April 2021 – Page 159 – 1stOncology™: Cancer Intelligence Service

Fusion Pharmaceuticals Announces Preclinical Combination Data Demonstrating Enhanced Efficacy in Multiple Preclinical Tumor Models

On April 10, 2021 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the presentation of preclinical data at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Fusion Pharmaceuticals, APR 10, 2021, View Source [SID1234577878]). The posters will be presented during the Preclinical Radiotherapeutics and Combination Immunotherapies sessions taking place today. The posters highlight the potential of Fusion’s targeted alpha therapies (TATs) to enable delivery of an alpha particle emitting isotope (actinium-225) as both monotherapies and combination therapies across multiple tumor types.

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 are the result of Fusion’s early investments in research to understand the power of combining our potent TATs with the latest generation of cancer therapies, such as checkpoint inhibitors and DNA damage response inhibitors (DDRis), and they reinforce our belief in the potential of our pipeline of TATs to redefine the utility of radiopharmaceuticals in the cancer treatment paradigm," said Fusion Chief Executive Officer John Valliant, Ph.D. "We believe we have an opportunity to advance clinical development of our product candidate FPI-1434 as monotherapy and in combination with these novel agents, leading to more treatment options for patients in earlier lines of therapy."

In one set of preclinical studies, highlighted in poster number LB130 titled, "Combination of IGF-1R Targeted Alpha Therapy with Olaparib Results in Synergistic Efficacy Against Colorectal and Lung Cancer Xenografts," results demonstrated that the delivery of alpha-particle radiation by FPI-1434 induced double-stranded DNA breaks and apoptosis in treated colorectal cancer tumor xenografts. Co-dosing with the PARP (poly ADP-ribose polymerase) inhibitor olaparib resulted in lower doses required for efficacy of FPI-1434 in lung and colorectal cancer tumor xenografts, supporting the potential clinical development of this combination.

In an additional set of preclinical studies, highlighted in poster number LB155 titled, "Combination of IGF-1R Targeted Alpha Therapy with Checkpoint Inhibitors Results in Synergistic Efficacy in Colorectal Cancer Syngeneic Model," data showed that treatment with IGF-1R TAT in combination with immune checkpoint inhibitors resulted in complete tumor eradication. Additionally, an increase in antigen-specific CD8 positive T cells and a strong "vaccine" effect were observed with the combination of IGF-1R TAT and immune checkpoint inhibitors, as noted by the prevention of tumor growth in animals that were reinoculated with the same tumor cells.

About FPI-1434
FPI-1434 is a radioimmunoconjugate designed to target and deliver alpha emitting medical isotopes to cancer cells expressing IGF-1R, a receptor that is overexpressed on many tumor types. FPI-1434 utilizes Fusion’s Fast-Clear linker to connect a human monoclonal antibody that targets IGF-1R with actinium-225, a powerful alpha-emitting isotope with desirable half-life and decay chain properties.

Sysmex Inostics Presents Data at AACR Demonstrating SafeSEQ NGS Liquid Biopsy Delivers Equivalent Performance to the Extensively Clinically Validated OncoBEAM dPCR Technology for NSCLC Patients

On April 10, 2021 Sysmex Inostics, Inc., a global leader of the liquid biopsy revolution for oncology,reported the poster "Clinical evaluation of NGS-based liquid biopsy testing in non-small cell lung cancer (NSCLC) patients" at the 112th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) on April 10, 2021, from 8:30 AM – 11:59 PM Eastern Daylight Time (EDT) (Press release, Sysmex, APR 10, 2021, View Source [SID1234577877]).

In a recent collaborative study, Johns Hopkins University School of Medicine and Sysmex Inostics’ researchers showed that the next-generation sequencing (NGS)-based liquid biopsy SafeSEQ NSCLC panel delivers equivalent performance with broader genomic coverage than testing with OncoBEAM digital PCR (dPCR). OncoBEAM technology is widely considered a gold standard for high sensitivity molecular testing and continues to be one of the most sensitive dPCR approaches.

SafeSEQ technology demonstrates ultra-sensitive detection of low-frequency mutations, with a calling threshold of 5 mutant molecules (0.025% mutant allele frequency [MAF]) from whole blood. Concordance analysis of SafeSEQ and OncoBEAM results demonstrated an overall percent agreement of 99.6% for detection of mutations in EGFR, KRAS, and BRAF (>0.1% MAF).

The 5-year survival rate for metastatic NSCLC (mNSCLC) patients is relatively low; however, it has improved with the advent of targeted therapies and uptake of circulating tumor DNA (ctDNA) based technologies in recent years. In groundbreaking NSCLC clinical trials AURA and TIGER-X, patients positive for EGFR T790M detected in plasma by OncoBEAM had equivalent outcomes to patients positive by a tissue-based assay when treated with third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), which have demonstrated potent activity against first-line EGFR TKI resistance mediated by EGFR T790M.

SafeSEQ NSCLC testing delivers broader genomic coverage than OncoBEAM, with the same ultra-sensitive detection for rare mutant molecules. Therefore, SafeSEQ is better suited to identify molecular mediators of treatment resistance to improve therapeutic strategies, delivering high-resolution monitoring of therapeutic efficacy, and enabling minimum residual disease (MRD) detection and recurrence surveillance for NSCLC patients.

Poster number LB053, "Clinical evaluation of NGS-based liquid biopsy genotyping in non-small cell lung cancer (NSCLC) patients," presented by Hillary Sloane, Associate Director of Medical & Scientific Affairs at Sysmex Inostics, will be available Saturday, April 10, 2021, from 8:30 AM – 11:59 PM EDT during the 112th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) during Session PO.CL11.04 – Liquid Biopsies: Circulating DNA.

Nuvalent Presents Preclinical Data Demonstrating That ROS1 Inhibitor NUV-520 and ALK Inhibitor NUV-655 are Selective, Brain-Penetrant, and Active Against Drug-Resistance Mutations

On April 10, 2021 Nuvalent, Inc., a biotechnology company creating precisely targeted therapies for clinically proven kinase targets in cancer, reported preclinical data supporting advancement of its parallel lead programs in non-small cell lung cancer (NSCLC), including NUV-520 – a potential best-in-class ROS1-selective inhibitor – and NUV-655 – an ALK-selective inhibitor (Press release, Nuvalent, APR 10, 2021, View Source [SID1234577876]). Data are being presented at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting from April 10-15 in two separate poster presentations. Posters will be archived on the Nuvalent website at www.nuvalent.com.

In addition, Nuvalent announces the appointment of leading medical oncologist Alexander Drilon, M.D., to its Scientific Advisory Board (SAB). Dr. Drilon currently serves as Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK) and brings deep expertise in early-phase clinical trials for cancer. At MSK, his research focuses on the development of novel therapeutics for cancer patients who have developed drug-resistance mutations.

"Our parallel lead compounds NUV-520 and NUV-655 were designed to meet a precise set of patient needs identified through close partnership with leading physician-scientists and advisors. We are pleased to share the data leading to the selection of these drug candidates for advancement towards clinical studies based on their demonstrated preclinical ability to meet the identified needs of selectivity, brain penetrance, and activity against drug-resistance mutations in ROS1-and ALK-driven tumors," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "We are also excited to welcome Dr. Alexander Drilon to our Scientific Advisory Board as part of this ongoing partnership with leading physician-scientists to understand the limitations of existing cancer therapies, with the goal of developing precisely targeted therapies to treat cancer."

NUV-520 and NUV-655 are designed to specifically solve for the dual challenges of kinase resistance and selectivity commonly seen with other kinase inhibitors approved for the treatment of advanced NSCLC. NUV-520 selectively inhibits ROS1 compared to the structurally related tropomyosin receptor kinase (TRK) with the potential to minimize TRK-related central nervous system (CNS) adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1-mutant variants. NUV-655 is designed to inhibit ALK fusions and remain active in tumors that have developed resistance to first-, second–, and third-generation ALK inhibitors.

In addition to selective ROS1 and ALK inhibition, Nuvalent is exploring a robust pipeline of programs with a focus on addressing the limitations of existing therapies for other clinically proven kinase targets in oncology.

"I am both encouraged by the treatment opportunities that targeted kinase inhibitors have enabled for patients and inspired to continue pursuing the development of additional therapy options that can overcome remaining clinical challenges," said Dr. Drilon. "Drug-resistant mutations and off-target adverse events can limit the therapeutic impact of kinase inhibitors across various targets in NSCLC as well as other tumor types. I look forward to working with Nuvalent to inform clinical development and advance its novel discovery pipeline of precisely targeted therapies designed specifically to meet these challenges."

AACR 2021 Presentation Overview:

Title: NUV-520 is a brain-penetrant and highly selective ROS1 inhibitor with antitumor activity against the G2032R solvent front mutation
Authors: Henry E. Pelish*, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan
Poster Number: 1465
Session Title: PO.ET06.07 Tyrosine Kinase and Phosphatase Inhibitors
Date: April 10, 2021, 8:30 a.m. – 11:59 p.m.

Summary:

NUV-520 is a potent, highly selective, and brain-penetrant ROS1 inhibitor as demonstrated by in vitro and in vivo studies.
NUV-520 has broad activity against ROS1 resistance mutations, including G2032R, and multiple ROS1 fusions.
NUV-520 is highly selective for ROS1 and ROS1 G2032R over TRKB, indicating the potential to minimize TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1 mutations.
Title: NUV-655 is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation
Authors: Henry E. Pelish*, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan
Poster Number: 1468
Session Title: PO.ET06.07 Tyrosine Kinase and Phosphatase Inhibitors
Date: April 10, 2021, 8:30 a.m. – 11:59 p.m.

Summary:

NUV-655 is a potent, selective, and brain-penetrant ALK inhibitor as demonstrated by in vitro and in vivo studies.
NUV-655 is active against G1202R+ mutations including compound mutations G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F, which confer resistance to all approved ALK therapies.
NUV-655 is selective for ALK and ALK G1202R+ mutations over TRKB, indicating the potential to minimize TRK-related CNS adverse events and drive more durable responses for patients.

ESSA Pharma Presents Preclinical Data Supporting the Therapeutic Potential of EPI-7386 at the 2021 American Association of Cancer Research (AACR) Annual Meeting

On April 10, 2021 ESSA Pharma Inc. ("ESSA" or the "Company") (Nasdaq: EPIX), a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported new preclinical data on ESSA’s lead product candidate, EPI-7386, at the 2021 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is taking place virtually April 10-15, 2021 (Press release, ESSA, APR 10, 2021, View Source [SID1234577875]). EPI-7386 is an investigational, highly selective, oral, small molecule inhibitor of the N-terminal domain of the androgen receptor, which exhibits high potency, low metabolism and on-target specificity.

An e-poster presentation titled, "Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal inhibitor" (Abstract number: 1209) was published and available for viewing starting April 10th at 8:30 a.m. ET.

"Previously, we presented in vitro data demonstrating that EPI-7386 binds to the full-length androgen receptor, inhibits the transcription of AR-regulated genes, and physically interacts with the splice variant form AR-V7. Today, we added to these data by demonstrating that EPI-7386 can prevent the androgen receptor from binding to genomic DNA and is active against additional androgen receptor splice variants, including AR-v567es," said Dr. David R. Parkinson, President and Chief Executive Officer, ESSA Pharma, Inc. "These preclinical data suggest EPI-7386 can potentially inhibit AR related transcription, a key driver of prostate cancer, and further supports our ongoing Phase 1 dose escalation study for metastatic-castration resistant prostate cancer patients, which is now dosing patients in the 800 mg cohort."

Dr. David R. Parkinson added, "Our data also showed that EPI-7386, in combination with enzalutamide, may result in broader and deeper inhibition of the AR pathway, underscoring the potential clinical benefit of combining EPI-7386 with current standard-of-care anti-androgen therapies for prostate cancer patients at earlier stages of the disease. We have recently entered into Phase 1/2 trial clinical partnerships with Janssen to evaluate EPI-7386 in combination with apalutamide or with abiraterone acetate + prednisone, as well as with Astellas to evaluate EPI-7386 in combination with enzalutamide."

The studies highlight new information about EPI-7386 including:

In an in vitro cellular thermal shift assay (CETSA), EPI-7386 was shown to physically interact with both the full-length and the splice variant (AR-V7) form of AR.

In the cellular model CWR-R1-AD1, driven by full-length AR, EPI-7386 inhibited the transcriptional activity of the AR similar to enzalutamide. EPI-7386 was also active in inhibiting AR transcriptional activity and reducing the cell viability in the AR splice variant AR-v567es-driven cellular model CWR-R1-D567 while enzalutamide showed no activity in this model. The AR-v567es splice variant is a clinically-detected AR splice variant that is constitutively active and is unresponsive to anti-androgens.

EPI-7386 demonstrated the ability to strongly reduce binding of AR to genomic DNA in a chromatin immunoprecipitation with sequencing (ChIP-seq) assay conducted in the full-length AR driven model LNCaP.

EPI-7386 exhibits superior activity to enzalutamide in the AR-V7-driven cellular model LNCaP95 by modulating AR-driven gene expression with or without the addition of an external androgen.

In the full-length AR-driven cellular model LNCaP, EPI-7386 inhibits the androgen regulated transcriptome similar to enzalutamide but with a few notable qualitative and quantitative differences.

In the same cellular model, combination treatment of EPI-7386 with enzalutamide displayed broader and deeper inhibition of AR-associated transcriptional activity than higher doses of each single agent alone.

EPI-7386 in combination with ‘lutamide molecules, including apalutamide, enzalutamide, and darolutamide, inhibited AR-associated transcriptional activity, demonstrating broader and deeper inhibition of the AR pathway in the AR amplified VCaP cellular model.
The poster is available on AACR (Free AACR Whitepaper)’s e-poster website and on the "Events & Presentations" section of the Company’s website at www.essapharma.com.

About EPI-7386
EPI-7386 is an investigational, highly-selective, oral, small molecule inhibitor of the N-terminal domain of the androgen receptor. EPI-7386 is currently being studied in a Phase 1 clinical trial (NCT04421222) in men with metastatic castration-resistant prostate cancer ("mCRPC") whose tumors have progressed on current standard-of-care therapies. The Phase I clinical trial of EPI-7386 began in calendar Q3 of 2020 following FDA allowance of the IND and Health Canada acceptance. The U.S. FDA has granted Fast Track designation to EPI-7386 for the treatment of adult male patients with mCRPC resistant to standard-of-care treatment. ESSA retains all rights to EPI-7386 worldwide.

About Prostate Cancer
Prostate cancer is the second-most commonly diagnosed cancer among men and the fifth most common cause of male cancer death worldwide (Globocan, 2018). Adenocarcinoma of the prostate is dependent on androgen for tumor progression and depleting or blocking androgen action has been a mainstay of hormonal treatment for over six decades. Although tumors are often initially sensitive to medical or surgical therapies that decrease levels of testosterone, disease progression despite castrate levels of testosterone can lead to metastatic castration-resistant prostate cancer ("mCRPC"). The treatment of mCRPC patients has evolved rapidly over the past ten years. Despite these advances, many patients with mCRPC fail or develop resistance to existing treatments, leading to continued disease progression and limited survival rates.

Sumitomo Dainippon Pharma Oncology Presents New Data from Investigational Pipeline of Novel Cancer Therapeutics at AACR Virtual Annual Meeting I 2021

On April 10, 2021 Sumitomo Dainippon Pharma Oncology, Inc., a clinical-stage company focused on research and development for novel cancer therapeutics, reported new findings on a range of investigational agents from the company’s pipeline at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Sumitomo Dainippon Pharma, APR 10, 2021, View Source [SID1234577874]).

The data presented at the meeting include preclinical and Phase 1 clinical data evaluating the potential anti-cancer activity of the PKM2 activator TP-1454, PIM inhibitor TP-3654, TNK1 inhibitor TP-5809 and CDK9 inhibitor alvocidib. Additionally, Sumitomo Dainippon Pharma Co., Ltd., the parent company of Sumitomo Dainippon Pharma Oncology (SDP Oncology), presented findings from preclinical studies of DSP-0509, a TLR7 agonist.

"As we advance our investigational agents, we are pleased to present the latest research on our diverse pipeline to the scientific community at the AACR (Free AACR Whitepaper) Virtual Annual Meeting," said Patricia S. Andrews, CEO and Global Head of Oncology, SDP Oncology. "These data reflect our relentless commitment to propelling drug discovery in oncology and our progress in advancing research in hematologic and solid malignancies."

Below are the details for the presentations:

Abstract Title

Details

Presenter

PKM2 Activation Modulates the Tumor-Immune Microenvironment and Enhances Response to Checkpoint Inhibitors in Preclinical Solid Tumor Models

Abstract #606