematopoiesis-related, which confounded the interpretation of driver gene associations with clinical outcomes and assessment of molecular responses. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases while maintaining the overall accuracy of landmark ctDNA molecular responses. Pre-treatment ctDNA burden but not blood tumor mutation burden, predicted survival. Overall, 77 patients were evaluable for landmark molecular response assessment; of these, 29 patients (38%) attained a mR. Landmark evaluation of molecular response enabled evaluation of all cases, was highly specific (92%), and achieved a higher sensitivity (66%) compared to clearance or ctDNA reduction from baseline (sensitivity 59%). In predicting landmark progression-free survival (PFS) at 6 months (durable clinical benefit, DCB), the tumor-agnostic WBC-informed approach strikes a balance between sensitivity (71.4%) and specificity (100%) compared to plasma-only (sensitivity=14.3%, specificity=100%) or tumor-informed (sensitivity=78.6%, specificity=71.4%) approaches. A significant enrichment in landmark ctDNA mR was noted among patients with DCB with immunotherapy (p=2.5e-05) and chemo-immunotherapy (p=0.02). Patients in the landmark mR group attained longer PFS (p=1.6e-06) and overall survival (p=2.5e-05) compared to those with molecular progression. The association between landmark molecular response and survival remained significant (PFS and OS, P < 0.001) after accounting for clinical covariates, line of therapy, and baseline ctDNA levels. Conclusions: Our findings indicate that landmark ctDNA molecular response at 3-9 weeks on treatment provides a real-time and accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential utility of ctDNA as an early endpoint in clinical trials.

利益披露 Disclosure

J. Wehr, None.. N. Niknafs, None. L. Sivapalan, ANGLE Employment. A. Balan, None.. G. Pereira, None.. S. Hosseini-Nami, None.. I. Beadles, None. A. Pabani, BMS ). ACF Pharmaceuticals ). Canadian Agency for Drugs and Technologies in Health Other, Personal Fees. AstraZeneca Other, Personal Fees. F. Hoffman-La Roche AG Other, Personal Fees. Merck & Co inc Other, Personal Fees. Pfizer Other, Personal Fees. K. Marrone, AstraZeneca Other, Consultant,Honoraria. Amgen Other, Consultant. Puma Biotechnology Other, Consultant. Jannsen Other, Consultant. Mirati Therapeutics ), Other, Consultant. Daiichi Sankyo/Lilly Other, Consultant. Bristol Myers Squibb ). Q. K. Li, None. J. C. Murray, AstraZeneca Other, Consultant. Johnson & Johnson Other, Consultant. NIH/NCI ). Merck ). CDC ). Maryland Cigarette Restitution Fund ). Curio Science Other, Honoraria. Caris Life Sciences Other, Honoraria. ION Oncology Practice Network Other, Honoraria. Nebraska Oncology Society Other, Honoraria. PRIME Other, Honoraria. iTeos Therapeytics Other, Advisory board. Doximity Stock Option. M. Sausen, LabCorp Employment, Stock. B. Chesnick, Delfi Diagnostics, Inc. Employment, Stock. L. Rinaldi, Delfi Diagnostics, Inc. Employment, Stock. C. L. Hann, AstraZeneca ), Other, Consultant. Daiichi Sankyo Europe GmbH ), Other, Consultant. Genentech Other, Consultant. Amgen ). S. C. Scott, AstraZeneca ), Other, Consultant. Johnson & Johnson ), Other, Consultant. Black Diamond ). Nuvalent ). EMD Serono Other, Consultant. Daiichi Sankyo Other, Consultant. Merus Other, Consultant. Genentech/Roche Other, Consultant. J. Feliciano, Astra Zeneca ), Other, Consultant. Takeda Other, Consultant. Pfizer ). Bristol-Myers Squibb ). Regeneron Other, Consultant. Coherus Other, Consultant. Eli Lilly Other, Consultant. Genentech Other, Consultant. Janssen Other, Consultant. Daiichi Sankyo Other, Consultant. V. K. Lam, Anheart Therapeutics Other, Consultant. Takeda Other, Consultant. Seattle Genetics ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. AstraZeneca ), Other, Consultant. Guardant Health Other, Consultant. GlaxoSmithKline ). Merck ). Lovance Biotherapeutics Other, Consultant. B. Levy, AstraZenca Other, Personal Fees. Novartis Other, Personal Fees. Eli Lilly Other, Personal Fees. Genentech Other, Personal Fees. Pfizer Other, Personal Fees. Guardant 360 Other, Personal Fees. Takeda Other, Personal Fees. BMS Other, Personal Fees. Novocure Other, Personal Fees. Janssen Other, Personal Fees. Daiichi Sankyo Other, Personal Fees. Merck Other, Personal Fees. P. M. Forde, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Novartis ), Other, Consultant. Regeneron ), Other, Consultant. Curevac Other, Consultant. BioNTech ), Other, Consultant. G1 Other, Consultant. Genelux Other, Consultant. Ascendis Other, Consultant. Genentech Other, Consultant. Gritstone Other, Consultant. F-Star Other, Consultant. Merck Other, Consultant. Janssen Other, Consultant. Sanofi Other, Consultant. Amgen Other, Consultant. Tavotek Other, Consultant. Teva Other, Consultant. Fosun,Synthekine,Flame,Iteos Other, Consultant. Polaris Other, DSMB. J. R. Brahmer, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ). RAPT Therapeutics Other, Consultant. Mestag Other, Consultant. GlaxoSmithKline Other, Consultant. Amgen Other, Consultant. Sanofi Aventis Other, Consultant. Summit Therapeutics Other, Consultant. Genentech Other, Consultant. Bayer Other, consultant. Genmab Other, Data Safety and Monitoring Board. V. Anagnostou, Astra Zeneca g., Board of Directors, non-salaried role), ). Bristol-Myers Squibb ). Personal Genome Diagnostics/Labcorp ). Delfi Diagnostics ). Neogenomics g., Board of Directors, non-salaried role). Foundation Medicine Other, Honoraria. Personal Genome Diagnostics Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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