On December 6, 2023 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company committed to advancing new standards of care for the frontline treatment of hematologic malignancies, reported strong and encouraging initial data from its ongoing SELECT-AML-1 Phase 2 trial evaluating tamibarotene, an oral, selective, retinoic acid receptor alpha (RARα) agonist, in combination with venetoclax and azacitidine in newly diagnosed, unfit patients with acute myeloid leukemia (AML) and RARA gene overexpression (Press release, Syros Pharmaceuticals, DEC 6, 2023, View Source [SID1234638212]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"I am highly encouraged by the initial data from the randomized portion of SELECT-AML-1," said Thomas Cluzeau, MD, PhD, Head of Hematology at Nice University Hospital, Côte d’Azur University in France. "Despite the recent advances in treatment for unfit AML patients, there remains a substantial need for options that offer higher response rates and improved overall survival, particularly for the one-third of patients who do not respond to existing standard-of-care. I believe tamibarotene may offer a significant therapeutic advance for the treatment of AML and I am eager to continue enrolling patients in the ongoing SELECT-AML-1 trial."

"These data highlight the potential of tamibarotene to be a cornerstone therapy for newly diagnosed, unfit AML patients with RARA overexpression, further demonstrating its differentiated product profile and validating our biologically targeted approach," said David A. Roth, M.D., Chief Medical Officer of Syros. "These results — the first from a randomized, controlled study — demonstrate the potential impact of adding tamibarotene to the standard-of-care, venetoclax and azacitidine and, importantly, are consistent with prior experience. Across multiple clinical trials, we have observed tamibarotene’s ability to rapidly deliver clinically relevant activity, with a well-tolerated safety profile, including in a combination setting. We look forward to advancing our comprehensive clinical development program for tamibarotene, with additional data from SELECT-AML-1 and pivotal complete response data from our SELECT-MDS-1 trial in higher-risk myelodysplastic syndrome with RARA overexpression expected next year, as we work to deliver profound benefit to patients with hematologic malignancies."

Initial Data from SELECT-AML-1 Phase 2 Trial

SELECT-AML-1 is evaluating the safety and efficacy of tamibarotene in combination with venetoclax and azacitidine compared to venetoclax and azacitidine in approximately 80 patients randomized 1:1. The trial is also evaluating the triplet regimen as a salvage strategy in patients in the control arm who do not respond to venetoclax and azacitidine. The primary endpoint of the trial is complete response rate (CR)/complete response with incomplete hematologic recovery (CRi). In December 2022, Syros reported data from the safety lead-in portion of SELECT-AML-1, in which five of six response evaluable patients (83%) achieved CR/CRi.

As of November 13, 2023, 23 newly diagnosed unfit AML patients positive for RARA overexpression had enrolled in the randomized portion of the trial, including 19 who were evaluable for response. The median age of the patients for the triplet arm was 77 (ranging from 66-85) and the median age of the patients for the doublet arm was 76 (ranging from 69-84).

Clinical Activity Data

– The primary endpoint (CR/CRi rate), defined in alignment with ELN AML criteria (Dohner 2017 and Bloomfield 2018), was 100% among response evaluable patients (nine of nine) treated with the combination of tamibarotene, venetoclax and azacitidine, as compared to 70% of patients (seven of ten) treated with the control (venetoclax and azacitidine alone).

Seven of the nine response evaluable patients (78%) treated with the combination of tamibarotene, venetoclax and azacitidine achieved a CR and two patients (22%) achieved a CRi.
Three of the ten response evaluable patients (30%) treated with the control achieved a CR and four patients (40%) achieved a CRi.
– Median time to CR/CRi response was 21 days (ranging from 14-28) among patients treated with the combination of tamibarotene, venetoclax and azacitidine, as compared to 25 days (ranging from 17-56) among patients treated with the control, with the CR/CRi being reached by 100% of patients in the triplet arm by the end of cycle one, compared with 60% of patients in the doublet control arm.

Safety Data

– Consistent with prior clinical experience from the safety lead-in portion of this study, tamibarotene administered in combination with approved doses of venetoclax and azacitidine was generally well tolerated, and the overall safety profile demonstrated no additive toxicities or new safety signals, or evidence of increased myelosuppression compared to treatment with the doublet combination of venetoclax and azacitidine. The majority of non-hematologic adverse events (AEs) were low-grade and reversible, and rates of serious adverse events (SAEs) were comparable between the study arms.

– Median duration of treatment was 66 days (ranging from 8-188) among patients treated with the combination of tamibarotene, venetoclax and azacitidine, and 75 days (ranging from 7-227) for patients treated with the control. Patients will be followed for duration of response, minimal residual disease (MRD)-negative response, and survival.

Syros continues to enroll patients in SELECT-AML-1 and anticipates reporting updated data from the trial in 2024.

