On December 6, 2023 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, reported new data being presented on its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, at the 2023 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas (Press release, Natera, DEC 6, 2023, View Source [SID1234638209]).

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Natera and its collaborators are presenting two poster spotlight discussions and three posters. The presentations feature tumor-informed MRD data spanning the neoadjuvant, adjuvant, surveillance, and metastatic treatment settings, including analyses from the DARE, monarchE, and LEADER trials in HR+/HER2- breast cancer.

"We are excited to showcase our leadership at SABCS with thought-provoking new data that demonstrate our commitment to personalizing patient care across the breast cancer continuum," said Minetta Liu, MD, chief medical officer of oncology, at Natera. "We are highly encouraged by the excellent preliminary findings from prospective, interventional clinical trials such as DARE and LEADER, which we believe will further demonstrate the utility of treatment on molecular recurrence with Signatera."

Highlights from selected abstracts include:

PS06-02 | Poster Spotlight Discussion | DARE Study | HR+/HER2- Surveillance (TOMR) | Presenter: Lajos Pusztai, MD
Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy

DARE is a first-of-its-kind, multi-center, prospective, randomized clinical trial, which was first announced in October 2020. An interim readout of over 400 patients prescreened for ctDNA detection and enrollment in the interventional trial demonstrates that ~9% of patients tested ctDNA-positive with a median screening time of 13.4 months per patient. Over 70% of patients experienced molecular-only relapse (i.e. ctDNA positivity with no evidence of metastatic disease on imaging), which is the highest rate seen in a prospective study to date and demonstrates the feasibility of TOMR study designs in breast cancer. These patients were successfully randomized to receive endocrine therapy in combination with palbociclib vs. continuing standard of care. Initial ctDNA dynamics were presented, including clearance events. The association of this data with treatment benefit will be presented at future meetings.

PS06-01 | Poster Spotlight Discussion | monarchE Study | HR+/HER2- Surveillance (adjuvant CDK4/6i) | Presenter: Stephanie Graff, MD, FACP
Results from a study exploring ctDNA detection in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer

This study investigated the technical feasibility of ctDNA testing beginning prior to adjuvant CDK4/6i therapy and examined rates of ctDNA persistence and clearance in a highly selected cohort of 178 patients from the phase 3 monarchE trial, which excluded any recurrences in the first 24 months after surgery. Persistent ctDNA positivity during two years of treatment was found to be associated with a 100% risk of relapse. Additionally, none of the patients developed recurrence if they were initially ctDNA-positive and later became ctDNA-negative during treatment (ctDNA clearance). An analysis of an expanded cohort is ongoing, which will be more reflective of the intent-to-treat population and will include additional time points and recurrent cases within the 2-year treatment period.

Below are additional Natera abstracts being presented at SABCS:

PO3-13-09 | Poster Session 3 | LEADER Study | HR+/HER2- Surveillance (TOMR) | Presenter: Arielle Medford, MD
Personalized ctDNA testing for detection of MRD in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes.
PO4-15-12 | Poster Session 4 | Neoadjuvant Treatment Monitoring (all subtypes) | Presenter: Mridula George, MD
Personalized ctDNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer
PO5-13-12 | Poster Session 5 | Metastatic Invasive Lobular Carcinoma (mILC) Treatment Monitoring (all subtypes) | Presenter: Steffi Oesterreich, PhD
Personalized ctDNA testing for recurrence detection and treatment response monitoring in patients with mILC
All abstracts can be found on the SABCS website here.

About Signatera

Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer (stage IIb and higher) and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 50 peer-reviewed papers.

On December 6, 2023 GRAIL, LLC, a healthcare company whose mission is to detect cancer early when it can be cured, reported the presentation of analytical and clinical validation data on a novel prognostic test in early-stage lung cancer, generated through collaboration with the Samsung Medical Centre and AstraZeneca (LSE/STO/Nasdaq: AZN) (Press release, Grail, DEC 6, 2023, View Source [SID1234638208]). The results of the studies demonstrate sensitive and specific detection of circulating tumor DNA (ctDNA) for Lung Adenocarcinoma (LUAD) at a clinically meaningful threshold for disease prognostication. This is a novel tissue-free diagnostic that has the potential to identify high-risk patients prior to surgery and/or treatment. The findings were presented in poster sessions at the North America Conference on Lung Cancer 2023 in Chicago, held Dec. 1-3, 2023.

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"These results are an important step in establishing oncology capabilities for GRAIL’s Methylation Platform for important cancer-specific applications beyond early cancer detection," said Jeffrey Venstrom, MD, Chief Medical Officer at GRAIL. "These studies demonstrate that a new tissue-free methylated ctDNA assessment in Stage I lung cancer can potentially identify patients at higher risk for recurrence."

The clinical validation studies analyzed pre-surgical plasma samples from 602 patients with EGFR/ALK wild-type clinical Stage I NSCLC (staging determined by TNMv8). A GRAIL assay was used to measure ctDNA detection with a prespecified threshold in a prospectively defined retrospective study. The presence of ctDNA correlated with an inferior two-year recurrence-free survival (HR 3.8 [95%CI 2.3–6.4], P<0.001 comparing ctDNA+ versus ctDNA-). ctDNA positivity in clinical stage I LUAD was associated with higher rates of mediastinal nodal upstaging at resection, PD-L1 positivity, and grade 3 histology.

In addition, analytical studies demonstrate analytical specificity of 96.9% (as determined in healthy donors), 100% accuracy to detect signal at low ctDNA input (2ng) and a robust LoD95 of 44 ppm tumor methylated fraction (TMeF: a measure of ctDNA abundance).

In 2022, GRAIL announced a broad strategic collaboration with AstraZeneca to develop and commercialize companion diagnostic (CDx) assays for use with AstraZeneca’s therapies.

In January 2023, GRAIL announced the availability of its state-of-the-art research use only (RUO) methylation solution which is being leveraged by pharmaceutical companies for custom oncology applications.

On December 6, 2023 Exai Bio reported new data demonstrating that its novel RNA-based and AI-driven liquid biopsy platform can detect breast cancer at the earliest stages and the smallest tumor sizes, including ductal carcinoma in situ (DCIS), using a standard blood sample (Press release, Exai Bio, DEC 6, 2023, View Source;and-AI-based-Liquid-Biopsy-Platform-Detects-Early-Stage-Breast-Cancer-with-High-Accuracy-Overcoming-Many-Limitations-of-DNA-based-Approaches [SID1234638207]). In a new early detection study building upon prior data, stage I breast cancer sensitivity was 87% and tumor size T1a-b (10 mm or smaller) sensitivity was 81%, both at 90% specificity. Overall sensitivity across all invasive breast cancer stages was 88% at 90% specificity, far exceeding any DNA-based liquid biopsy performance. Exai additionally reported sensitivity of 78% for DCIS at 90% specificity. These results will be presented at a poster session today at the San Antonio Breast Cancer Symposium (SABCS) 2023 meeting.

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Earlier detection of breast cancer is crucial for improved patient outcomes but cannot always be achieved through mammography, a modality which has well-established limitations. Confounding issues such as breast density, which masks the appearance of tumors and affects more than 40% of women, small tumor sizes, and imaging anomalies can result in false negatives and delayed diagnosis. In addition to mitigating these risk factors and technical issues, a blood test will also offer improved access and an increase in the number of women who receive screening each year. The data released today further support the potential of the Exai platform to complement mammography and enable earlier detection of breast cancer for more women.

"A routine blood test could meaningfully improve breast cancer screening and be a powerful complementary solution to mammography, especially for the millions of women with dense breast tissue," stated Pat Arensdorf, Chief Executive Officer of Exai Bio. "Exai’s platform has demonstrated high accuracy in this expanded dataset by detecting the smallest tumors and earliest stages of disease, once again overcoming performance barriers that limit utility DNA-based liquid biopsy approaches."

Exai’s platform uses RNA sequencing to identify a novel category of cancer-associated, small non-coding RNAs, termed orphan non-coding RNAs (oncRNAs). OncRNAs are actively secreted from living cancer cells and are stable and abundant in the blood of cancer patients. Exai has created a catalog of hundreds of thousands of oncRNAs and thousands of patient oncRNA profiles, spanning all major cancer types. When combined with proprietary artificial intelligence technology, the Exai platform has multiple technical and operational advantages over tests that focus on circulating tumor DNA. These include superior sensitivity and specificity, as well as the ability to reveal dynamic changes in the biology of a patient’s tumor over time. Exai’s universal platform can be used across multiple cancer care settings such as screening and early detection, monitoring, molecular residual disease and therapy selection.

