On April 10, 2021 F-star Therapeutics, Inc. (NASDAQ: FSTX), a clinical-stage biopharmaceutical company dedicated to developing next generation bispecific immunotherapies to transform the lives of patients with cancer, reported that preclinical data from FS222, a potentially best-in-class tetravalent bispecific antibody targeting both CD137 and PD-L1 will be presented in a poster at the 2021 American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place virtually from April 10-15 and May 17-21 (Press release, F-star, APR 10, 2021, View Source [SID1234578009]). Poster #1864, entitled ‘FS222, a Tetravalent Bispecific Antibody Targeting CD137 and PD-L1, is Designed for Optimal CD137 Interactions Resulting in Potent T cell Activation Without Toxicity’ will be available via on-demand viewing starting today, April 10, at 8:30 a.m. ET.

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FS222 targets PD-L1, the immune checkpoint protein that regulates the balance of activated T cells in the immune system and is overexpressed on many solid tumors and CD137, a co-stimulatory molecule from the tumor necrosis factor receptor superfamily (TNFRSF), which is widely known to be upregulated on tumor-reactive CD8+ T cells or "killer T cells". Currently, only a minority of patients have a long-lasting response to monotherapies that block the PD-(L)1 pathway.

Neil Brewis, Chief Scientific Officer at F-star Therapeutics, said: "We are encouraged by the results of these latest preclinical studies of FS222, our tetravalent bispecific antibody targeting PD-L1 and CD137. This work further demonstrates that FS222’s tetravalent binding mechanism is the most efficient and effective format for bispecific antibodies. The early onset of activity and T cell proliferation gives us confidence that FS222 will allow for a wide range of treatment options."

FS222 was designed to be a potent human CD137/PD-L1 tetravalent conditional agonist with a unique combination of high affinity PD-L1 binding, and moderate affinity, but with high avidity, binding to CD137 on activated T cells to result in optimal receptor clustering. Previously, FS222 has been shown to exhibit a favorable safety profile in preclinical safety studies.

Tetravalent binding by FS222 demonstrated optimal activity in multiple preclinical pharmacology studies, outperforming classic heterodimeric bispecific antibodies. These data showed that there was no evidence of a hook effect, or bell-shaped dose response curve, in vitro, and coupled with FS222’s favorable safety profile, presents a potentially broad and differentiated therapeutic window. A murine surrogate mAb2 for FS222 had peripheral immunopharmacology, as shown by CD8+ T cell proliferation, at high dose levels, mirroring the in vitro data, whereby the tetravalent FS222 surrogate mAb2 outperforms other lower valency formats.

In January 2021, F-star announced that the first patient had been dosed in a Phase 1 clinical trial of FS222, a multicenter, open-label, first-in-human trial to evaluate the safety, tolerability, and early signs of efficacy of FS222 in adult patients diagnosed with advanced malignancies. The adaptive study design will allow for the early exploration of clinical activity of FS222 in a range of selected solid tumors that will guide future targeted clinical development.

On April 10, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer and castrate-resistant prostate cancer, in collaboration with scientists in the Center for Precision Cancer Medicine at the Massachusetts Institute of Technology (MIT), reported that new gene signature and mechanistic analyses related to its ongoing Phase 2 trial of onvansertib in metastatic castrate-resistant prostate cancer (mCRPC) were featured in a virtual oral poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Cardiff Oncology, APR 10, 2021, View Source [SID1234577879]).

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Analyses presented in the poster suggest that the androgen receptor signaling inhibitor (ARSi) abiraterone sensitizes certain prostate cancer cells to onvansertib by upregulating a set of mitosis related genes and disrupting mitotic spindle orientation. These results are consistent with previous findings showing that onvansertib and abiraterone synergize in an androgen receptor (AR)-independent manner in-vitro and in-vivo.

"The latest results from our collaborative studies with Cardiff Oncology provide important insight into the mechanisms of synergy between onvansertib and abiraterone in mCRPC," said Michael B. Yaffe, M.D., Ph.D., David H. Koch Professor of Science and Professor of Biology and Biological Engineering at the Massachusetts Institute of Technology. "Data showing a cellular mechanism for how these two compounds synergize in an AR-independent manner provide a strong scientific rationale for Cardiff Oncology’s ongoing Phase 2 trial and explain how the addition of onvansertib can improve clinical outcomes in patients showing initial abiraterone resistance. We have also identified a set of genes that appear to drive this mechanism of onvansertib-abiraterone synergy as well as predict patient response and archived clinical trial tissue from patients enrolled in the ongoing trial are being analyzed to confirm this hypothesis."

Mark Erlander, Ph.D., chief executive officer of Cardiff Oncology added, "The identification of a gene signature that appears to predict patient response to onvansertib-abiraterone combination therapy is encouraging, as is the finding that this signature is enriched in mCRPC patients with the known molecular basal tumor subtype. We look forward to continuing to work with our collaborators at MIT and Decipher Biosciences to validate this gene set as a predictive response biomarker. Validation of such a biomarker would be significant, as it would allow us to take a precision medicine approach to future trials by enabling the identification of patients most likely to benefit from therapy with onvansertib."

Highlights from the AACR (Free AACR Whitepaper) presentation include:

Inhibition of polo-like kinase 1 (PLK1) sensitizes CRPC cells to abiraterone, but not the ARSi enzalutamide, indicating that abiraterone and PLK1 inhibitors synergize in an AR-independent manner.
In vitro experiments and RNA sequencing analyses indicate that abiraterone’s AR-independent effects include the disruption of mitotic spindle orientation and the induction of a mitosis related gene signature.
Data suggest that the identified mitosis related gene signature may be predictive of patient response to onvansertib-abiraterone combination therapy, a hypothesis that is being further assessed in an ongoing Phase 2 trial evaluating the all-oral regimen of onvansertib, abiraterone and prednisone in mCRPC patients.
The identified mitosis related gene signature was found to be significantly enriched in the basal molecular subtype of prostate cancer.
The virtual poster, "The selective polo-like kinase (Plk1) inhibitor onvansertib and the antiandrogen abiraterone synergistically kill cancer cells through disruption of mitosis independently of androgen receptor signaling" by Patterson et al, is available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and is also posted on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

About the Phase 2 Trial of Onvansertib in Metastatic Castrate-Resistant Prostate Cancer

This trial is a Phase 2 open-label study of onvansertib in combination with abiraterone and prednisone, all administered orally, in patients with metastatic castration-resistant prostate cancer showing signs of early progressive disease (demonstrated by two rising prostate-specific antigen values separated by at least one week with no or minimal symptoms) while on Zytiga/prednisone therapy. The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by a lack of prostate-specific antigen (PSA), radiographic, or symptomatic progression. The trial is being conducted by Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer Institute (DFCI), and Massachusetts General Hospital Cancer Center (MGH). David Einstein, M.D., Genitourinary Oncology Program at BIDMC, is the principal investigator for the trial. For more information on the trial, please visit View Source

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.

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"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.

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]).

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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.

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.

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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.