TEST:

Signatera™

The results of this study show that breast cancer patients that are positive for ctDNA and undergo neoadjuvant treatment are more likely to decrease their ctDNA. The utilization of ctDNA in the breast cancer treatment process offers the opportunity for ease of access, specificity, and longevity for patients following treatment.

P2, N=25, Recruiting, University of Southampton | Not yet recruiting --> Recruiting | Trial primary completion date: Nov 2025 --> Mar 2026

Herein, we add to the sparce literature regarding tumor gene characteristics of rare GU malignancies. MDR testing appears to be a useful adjunct in postoperative rare GU malignancy surveillance. MDR may anticipate recurrence or progression compared to standard techniques and correlation with response to systemic therapy.

P=N/A, N=0, Withdrawn, Case Comprehensive Cancer Center | Not yet recruiting --> Withdrawn | N=30 --> 0

P3 | N=520 | IMvigor011 (NCT04660344) | Sponsor: Hoffmann-La Roche | "The analysis presented at the EAU Congress evaluated clinical outcomes in 171 high-risk MIBC patients who entered screening for IMvigor011 and remained MRD-negative during the surveillance window. Key takeaways from the presentation include: Overall survival (OS) rates of 100% at 12 months and 98% at 18 months, in patients who remained serially MRD-negative; Disease-free survival (DFS) rates of 92% at 12 months and 88% at 18 months, in patients who remained serially MRD-negative."

"Natera, Inc...today announced the launch of Alliance A032103 (MODERN), a randomized, phase II/III, biomarker-integrated trial. Alliance A032103 (MODERN) will utilize Signatera, Natera’s personalized and tumor-informed molecular residual disease (MRD) test, to help guide personalized treatment based on molecular status in patients diagnosed with muscle-invasive urothelial cancer (MIUC) after radical cystectomy....In the Alliance A032103 (MODERN) trial, approximately 1,000 patients will be enrolled at more than 300 sites in North America. Patients will be divided into two cohorts based on an initial assessment of MRD status. Patients who are Signatera MRD-positive will have treatment randomized to either nivolumab, a PD-1 antibody, or escalation with nivolumab, a PD-1 antibody plus relatlimab, a LAG-3 antibody; LAG-3 and PD-1 are distinct inhibitory immune checkpoints."

P2, N=44, Not yet recruiting, Diwakar Davar | Trial completion date: Nov 2028 --> Jun 2029 | Initiation date: Nov 2023 --> Jun 2024 | Trial primary completion date: Nov 2026 --> Jun 2026

P3; Phase classification: P2/3 --> P3

"Natera, Inc...announced a collaboration with the Fédération Francophone de Cancérologie Digestive and CHU Dijon Bourgogne on the CIRCULATE-PRODIGE-70 study, a randomized, multicenter, prospective phase III clinical trial in France investigating molecular residual disease (MRD)-guided adjuvant treatment in stage II colorectal cancer (CRC) patients....The initial readout is expected in 2025."

In our study, the Signatera ctDNA assay was a reliable reflection, or even predictor, of relapse or progression in five pediatric patients with solid tumors. Further investigation is needed to validate the reliability and best utility of this test. This study was supported by the Natera early adopter program.

Our data shows that tumor-informed serum ctDNA levels are concordant with surveillance imaging and pathologic staging for PUC and pSCC. Monitoring serial ctDNA results may characterize treatment response and disease progression better than conventional methods which can help tailor patient specific therapy and improve outcomes.

ctDNA status was found to be correlated with the different stages of testicular cancer. ctDNA may be used for tailoring treatment protocols to patients with negative/mildly elevated serum tumor markers and for treatment escalation/deescalation. Prospective studies with larger cohorts are necessary to validate these initial results.

