TEST:

GuardantOMNI

"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.

P1b | "Venadaparib in combination with irinotecan showed synergistic effect in vitro assays and promising clinical efficacy in the systemic treatment of refractory GC, particularly in patients with HRD. The dose expansion phase of the study is ongoing to investigate the optimal biological dose and patient selection strategies, in a randomized design. Clinical trial information: NCT04725994."

"Guardant Health, Inc...will present data showing the utility of liquid biopsy tests in the management of breast cancer patients at the San Antonio Breast Cancer Symposium, December 5-9 in San Antonio, Texas. Highlights of the eight poster presentations include the use of blood-based testing to identify actionable biomarkers and predict therapy response in advanced breast cancer, and to detect residual disease and predict recurrence in patients with early-stage breast cancer."

'Clearance' of ctDNA to become undetectable at C2D1 identified sporadic TNBC patients who benefited from olaparib and ceralasertib. Although 'clearance' of ctDNA was associated with good outcome on olaparib plus ceralasertib, median CDR was not predictive of treatment benefit. This contrasts the results of ctDNA dynamic assessment of cohort A-D, where median CDR was highly predictive of treatment benefit.

Methods Pts with treatment-naïve, EGFRm advanced NSCLC received osi + CT (osi 80 mg once daily [QD] + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5 every 3 weeks [Q3W] for 4 cycles, followed by osi 80 mg QD + pemetrexed 500 mg/m2 Q3W) or osi monotherapy (80 mg QD) until PD/discontinuation criterion. Osi + CT resulted in similar resistance mechanisms to osi monotherapy, and should not impact subsequent targeted second-line tx options. This analysis was enriched with pts who had early progression; further follow-up is required.

Updated results will be presented (data cutoff, December 2021). Table: 151P Efficacy according to mutation status

Detection of HER2 amplification in plasma was accurate, as indicated by the low rate of false positives; however, sensitivity was poor. This suggests that ctDNA testing may help identify pts with HER2 amplification but is not yet a substitute for tissue-based HER2 ISH and IHC testing.

Conclusions Neoadjuvant D+GemCis resulted in a higher surgical resection rate in pts with localized BTC, and surgical resection was associated with better survival. ctDNA analysis was shown to be a feasible method for assessing actionable target gene alterations in early BTC.

In this exploratory analysis, patients with co-occurring ATMm and ASXL1m showed higher tumor response. This signals potential value from ATM and ASXL1 co-mutation predicting efficacy of Venadaparib in PC and warrants further validation. Clinical trial information: NCT04174716.

ctDNA analysis from plasma samples supported MR assessment in patients treated with ICI, indicating its utility as an adjunct to RECIST in monitoring of tumor response. Blood-based TMB-high was associated with immunotherapy treatment benefit. Analysis of b-TMB and MR allowed identification of patients with improved PFS in both treatment arms.

Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029. >aIncluded only pts with prior CDK4/6i and ≥1 gene alternation (CCND1, CCNE1, CDK6, FGFR1/2 amplification; RB1, PTEN, RAS, AKT1, ERBB2, FAT1 mutation).

In this analysis, we demonstrate that a probabilistic model of genomic and methylation predictors can detect HRD status in patients with breast cancer from cfDNA using GuardantINFINITY. Additional analytical and clinical studies to further evaluate this model are ongoing. With HRD prediction, GuardantINFINITY provides a comprehensive minimally-invasive solution for PARPi and DNA damage treatment selection, longitudinal monitoring, and an exploratory platform for investigating epigenetic signals that may underpin resistance.

Materials and SAR'245 was given IV as monotherapy Q2W [Cohort A], monotherapy Q3W [Cohort B] or Q3W + IV pembrolizumab 200 mg Q3W/400 mg Q6W [Cohort C] and Q3W + Cetuximab [Cohort D]. In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR'245 that further explore the dosing and scheduling are on-going.

CheckMate 9KD (NCT03338790) was a nonrandomized, open-label, multicohort, phase 2 trial of nivolumab combined with rucaparib, docetaxel, or enzalutamide for mCRPC, which showed encouraging clinical activity for the nivolumab plus docetaxel combination. This investigation highlights the utility of liquid biopsy for evaluating tumor genomic alterations in late-stage mCRPC trials and provides translational insights into potential resistance mechanisms to inform patient selection and combination strategies for future clinical development.

A high proportion of tumors with locally identified NTRK gene fusions were confirmed centrally. At present, analysis of ctDNA is significantly less sensitive at detecting NTRK gene fusions. A negative ctDNA result requires next-generation sequencing testing of a tissue biopsy.

We present a plasma-only method that has high PPA and PPV with WBC genotyping for classifying non-tumor, CH variants in the cfDNA. Further investigation is underway to improve the sensitivity of annotating rare CH variants. Accurate CH identification is critical for treatment selection across targeted therapies, particularly for loss of function variants in DNA repair genes that may confer sensitivity to PARPi or ATRi therapies.

In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR’245 that further explore the dosing and scheduling are on-going.

In pts with mNSCLC, treatment with a limited course of T plus D (until progression) and four cycles of CT consistently improved clinical outcomes vs CT alone in both bTMB high and low subgroups, supporting the use of this regimen as a 1L treatment option for pts with mNSCLC. The clinical benefit vs CT appeared to be greater in pts with higher bTMB over a range of cutoffs, consistent with expectations based on mechanistic biology and previous clinical data.

Conclusions Larotrectinib demonstrated durable responses, extended survival benefit, and a favourable safety profile in patients with advanced lung cancer harbouring NTRK gene fusions, including those with treatment-naive NSCLC or with prior EGFR inhibitor therapy. ctDNA next-generation sequencing represents a promising technology to test NTRK gene fusions or resistance mutations.

P3; Trial completion date: Dec 2022 --> Dec 2023

Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Multivariate analysis further showed that high pTMB was an independent predictive biomarker for both PFS [hazard ratio (HR) = 0.44, 95% confidence interval (CI): 0.22-0.88, p = 0.02] and OS (HR = 0.37, 95% CI: 0.18-0.76, p = 0.007). High pTMB (⩾19 mut/Mb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents.

Acquired reversion mutations were infrequent but associated with worse outcomes. Other causes of resistance may be dominant. Detection of KRAS mutation in the peripheral blood may be associated with disease burden and clinical outcome.

We report analyses of ctDNA in pts with mNSCLC treated with 1L durvalumab (D), D + tremelimumab (T), or CT in the phase 3 MYSTIC trial. Results indicate that BL ctDNA level is prognostic in 1L mNSCLC; further, MR is predictive of clinical benefit with IO but not CT. On-treatment ctDNA dynamics may have important predictive value for long-term outcomes with IO, complementing radiologic assessment and enabling early decision-making. Funding: AstraZeneca

A bioinformatic filtration step was required to account for low VAF artefact variants. We demonstrate the feasibility and challenges of producing and using bTMB reference standards across a range of bTMB levels, and how such standards could support the calibration and validation of bTMB platforms and help harmonization between panels and laboratories.

Conclusions In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC. Exploratory analyses suggest that tumor inflammation, measured by 4-gene inflammatory gene signature score, may increase with NIVO + IPI treatment.

"Guardant Health, Inc...announced today that new data from its portfolio of blood tests will be presented at the 2022 European Society for Medical Oncology (ESMO) Congress, September 9-13 in Paris, France. Among the seven abstracts are an oral presentation and posters highlighting the use of Guardant Health’s blood tests and real-world evidence dataset to advance cancer therapy trials, predict and monitor patient response to therapy, and identify genomic mechanisms of acquired resistance to cancer therapy."

Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

"Guardant Health, Inc...announced today that studies utilizing its portfolio of blood tests and real-world data will be presented at the IASLC 2022 World Conference on Lung Cancer (WCLC 2022), hosted by the International Association for the Study of Lung Cancer, August 6-9 in Vienna, Austria. Among the 10 abstracts are oral presentations and posters highlighting the use of Guardant360™ to help physicians inform treatment decisions, GuardantOMNI™ to advance cancer therapy trials, and GuardantINFORM™ for targeted drug development to improve outcomes for patients with lung cancer....'The data from retrospective and real-world analyses will show how blood-based tests provide critical insights into tumor evolution and treatment resistance throughout each lung cancer patient’s treatment journey and contribute more broadly to further developing the field of thoracic oncology'."

Methods Fifty-two plasma samples were obtained from 21 pts treated with 1L avelumab, cetuximab, gemcitabine, and cisplatin for 4 x 3-week cycles followed by avelumab and cetuximab maintenance. Z. Feng are acknowledged as first authors and equal contributors to this abstract.

Background In the randomized phase III BEACON study (NCT02928224), encorafenib + cetuximab ± binimetinib regimens improved overall survival and objective response rate vs standard of care (control) in pts with previously treated BRAF V600E-mt mCRC. Conclusions ctDNA analyses revealed that MAPK pathway reactivation is a common mechanism of resistance for BRAF V600E-mt mCRC following inhibition of BRAF and EGFR ± MEK inhibition. Acquired mutations in RAS-MEK signaling were more prevalent in the doublet arm, while enhanced receptor signaling was more prevalent in the triplet arm.

"Guardant Health, Inc...and Adicon Holdings Limited...announced a strategic partnership to offer Guardant Health's comprehensive genomic profiling (CGP) tests to biopharmaceutical companies conducting clinical trials in China...As part of the relationship, Guardant Health will license to Adicon its industry-leading liquid biopsy technology, including the Guardant360® and GuardantOMNITM tests, and the Guardant360 TissueNextTM tissue-based biopsy for patients with any solid cancerous tumor."

P3; Trial completion date: Oct 2021 --> Dec 2022

"Guardant Health, Inc...announced today it will present new data at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting from June 3-7 in Chicago. Among the 19 abstracts are oral presentations highlighting the use of real-world data to identify resistance to early treatment in advanced breast cancer and the use of enhanced biomarker analysis to evaluate progression-free survival data in metastatic breast cancer therapy."

Updated analysis of the FAKTION trial data show a significant improvement in OS in the ITT population. Enhanced subgroup analysis suggests that the benefit of capivasertib in both PFS and OS may be predominantly in patients with PIK3CA/AKT1/PTEN pathway altered tumours, but further elucidation will be forthcoming from the ongoing Phase 3 CAPItello-291 study in which participants with PA and PNA tumours have been recruited.

We demonstrate that ctDNA analysis of plasma samples taken at early timepoints (4-10 weeks) after treatment initiation are sufficient to support MR assessments and highlight the advantage of the patient-centric liquid biopsy approach over genetic testing of diagnostic tumor samples in detecting potential resistance mutations prior to therapy.

The results provide proof of principle that estimation of GuardantOMNI bTMB score precision via an intuitive and interpretable simulation model is viable. The simulation results were consistent with empirical data and general expectations regarding the precision of the bTMB scores.

Background: In the randomized, two-part, phase 3 COLUMBUS study (NCT01909453), encorafenib (enco) + binimetinib (bini) and enco alone improved 5-year progression-free survival (PFS) and overall survival (OS) vs vemurafenib (vem) in patients (pts) with advanced BRAF V600E/K-mutant melanoma. These exploratory analyses of Part 1 of the COLUMBUS study suggested that treatment with enco + bini significantly reduced BRAF V600 VAF, which was prognostic for PFS and OS at both baseline and C2D1. ctDNA provides a powerful tool for understanding the molecular basis for response and resistance to treatment and may impact future treatment decisions.

Taken together, these data suggest that alterations in PTEN and MTOR, two key genes of the PI3K signaling pathway, are potential biomarkers for sensitivity to onvansertib/abi combination in mCRPC patients with early abi-resistance. Preclinical studies are underway to assess the activity of onvansertib/abi in combination with PI3K-pathway inhibitors.