SABCS Poster Details

Poster Title: Cell-free orphan noncoding RNAs and AI enable early detection of invasive breast cancer and ductal carcinoma in situ

Poster ID: POS-13-08

Abstract Number: #1578895

Session Title: Spotlight Session: Poster Session 2

Authors: N. Tbeileh, T. Cavazos, M. Karimzadeh, Jeffrey Wang, A. Huang, T. Lam, S. Kilinc, Jieyang Wang, X. Zhao, A. Pohl, H. Li, L. Fish, K. Chau, M. Francis, L. Schwartzberg, P. Arensdorf, H. Goodarzi, F. Hormozdiari, B. Alipanahi

On December 6, 2023 Marengo Therapeutics, Inc., a clinical-stage biotech company pioneering a new way to activate T cells by targeting germline-encoded alleles in the β chain of the T cell receptor (TCR) to selectively activate the right T cell subsets to fight cancer, reported that its lead program, STAR0602, is the subject of an article published in the latest edition of Science Translational Medicine (Press release, Marengo Therapeutics, DEC 6, 2023, View Source [SID1234638206]).

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The publication, titled "A T cell receptor β chain-directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity," highlights the potent and durable anti-tumor activity of STAR0602 across a broad range of PD1-refractory murine and human solid tumor models via a mechanism that is distinct to checkpoint inhibitors and cytokine therapies. Lead authors on the publication are Jonathan Hsu, M.Sc., Principal Scientist at Marengo, and Renee Donahue, from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).

"The comprehensive data reported in our Science Translational Medicine publication underscore the potential of Marengo’s broad STAR platform to target and activate subsets of T cells expressing different beta chain TCRs," said Andrew Bayliffe, Ph.D., Chief Scientific Officer of Marengo. "Our studies of STAR0602 show Vβ T cells expand to create a new, much more fit population of tumor-infiltrating T cells that recognize a broader set of tumor antigens or epitopes, and we are excited for the continuation of our clinical trial and the potential for STAR0602 to help patients with checkpoint inhibitor-resistant tumors."

Through a novel bi-specific antibody-fusion molecule design, STAR0602 achieves dual boosting of T cells through the TCR and costimulatory receptors that leads to profound activation, expansion and reprogramming of Vβ6 T cells representing a specific subset of the total T cell pool. STAR0602-expanded Vβ6 T cells acquire a novel effector memory phenotype with a highly expanded TCR repertoire suggesting reinvigoration and diversification of tumor antigen-specific T cell responses.

"The biology elicited by STAR0602 through engaging the TCR in this novel way seems quite different to canonical routes of TCR activation, including anti-CD3 antibodies. The atypical memory T cell phenotype observed in preclinical models dosed with STAR0602 also seem to be quite distinct and serve to illustrate that there may be many different routes to boosting anti-tumor T cell responses," said John Wherry, Ph.D., Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine at the University of Pennsylvania (UPenn), Director of the UPenn Institute for Immunology, and Co-Chair of Marengo’s Scientific Advisory Board.

In large animal studies, dosing of STAR0602 was associated with less release of proinflammatory cytokines and cytokine-related toxicities, suggesting the potential for a potent treatment option with lower risk of cytokine-related adverse effects.

"As clinicians, we have mostly immune checkpoint inhibitors and some experimental CAR-Ts to treat solid tumor patients, but only a subset of them respond, and some who respond initially then relapse." said James Gulley, M.D., Ph.D., Co-Director of the Center for Immuno-Oncology at the NCI and Clinical Director, NCI. "Having a new strategy to activate the immune system for these patients is important and currently an unmet need. STAR0602 may offer a new way to selectively activate a subset of T cells with potent antitumor activity, with the added potential to avoid the toxicity associated with activating all T cells. This unique modality of T cell activation holds significant promise for patients."