Syros is also evaluating tamibarotene in combination with azacitidine in the SELECT-MDS-1 Phase 3 clinical trial in newly diagnosed higher-risk myelodysplastic syndrome patients with RARA gene overexpression. Syros expects to complete patient enrollment in SELECT-MDS-1 in the first quarter of 2024 and to report pivotal CR data by the middle of the fourth quarter of 2024.

Conference Call and Webcast

Syros will host a conference call today at 8:30 a.m. ET to discuss these data. To access the live conference call, please dial (888) 259-6580 (domestic) or (416) 764-8624 (international) and refer to conference ID 19696416. A webcast of the call will also be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the presentation.

Upcoming Investor Conference

Syros will also present at the JMP Securities Hematology and Oncology Summit today. Management will participate in a fireside chat at 11:00 a.m. ET. To access the live webcast and subsequent archived recording of the event, please visit the Investors & Media section of the Syros website at www.syros.com.

On December 6, 2023 CatalYm reported that maturing Phase 2a results from its ongoing GDFATHER-2 trial (GDF-15 Antibody-mediaTed Human Effector Cell Relocation Phase 2) (NCT04725474) were presented today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress 2023 in Geneva, Switzerland (Press release, Catalym, DEC 6, 2023, View Source [SID1234638211]). The data highlights that treatment with a combination of CatalYm’s lead candidate visugromab and nivolumab achieves compelling anti-tumoral activity in (as per strict criteria) anti-PD-1/PD-L1 relapsed/refractory non-small cell lung cancer (NSCLC) and urothelial cancer (UC) patients while retaining an excellent safety and tolerability profile. Visugromab is a monoclonal antibody designed to neutralize the tumor-produced Growth Differentiation Factor-15 (GDF-15), a central mediator of immune resistance to cancer therapies. The presentation by International Coordinating Investigator Prof. Ignacio Melero, MD, PhD, Co-Director of Immunology and Immunotherapy (CIMA) at the Universidad de Navarra, Pamplona/Spain, expands the clinical data for visugromab significantly and highlights the benefits that neutralizing GDF-15 can provide for patients with metastatic solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These data, in particular the clinical efficacy and durability of responses observed with visugromab/nivolumab in non-squamous NSCLC and UC are truly exceptional for advanced-stage/last-line, anti-PD-1/PD-L1 relapsed/refractory solid tumor disease treated with an I/O combination therapy. It underscores visugromab’s potential for reversing immunotherapy-refractoriness and restoring CPI activity back to levels that are at or near CPI-naïve disease," said Professor Eugen Leo, Chief Medical Officer at CatalYm. "The impressive duration of response, still expanding with 6/8 responses ongoing, is indicative of restoration of a lasting immunologic tumor control in advanced solid tumor patients that had previously exhausted available standard of care and are relapsed/refractory to prior anti-PD-1/PD-1 treatment as defined by strict criteria."

The matured results from the NSCLC and UC Phase 2a cohorts included a total of 27 patients in each indication. The Objective Response Rate (ORR) as per RECIST criteria in both the NSCLC and the UC cohorts was 14.8% (4/27, respectively), and 21.1% (4/19) in non-squamous NSCLC. The mean Duration of Response (DoR) has surpassed 11 months in non-NSCLC and 10 months in UC and is further expanding with 6/8 subjects in response continuing on study treatment. Non-sq NSCLC and UC both had been predicted as major GDF-15 immunosuppressed tumor types by a proprietary translational research analysis involving several thousand tumor samples (data unpublished), and the clinical results are in line with this. Interestingly, responses were observed in both PD-L1 positive and negative tumors, but all three patients in the urothelial tumor cohort with PD-L1 levels of Tumor Proportion Score (TPS) >5 responded to treatment, including one complete response (in fourth line of treatment) and two partial responses (PR), all ongoing. The ORR rates and the emerging and still maturing DoR favorably compare to existing historical data of various PD-1 mono- (with reported ORR of 0-5% in as per strict criteria anti-PD-1/PD-L1 r/r patients) or various I/O combo-retreatment regimens in similar third and fourth line populations. Further biomarker correlative analyses are ongoing and are an integral part of future trials in preparation.

Regarding safety, the majority of Treatment-Emergent Adverse Events (TEAE) reported were mild to moderate, with just 5.2% of patients (9/174) experiencing TEAE of Grade > 3, demonstrating a good overall tolerability and safety of the combination in heavily pretreated patients. As of December 2023, for only 1/174 (0.6%) subjects treated/exposed, a single Serious Adverse Reaction (SAR) > Grade 3 was reported that was assessed as per investigator judgement as at least possibly Treatment-Related Adverse Event (TRAE).

"We continue to make important progress in our Phase 2 evaluation of visugromab, further demonstrating the potential of GDF-15 neutralizing approaches as a critical component for treatment success in a broad range of anti-cancer regimens," said Phil L’Huillier, Managing Director and Chief Executing Officer at CatalYm. "The next stage is to expand our clinical evaluation in 2024 to further maximize the value of GDF-15-targeting therapies for patients both in advanced and earlier stages of their disease. There is a huge unmet medical need not only in CPI-relapsed/refractory solid tumors but also in newly diagnosed metastatic solid tumor disease, where despite all encouraging recent advances, a cure or at least true long-term-remission/-disease control are still far out of reach for the vast majority of patients, who ultimately will die from their disease. We want to improve patient’s lives and outcome with a well tolerable immunotherapy concept that we see emerge here."

The Phase 2a GDFATHER-2 program was initiated in March 2022. The ongoing study consists of two segments with up to seven cohorts, expected to enroll a total of over 200 patients in various cohorts. Based on the matured Phase 2a results, CatalYm plans to launch randomized, controlled studies in several major cancer indications in combination with checkpoint inhibitors and standard-of-care in early lines of treatment in the first half of 2024.

Presentation Details

Title: Definitive results for NSCLC and bladder cancer cohorts in the phase 1/2a trial of visugromab (CTL-002) in advanced/metastatic anti-PD/PD-L1 relapsed/refractory solid tumors (GDFATHER-1 trial)

Presenter: Dr. Ignacio Melero, Co-Director of the Department of Immunology and Immunotherapy Researcher at the Universidad de Navarra, Spain

Abstract number: 318

Date and time: Wednesday, December 6th, 2:15-2:25pm CET

About the GDFATHER-2 Trials

The GDFATHER-2a trial (GDF-15 Antibody-mediaTed Human Effector Cell Relocation Phase 2) (NCT04725474) is the Phase 2a part of the ongoing Phase 1/2a trial with several cohorts investigating the effect of visugromab (CTL-002) in combination with a PD-1 checkpoint inhibitor in patients in various advanced-stage/last-line and by strict criteria anti-PD1/PD-L1 relapsed/refractory solid tumor types. The study can enroll up to 200 patients and has extensive biomarker-evaluations integrated to assess for potential responder patient population identification or similar.

About Visugromab (CTL-002)

Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by reenabling immune cell activation and tumor infiltration. Visugromab has demonstrated already in Phase 1 a good safety profile and potent and durable anti-tumor efficacy in combination with anti-PD-1 treatment in advanced cancer patients. The antibody is currently being investigated in ongoing Phase 2 studies in multiple solid tumor indications.

On December 6, 2023 BostonGene, a leading provider of AI-driven, molecular and immune profiling solutions, reported that two abstracts have been accepted for poster presentations for the 2023 San Antonio Breast Cancer Symposium (SABCS), which will be held December 5 – 9, 2023, at the Henry B. Gonzalez Convention Center in San Antonio, Texas (Press release, BostonGene, DEC 6, 2023, View Source [SID1234638210]). BostonGene will also exhibit at booth 1515.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to present our research at the 2023 San Antonio Breast Cancer Symposium, showcasing our commitment to improving breast cancer treatment through innovative molecular profiling. By developing novel approaches to transcriptomic classification, we aim to revolutionize the way we understand and treat breast cancer," said Nathan Fowler, MD, Chief Medical Officer at BostonGene.

Details about the abstracts selected for presentation can be found below:

Abstract Number: 1580341
Title: Novel Transcriptomic Classification System Unveils HER2-Low Breast Tumors
Date and Time: Wednesday, December 6 | 5:00 PM – 7:00 PM
Location: Poster Session 2
Poster Number: PO2-15-12
Speaker: Konstantin Chernyshov, MS, BostonGene

This study presents a novel approach to the PAM50 transcriptomic classification of breast cancer to potentially guide optimal treatment selection. The new system offers a more refined categorization, identifying patients with the HER2-low breast cancer subtype who could benefit from recently approved trastuzumab deruxtecan targeted therapy.

Abstract Number: 1582800
Title: An integrated approach for comprehensive molecular and tumor microenvironment characterization of invasive lobular carcinoma.
Date and Time: Friday, December 8 | 12:00 PM – 2:00 PM
Location: Poster Session 5
Poster Number: PO5-24-11
Speaker: Jason Mouabbi, MD, MD Anderson

In this study, the use of BostonGene’s integrated analysis platform provided an in-depth understanding of the molecular differences between invasive lobular carcinoma (ILC) and invasive breast cancer of no special type (NST), revealing mechanistic insights that can be used for the development of more effective therapeutic strategies.

Research done in collaboration with The University of Texas MD Anderson Cancer Center

For more information, please visit the 2023 San Antonio Breast Cancer Symposium website. The abstracts will be published in the Abstracts2ViewTM online database at the conclusion of the symposium.

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.