TEST:

Guardant360® CDx

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts. Previously presented at the 2024 ESMO Sarcoma and Rare Cancers Congress.

This study is one of the largest cohorts of ctDNA currently reported in EC. The presence of TP53 mutation and other co-mutations detected by ctDNA have a negative effect on outcomes. This report suggests that ctDNA analysis is feasible and could become a useful biomarker for EC.

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was favorable for pts with KIT exon 11 + 17/18 mutations in the ripretinib arm.

P3; Active, not recruiting --> Completed

Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.

Overall, our findings provide insight into the genomic landscape of individuals with advanced solid organ malignancies from the MENA region and support the role of ctDNA in guiding therapeutic decisions.

P2; Trial completion date: May 2029 --> Sep 2024 | Trial primary completion date: May 2025 --> Sep 2024

P=NA | N=7,000 | GOZILA (UMIN000029315) | "Guardant Health, Inc...announced the peer-reviewed journal Nature Medicine published results from the SCRUM-Japan GOZILA study confirming that selecting targeted therapy on the basis of Guardant360 CDx liquid biopsy results may significantly extend survival for patients with advanced cancer....The results showed that 24% of participants were able to receive targeted treatment tailored to them based on comprehensive genomic profiling results from the test, which analyzes 74 cancer-related genes. The patients who received targeted treatment guided by liquid biopsy results lived approximately twice as long as those who did not....Patients who received targeted therapy had a median survival of 18.6 months compared to 9.9 months for those who did not."

"Guardant Health, Inc...announced the company and its research collaborators will present data from several studies utilizing Guardant technology to advance precision oncology at the European Society for Medical Oncology Congress (ESMO) in Barcelona, Spain, Sept. 13-17, 2024."

"Guardant Health, Inc...announced a partnership with the Agostino Gemelli University Polyclinic Foundation IRCCS ('Policlinico Gemelli') to establish an in-house liquid biopsy testing service as a part of its diagnostics services within its hospital system. Leveraging Guardant Health’s cutting-edge proprietary digital sequencing platform, this initiative will include on-site analysis of Guardant360 ® CDx liquid biopsy tests directly within the Policlinico Gemelli facilities in Rome, Italy."

The differential effect of treatment by smoking was not explained by TP53 mutation or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected but no novel molecular alterations were identified in the combination arm.

Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

"Guardant Health Japan Corp...announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has approved Guardant360® CDx as a companion diagnostic to identify EGFR exon 20 insertion mutations in patients with inoperable or recurrent non-small cell lung cancer (NSCLC) for consideration of treatment with amivantamab-vmjw combined with chemotherapy. This approval makes the Guardant360 CDx comprehensive genomic profiling panel the first blood-based companion diagnostic to be approved in Japan for the detection of EGFR exon 20 insertion mutations."

Further research and awareness is necessary to highlight the different types of ampullary cancer given the significant clinical implications. Figure: Image 1: (A) Endoscopic imaging of ampullary mass (B) EUS depicting ampullary mass

The AEGEAN trial suggested that patients with stages II to IIIB resectable NSCLC be treated with neoadjuvant chemotherapy before surgery, followed by adjuvant durvalumab, which significantly extends event-free survival... In light of evolving advancements in tumor marker identification and targeted therapies, there is a paradigm shift in the management of lung malignancies. Given the substantial burden associated with advanced lung cancer, further research is imperative to delineate optimal treatment strategies for patients undergoing curative surgery. The question of whether neoadjuvant therapy should be standard practice for all lung cancer patients versus patients with limited-stage metastasis to the mediastinal lymph node, as suggested by the AEGEAN trial, remains open and warrants rigorous investigation.

P2; N=30 --> 0 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2024 --> May 2025

We previously reported that an early decrease in ctDNA from the baseline (BL) in ES-SCLC patients treated with nivolumab and temozolomide (N+T) was associated with improved PFS (NCT03728361). These data suggest the potential utility of BL and early on-treatment assessment of ctDNA and methyl-TF in predicting treatment response. additional trials should continue to explore these patterns, which can provide valuable insights into the clinical utility of these assays.

Conclusions : This pilot study using a unique cohort of EGFR ex20+ NSCLC patients treated with high dose Osimertinib highlights the complexity of variant dynamics during treatment and disease progression, suggesting a potential link between changed levels of variants detected at progression. Potential resistance mechanisms were shown in 11/18 patients using ctDNA.

These data support the updated guideline language and demonstrate that concurrent testing captures the greatest number of on-label alterations with faster time to results, which is especially important given risk of tissue QNS. Additionally, there are other alterations detected by these assays that provide prognostic information and opportunities to enroll patients in clinical trials that may expand actionability of test results.

Our findings highlight the potential role for utilizing ctDNA VAF as a prognostic biomarker. Further studies are needed to assess the benefit of integrating analysis of ctDNA VAF into clinical practice to better predict patient outcomes and tailor treatment plans.

Notably, individuals with exclusive reciprocal rearrangements of RET or ROS1 might be less prone to co-mutations in TP53, ATM, and ARID1A, than are those with detectable activating rearrangements. This emphasizes the significance of evaluating co-mutations in DNA repair genes alongside fusions to refine treatment approaches.

This suggests that ctDNA shedding might be associated with some underlying tumor biology, reflective of a more aggressive phenotype. Given the small sample size, validation using a larger cohort should be performed.

As liquid biopsy becomes more integrated into clinical practice, its potential for providing prognostic insights and enabling a more tailored therapeutic approach may become increasingly evident. Our findings highlight the potential role of total VAF in ctDNA as a predictive biomarker for ICI therapy outcomes in patients with NSCLC.

Conclusions : To our knowledge, this is the largest liquid biopsy analysis comparing common/uncommon ex19dels in NSCLC and shows similar genomic findings across groups. Further work should be done to explore additional genomic and non-genomic factors to aid in patient selection for EGFR TKIs for uncommon findings.

In PAPILLON (NCT04538664), amivantamab plus carboplatin-pemetrexed (amivantamab-chemotherapy) demonstrated significantly longer progression-free survival (PFS) versus chemotherapy (hazard ratio [HR], 0.395 [95% confidence interval [CI], 0.30-0.53]; P <0.0001). Consistent benefit favoring amivantamab-chemotherapy was seen across all Ex20ins sites. Amivantamab-chemotherapy is the first-line, standard of care for Ex20ins advanced NSCLC.

"Guardant Health, Inc...announced the launch of a major upgrade to its market-leading Guardant360 liquid biopsy test. The new enhanced test evaluates biomarkers in 739 genes in total, which is 10 times more cancer biomarkers than the previous version of Guardant360 evaluated....The updated Guardant360 test is covered for Medicare fee-for-service patients with advanced solid tumor cancers as a standalone service, based on coverage conveyed by Palmetto GBA, a Medicare administrative contractor for the Molecular Diagnostics Services program (MolDX), under the existing local coverage determination. The test is also covered by all major insurers, representing over 300 million covered lives."

Background: The VOYAGER-trial compared avapritinib (ava) with regorafenib (rego) in patients (pts) with advanced gastrointestinal stromal tumors (GIST) in a 3rd-line setting. In a 3rd-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.

53.0% and 36.8% had previously received both abiraterone and enzalutamide, and 69.7% and 64.7% had received cabazitaxel in patients with and without AR-LBD mutation respectively. Administration of Opevesostat to heavily pre-treated mCRPC patients shows promising antitumor activity. PSA50 responses were most frequent among patients harbouring activating AR-LBD mutations.

Acquired MoR was identified in 45% of liquid biopsies in the largest prospective dataset studying MoR to RET inhibition. On-target MoR including RET SF G810 muts were more common in MTC than NSCLC. Bypass MoR (30%) included RAS/RAF activating and potentially targetable MET amps.

Background: We previously reported that intratumoral HER2 heterogeneity was associated with limited treatment efficacy to trastuzumab-based chemotherapy for HER2 positive advanced gastric cancer (AGC)... Intra-tumor HER2 heterogeneity, classified to homogenous or heterogenous, may be a useful biomarker associated with distinct tumor biology to predict the clinical efficacy of anti-HER2 and anti- PD-1 dual targeted therapy in patients with HER2 positive AGC.

Considering the recent approval of capivasertib for HR+/HER2- metastatic breast cancer (MBC) harboring PI3K-AKT pathway alts based on tissue NGS, we assessed the concordance of tissue and ctDNA NGS for PIK3CA, AKT1, PTEN as well as ESR1. We identified 367 HR+/HER2- MBC pts treated at MSK with tissue NGS by MSK-IMPACT within 60 days of ctDNA NGS by either Guardant360 or MSK-ACCESS, without intervening therapy... Tissue-ctDNA concordance for the detection of any oncogenic alteration was high for PIK3CA, AKT1, moderate for ESR1, and low for PTEN. More alts were detected in ctDNA for ESR1 and in tissue for PTEN, reflecting acquired ESR1 alts after estrogen deprivation and the current lack of ctDNA assay PTEN copy number loss detection. Additional correlative analyses (e.g.

Although preliminary, integration of diverse circulating biomarkers showed the potential to refine prognosis, inform clinical decisions, and deepen our understanding of the biology of the IBC subtype.

This study underscores the potential of ctDNA as a predictive and prognostic biomarker for patients with HER2-mutated advanced-stage solid tumors treated with neratinib and trastuzumab. The presence of HER2 mutations in ctDNA generally matched those in tumor tissues, and elevated ctDNA fractions were linked to poorer outcomes. Further research is necessary to validate the role of ctDNA in optimizing anti-HER2 therapy for HER2-mutated tumors.

We present data from the exploratory ctDNA analysis of the study. ctDNA samples were collected at baseline (cycle 1, day 1 [C1D1]), C1D15 and end-of-treatment (EOT) in patients (pts) with HR+/HER2− mBC treated with oral 300 or 400 mg BID PF-07220060, with fulvestrant (Part 1B, n=18) or letrozole (Part 1C, n=15) and analyzed with the Guardant360 platform (Guardant Health). Longitudinal ctDNA profiling enabled the identification of key genetic alterations and demonstrated that PF-07220060 plus ET may benefit pts with or without ESR1 and PI3K pathway mutations. Early ctDNA MR trended with favorable clinical outcomes, while pts with undetectable ctDNA on treatment had improved PFS.

Initially, she received three cycles of Nabpaclitaxel and carboplatin and upon progression plasma ctDNA NGS was ordered and reported EML4-ALK fusion (0.7% VAF) in Nov 2022 resulting in treatment with alectinib. ctDNA CGP can provide genotyping at fast TAT for effective management of aBC. Fusions, though rare in aBC, should be considered for detection for targeted therapy.

Our study provides an example of successful implementation of ctDNA molecular profiling in an academic pre-screening program, facilitating the non-invasive identification of AA that positively impact on GMT access and tumor response.

Ami+laz had significantly lower rates of EGFR and MET resistance alterations with trends for lower rates of TP53 resistance mutations and RB1 loss compared with osi. These initial findings suggest that first-line ami+laz is changing the biology of acquired resistance and demonstrate clear proof of mechanism with potent inhibition of resistance via the EGFR and MET pathways.

Multidisciplinary tumor board review followed, the patient was enrolled in the PREVAIL-2 clinical trial and was treated with gemcitabine and carboplatin; they had disease regression on CT after 4 cycles.Conclusions This patient had suspected BTC and multiple non-diagnostic invasive procedures over a prolonged period. LB-based diagnosis was made quickly and with high degree of certainty which allowed for chemotherapy treatment without pathological verification on a clinical trial. The patient had a favorable response to chemotherapy that they would not have been able to access otherwise, demonstrating the value of a LB supplemented pathway.

In early-stage EC patients, mutations in cfDNA are detectable at diagnosis using an MRD approach. A larger cohort and improved assay sensitivity would be required to determine if this method can be reliably used to understand EC patients' response to neoadjuvant therapy.

Real-world overall survival was significantly (log-rank P < 0.0001) better for patients enrolled in clinical trials with similar costs of care, albeit with more outpatient encounters among those enrolled compared with matched controls. The results, together with previous analyses, suggest that, in addition to the clinical benefits associated with targeted therapies directed by CGP and other testing approaches, payers and specialty pharmacy managers may consider clinical trial direction and enrollment as a clinical and economic benefit of liquid biopsy CGP and adopt this into coverage decision frameworks and formularies.

Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

&lsqb;Future Issues] Although we have established a Cancer Genomic Medical Center and aim to centralize the workflow, we are not blessed with as many specialized personnel as the core hospitals. In the future, as the number of CGP tests increases, reducing the burden of sending out tests and entering information into C-CAT is considered to be one of the important issues for affiliated hospitals