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GuardantOMNI

Intrapatient ctDNA variability over time in EGFR-mutant advanced NSCLC includes changes that may confound interpretation of treatment activity, depending on the magnitude of change used to indicate molecular response. These findings demonstrate that evaluation of on-treatment changes must account for potential background variability, including technical variability because of factors such as cfDNA input level and tumor-related VAF, and that baseline samples should be obtained as close as possible to treatment initiation to minimize the impact of background variability.

Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcome.

Our findings underscore the significant predictive value of baseline EGFR ex20ins VAF for amivantamab treatment. Furthermore, changes in ctDNA VAF during treatment emphasize the role of early ctDNA dynamics as critical predictors of therapeutic response and long-term outcomes, which may inform treatment strategies.

The study was conducted in accordance with the International Council for Harmonisation E6(R2) guidelines on good clinical practice and the principles of the Declaration of Helsinki. All patients provided written informed consent.

P3 | "Conclusions : Although the plasma analysis set remains enriched for patients with early progression, these more mature data show acquired resistance mechanisms remain similar across treatment arms. Preliminary baseline tissue analyses suggest TP53 alterations to be a prognostic factor; the benefit of osi+CTx versus osi was similar in patients with or without TP53 alterations."

Treatment with T-DXd demonstrated clinically meaningful improvement in PFS and ORR versus TPC across all biomarker subgroups analyzed, including HER2 gene expression level, BRCA1/2 or HRR gene alteration status, DDR/cell proliferation signature status, and immune status (sTILs). Table: 432P

Venadaparib in combination with irinotecan showed promising efficacy outcomes in patients with mGC, especially for those with mutations of HRD-related genes. Further development of this combination may consider a biomarker-based approach. Clinical trial information: NCT04725994.

"Guardant Health, Inc...announced it will present data from nine studies highlighting advances in methylation-based epigenomic analysis for precision oncology at the 2024 American Association for Cancer Research (AACR) Annual Meeting, April 5-10 in San Diego. Multiple poster sessions will report on the utility of using the Guardant Infinity platform across the continuum of cancer care, ranging from predictive histologic subtyping of tumors to cardiac adverse event prediction. Data will also be presented demonstrating strong performance of Guardant Reveal for minimal residual disease (MRD) detection in breast cancer, allowing quantification of ctDNA even in early-stage disease without the need for a tissue specimen."

This study provides a comprehensive longitudinal ctDNA analysis in patients with EGFR ex20ins mutant NSCLC who were treated with amivantamab. Our results suggested that the presence of ctDNA for EGFR ex20ins mutation and co-alteration with EGFR amplification at baseline might be related to the clinical outcomes of amivantamab.

In patients with HER2 negative MBC, two ADCs have FDA approval: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), both with topoisomerase-I (topo-I) inhibitor payloads. This is the first report describing emergence of TOP1 mutations under selective pressure from ADCs and the impact on mediating cross-resistance to ADC after ADC with topo-I inhibitor payloads. Novel ADCs with alternative payloads may potentially be more effective when used sequentially after an ADC with a topo-I inhibitor. Further biomarker research is needed to optimize ADC sequencing for patients with TOP1 mutant MBC.

WGD was detected in 41% of samples with greater than 10% tumor fraction in cell-free DNA across three cancer types. While this represents a substantial percentage of advanced cancers, more research needs to be done regarding the impact of these events on clinical outcomes and treatment response. Additionally, co-occurrence of these events with other advanced cancer biomarkers such as microsatellite instability or homologous recombination deficiency was not reported.

Conclusions Laro demonstrated durable responses, extended survival benefit and a favourable safety profile in pts with advanced lung cancer harbouring NTRK gene fusions. These results support the adoption of ctDNA next-generation sequencing panels that include NTRK gene fusions in clinical practice.