Initial data suggest that ABX is active in combination with pembrolizumab in advanced urothelial carcinoma (UC; PMID:32979512). The first results from Nure-Combo trial suggest this novel chemo-immunotherapy combination with NIVO+ABX could be an effective and safe perioperative strategy in pts with MIBC with sustained efficacy post-RC. These results could expand the opportunities of chemotherapy combinations beyond cisplatin. Results also strengthen the role of clinical complete response to envision organ-sparing approaches.

Preoperative ctDNA status is associated with disease relapse after radical cystectomy regardless of disease stage and neoadjuvant treatment. ctDNA status holds the promise of informing urologists and oncologists of disease status for optimally selecting patients for neoadjuvant, adjuvant, and treatment escalation regardless of disease stage. A negative preoperative ctDNA could be a marker for treatment deescalation, treating patients only with radical cystectomy.

Preoperative ctDNA status is highly predictive of disease upstaging, locally advanced disease, and nodal disease, regardless of preoperative disease stage. Preoperative ctDNA status holds the promise of informing urologists and oncologists of disease status before radical cystectomy for optimally selecting patients for neoadjuvant treatment and treatment escalation regardless of disease stage.

In this real-world data analysis, ctDNA during the MRD and surveillance windows appears to be significantly associated with non-urinary tract DFS. This is an emerging potential biomarker fordetecting non-urinary recurrences and can be used to guide patient management in the post-surgical period.

"Natera, Inc...announced new data being presented on its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, and hereditary cancer test, Empower, at the 2024 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer taking place March 16-18, 2024. A total of seven abstracts will be presented, including two oral presentations and five poster presentations. The presentations will feature new data highlighting Signatera’s predictive and prognostic utility in ovarian cancer and other gynecologic malignancies."

These findings point to several genomic alterations that may underlie cancer recurrence after a long period of undetectable disease with a differential impact across different stages. This may allow, in the future, for a personalized surveillance strategy based on driver mutations and stage of the disease. Correlation of ctDNA positivity with clinical outcomes based on driver mutational status may inform to what extent tumor-specific characteristics drive patient outcomes following a successful surgery.

In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed.

These data demonstrate that abundance of differential methylation in CRC patients correlates with VAF regardless of clinicopathologic features of patients with CRC. Methylation-based assays are a promising tool for cancer detection and quantifying the disease burden.

P1; Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

"Natera, Inc...announced that its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, has met coverage requirements from the Centers for Medicare & Medicaid Services’ (CMS) Molecular Diagnostics Services Program (MolDX) in two new indications: ovarian cancer in the adjuvant and surveillance settings, and breast cancer in the neoadjuvant setting. These determinations add to a growing list of covered indications for Signatera, including adjuvant and recurrence monitoring coverage in colorectal cancer, muscle-invasive bladder cancer, and breast cancer; and pan-cancer immunotherapy response monitoring."

P2/3; Initiation date: Oct 2024 --> Feb 2024

P2; N=16 --> 0 | Trial completion date: Dec 2026 --> Feb 2024 | Initiation date: Nov 2024 --> May 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2024 --> Feb 2024

P2; N=244 --> 7 | Trial completion date: Nov 2028 --> Nov 2023 | Recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Nov 2023; Sponsor made decision to terminate study.

P2; N=46; Not yet recruiting; Sponsor:Gruppo Oncologico del Nord-Ovest

"Natera, Inc...today announced a new study published in Gynecologic Oncology validating its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, in endometrial cancer....This real-world study analyzed 267 plasma samples drawn after surgery from 101 patients with EC. The patient cohort was composed of multiple histological subtypes, with patients stratified based on clinicopathological risk factors into high-risk (52%), high-intermediate (22%), low-risk (15%), and other (12%). Key findings include: Patients who tested Signatera MRD-positive at either a single time point or longitudinally experienced significantly higher rates of recurrence than those who remained Signatera-negative (58% and 52%, vs. 6% and 0%, respectively), regardless of mismatch repair (MMR) or p53 status."

ctDNA values were elevated in patients with vulvar cancer pre-RT/CRT but sustained reduction mid-way, and became undetectable at the end of treatment and in follow-up with a strong correlation with imaging. A mid-way ctDNA test identified future responders to RT/CRT and requires further investigation as a potential early biomarker of response. To our knowledge, these early promising results suggest that there is a role for ctDNA in the management of patients with vulvar cancer and warrants a larger cohort assessment in a prospective study.