On December 6, 2023 MEDSIR reported the results from the PARSIFAL-LONG study, a 5-year extended follow-up of the PARSIFAL study on endocrine-sensitive hormone receptor-positive/HER2-negative advanced breast cancer, demonstrating the effectiveness of two combined option therapies (palbociclib-letrozole and palbociclib-fulvestrant) as first-line treatments for metastatic breast cancer (Press release, MedSIR, DEC 6, 2023, View Source;advanced-breast-cancer-302007622.html [SID1234638205]). With a median follow-up of 59.7 months, the study found no significant differences in progression-free survival and overall survival when palbociclib was paired with either letrozole or fulvestrant. Given that there was no difference between groups, they were combined, and it was determined that the median progression-free survival was 33.2 months (95%CI, 27.7-39.5), and the median overall survival was 65.4 months (95%CI, 57.8-72.0).

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PARSIFAL explored the optimal endocrine agent (letrozole vs fulvestrant) to combine with palbociclib in patients with untreated, endocrine-sensitive, hormone receptor positive/HER2-negative advanced breast cancer in the first-line setting. The trial failed to demonstrate an improvement in progression-free survival of palbociclib-fulvestrant over palbociclib-letrozole, with a median follow-up of 2.7 years. At data cutoff, overall survival data were immature.

PARSIFAL-LONG extended the efficacy assessment of the PARSIFAL study with a median follow up of 5.0 years. It included a total of 389 patients, which represents 80.5% of all patients initially enrolled in PARSIFAL. Among them, 86 patients (22.1%) had a progression within the first year of treatment (early progressors), with a median overall survival of 24 months. The remaining 303 patients (77.9%) were progression-free on palbociclib-based regiments at 12 months and showed an improved median overall survival of 81.5 months.

Patients who experienced a progression during the 5-year follow-up were then assessed based on the time that they progressed. Those who progressed within the first year had an overall survival of 18 months compared to 27 months for patients that progressed after a year (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007), indicating that early progression (<12 months) on a palbociclib-based regimen is a strong predictor for overall survival.

These results were presented at the 46th annual San Antonio Breast Cancer Symposium by Dr. Antonio Llombart-Cussac, Head of the Oncology Department at Arnau de Vilanova Hospital and Medical Senior Scientific Lead at MEDSIR, a Spanish company specialized in the strategic design of independent clinical research. This year, MEDSIR had a significant participation at the conference by showcasing 5 studies including PARSIFAL-LONG, DEBBRAH, ATRACTIB, PARALEAL and MiRaDor. He emphasized, "Upon combining the two arms, our overall survival and progression-free survival values align comparably with other CDK4/6 inhibitors." Dr. Llombart-Cussac further noted, "Early progression with a palbociclib-based regimen serves as a robust early clinical biomarker for survival."

A total of 389 patients from 32 of the original 47 sites participated in this trial, which is the only study for a CDK4/6 regimen that recruited patients exclusively across European countries including Spain, France, Italy, Great Britain, Deutschland and Czech Republic.

The PARSIFAL-LONG study provides valuable insights, expanding the understanding of the magnitude of benefit and further reinforces the evidence supporting palbociclib in combination with endocrine therapy as a first-line treatment for patients with hormone receptor-positive/HER2-negative metastatic breast cancer.

ABOUT PARSIFAL-LONG

PARSIFAL-LONG, is a 5-year extended follow-up of the PARSIFAL study. In this analysis, the primary goal was to assess the overall survival, or the time from enrollment to death from any cause, between the two groups (palbociclib-letrozole vs palbociclib-fulvestrant). In addition, the study assessed the extended progression-free survival (time from randomization until the disease getting worse), the overall survival from the combined groups, and the post progression effectiveness or the how well the treatment worked in terms of the time from disease worsening after the first treatment to the passing of any cause. As exploratory analysis, this extended follow-up also aimed to determine if having an early progression (the disease getting worse in under 12 months while on treatment) could be an indicator of resistance to therapy.

ABOUT BREAST CANCER

Breast cancer is the second most common cause of death from cancer in women in the United States. Metastatic breast cancer causes the vast majority of deaths from the disease. In 2023, it is estimated that there will be 297,790 new cases of female breast cancer. The breast cancer subtype HR[+]/HER2[-], whose tumors express hormone receptors (HR[+]), but do not express HER2 protein (HER2[-]), is the most common subtype with an age-adjusted rate of 87.2 new cases per 100,000 women, based on 2016–2020 cases, according to the US National Cancer Institute.