A significant proportion of patients in clinical remission by imaging and CA-125 after initial treatment have MRD. SLL identified more patients with MRD, however ctDNA provided a less invasive means of MRD detection with greater prognostic discrimination for PFS. Both methods were able to identify women at high risk for clinical recurrence, with ctDNA positivity representing an especially poor prognostic subgroup.

The patients were followed over the course of therapy (lenvatinib+paclitaxel+pembrolizumab) with plasma samples collected pre-treatment, on-treatment ( cycle (C) 2 day (D)1, C3D1, C6D1), and at the time of progression/end of treatment. Our data demonstrates the feasibility of ctDNA testing for treatment response monitoring in patients with rEC and PROC undergoing this novel treatment regimen. ctDNA status/dynamics during early treatment (pT-C3) was associated with patient outcomes and ctDNA-positivity had a median lead-time of 4.6 months (range: 2.4-17.6) over radiographic imaging. Early ctDNA clearance was associated with being on therapy longer and may help inform treatment decisions especially if the patient experiences treatment toxicity.

Collectively, these data demonstrate the feasibility of monitoring ctDNA in the postoperative and adjuvant settings in early-stage EC. Detection of ctDNA before initiation or after completion of AT was associated with significantly worse DFS. Analysis of ctDNA in addition to other risk factors may help identify patients at the highest risk of recurrence, inform surveillance strategies, and support treatment decision-making for these patients.

ctDNA is detectable in both primary and recurrent patients with EC. Dynamics of ctDNA during treatment is associated with treatment response and could be useful for clinical decision-making in both of these settings. This study warrants further investigation to better understand ctDNA dynamics and its association with radiographic findings within the treatment setting in this patient population.

This study demonstrates the prognostic value of ctDNA detection prior to initiation of PARPi therapy. Moreover, a rise in ctDNA levels during treatment was strongly associated with PD. Conversely, all patients with serially negative results or a decrease in ctDNA levels had clinical benefit on imaging.

Peritoneal-only recurrence was associated with delayed ctDNA detection and low levels of ctDNA after optimal resection for mCRC. ctDNA testing may effectively characterize recurrence sites and may help guide subsequent treatments specific to the disease sites involved.

P=N/A; Recruiting --> Active, not recruiting

"Natera, Inc...today announced a new study published in The Journal of Thoracic and Cardiovascular Surgery demonstrating the ability of Natera’s personalized and tumor-informed molecular residual disease (MRD) test, Signatera, to risk stratify and detect recurrence early in patients with resected stage I-II non-small cell lung cancer (NSCLC)....Key findings include: Patients who were ctDNA-positive within 6 months post-resection and prior to adjuvant treatment were 53-times more likely to recur (p<0.0001) as compared to ctDNA-negative patients; ctDNA detection demonstrated a median lead time of 5.5 months when compared to confirmation of recurrence by radiographic imaging."

"Natera...announced the publication of two new studies in Nature Medicine evaluating Natera’s personalized and tumor-informed molecular residual disease (MRD) test, Signatera™."

ctDNA was detected frequently in the HNSCC patients with high-risk features post-operatively. Although we have a small number of the patients, the patients with recurrence following adjuvant treatment had high rates of positive ctDNA after the surgery. Therefore post-operative ctDNA for high-risk patients may be prognostic and considered in clinical trials designed for treatment intensification.

P3; Not yet recruiting --> Recruiting

P2/3; Not yet recruiting --> Recruiting | Initiation date: Jan 2024 --> Oct 2024

Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification.