On December 16, 2022 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported positive topline results from the Phase 3 GLOW clinical trial evaluating the efficacy and safety of zolbetuximab in combination with CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) (Press release, Astellas, DEC 15, 2022, View Source [SID1234625296]). Zolbetuximab is an investigational first-in-class Claudin-18.2 (CLDN18.2) targeted monoclonal antibody, for the first-line treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

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The GLOW study met its primary endpoint showing statistical significance in progression-free survival (PFS) for patients treated with zolbetuximab plus CAPOX compared to placebo plus CAPOX. In addition, the study met a key secondary endpoint, overall survival (OS), showing statistical significance for patients treated with zolbetuximab plus CAPOX compared to placebo plus CAPOX. The most frequent treatment-emergent adverse events (TEAEs) were nausea and vomiting. Detailed results will be presented at a future scientific congress and submitted for publication.

"Zolbetuximab has the potential to be an innovative therapeutic option for patients with locally advanced unresectable or metastatic gastric or GEJ cancer, a difficult disease for which treatment options are still limited," said Ruihua Xu, MD, PhD, Primary Investigator for the GLOW study and Professor in the Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China. "I am so pleased with the topline results from GLOW that establish progression-free survival and overall survival in patients treated with zolbetuximab plus CAPOX."

"We are extremely pleased to share positive topline results from GLOW following the positive SPOTLIGHT readout last month. This further confirms the potential role of zolbetuximab in gastric cancer treatment, an important milestone in our gastric cancer development program," said Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Development Therapeutic Areas, Astellas. "We intend to discuss these results with regulatory authorities as we continue to develop zolbetuximab for the first-line treatment of patients with locally advanced unresectable or metastatic gastric and GEJ cancer."

Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways – antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).1 CLDN18.2 is a type of transmembrane protein found in normal gastric cells and is a major component of epithelial tight junctions controlling the flow of molecules between cells.2 Pre-clinical studies have shown that CLDN18.2, which is frequently present in gastric tumors, may become more exposed and accessible to targeted antibodies as gastric tumors develop.3,4,5 Based on the SPOTLIGHT and GLOW studies, approximately 38% of these patients have CLDN18.2-positive tumors, meeting the qualification of CLDN18.2 expression in ≥75% of tumor cells with strong to moderate staining intensity based on a validated immunohistochemistry assay.6

The Phase 3 GLOW trial (n=507) is a global, multi-center, double-blind, randomized study assessing the efficacy and safety of zolbetuximab plus CAPOX compared to placebo plus CAPOX. This study, and the Phase 3 SPOTLIGHT trial (n=565), which evaluated the efficacy and safety of zolbetuximab plus a combination regimen of oxaliplatin, leucovorin and fluorouracil (mFOLFOX6) compared to placebo plus mFOLFOX6, were conducted to provide foundational data for regulatory submissions in the U.S., Europe, Asia and other countries globally. These studies are part of Astellas’ gastric cancer development program to investigate new treatment options such as zolbetuximab and address patient needs in locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

Gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor’s origin to other body tissues or organs.7 The five-year relative survival rate for patients at the metastatic stage is approximately six percent.

On December 15, 2022 Akoya Biosciences, Inc., (Nasdaq: AKYA), The Spatial Biology Company, reported the latest wave of spatial biology innovations, new products, and partnerships that further accelerate and simplify spatial signature discovery and validation, at its second annual Spatial Day event (Press release, Akoya Biosciences, DEC 15, 2022, View Source [SID1234625295]). Company leadership and leading scientists came together to discuss advancements in spatial biology and the progress towards delivering spatial signatures to advance the field of precision medicine.

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Akoya’s flagship platforms, PhenoCycler-Fusion and PhenoImager HT, enable a deeper understanding of biology, disease progression, and response to therapy through rapid and scalable multiomic mapping of tissue architecture.

At this year’s Spatial Day, the company introduced a suite of ready-to-use PhenoCode panels to accelerate the adoption and utilization of the company’s spatial phenotyping solutions for discovery and translational research. The company also announced PhenoCycler-Fusion platform improvements to double throughput and an expanded list of software and data analysis partners to provide customers with a range of flexible and fit-for-purpose data analysis solutions.

"With the launch of our PhenoCycler-Fusion system, we set a new standard for accelerating spatial biology at scale, allowing meaningful conclusions to be drawn from increasingly larger and more complex cohorts of samples," said Brian McKelligon, Chief Executive Officer of Akoya Biosciences. "With our new PhenoCode Discovery and Signature Panels, rapidly expanding and powerful options for data analysis, and instrument enhancements, we deliver a higher standard enabling the most productive and scalable spatial biology workflow, putting even more power into the hands of our customers."

The following new product introductions to Akoya’s end-to-end spatial biology solutions address specific requirements of discovery, translational, and clinical researchers.

PhenoCode Ready-to-Use Panels to Accelerate Spatial Discovery and Signature Development – To further accelerate system utilization, Akoya is introducing a series of ready-to-use panels for use across the entire portfolio. Launched at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting this year, the PhenoCode Signature Panels for the PhenoImager instruments are based on a novel barcoded chemistry and include markers for phenotyping the tumor microenvironment and immune status. The customizable panels provide translational and clinical researchers with a ready-made solution to rapidly advance biomarker programs. Additional PhenoCode Signature Panels will be announced and introduced in 2H 2023. In 1H 2023, PhenoCode Discovery Panels will be introduced for the PhenoCycler-Fusion system. These discovery panels will focus on providing comprehensive coverage of key biomarkers in oncology and inflammatory disease. Similar to the PhenoCode Signature Panels, additional PhenoCode Discovery Panels will be introduced in 2H 2023, expanding into additional therapeutic areas such as neuroscience. The company also detailed the rollout of a co-marketed offering with Bio-Techne in 1H 2023 and the introduction of Akoya’s spatial transcriptomics offering in 2H 2023.

An Ecosystem of Software Partners to Simplify Data Analysis – The growing adoption of spatial biology across all market segments is catalyzing development of a rapidly expanding list of organizations focused on developing data analysis and software solutions. To capitalize on this, and for the benefit of the company’s customers, Akoya continues to expand on its current ecosystem of software partnerships to now include OracleBio, Indica Labs, and Enable Medicine. These are in addition to Akoya’s long-standing partnerships with both Visiopharm and PathAI. The result is a suite of tools and services that can enable turnkey analysis of whole-slide, high-plex data to meet the needs of all customer segments.

The key to enabling these partnerships is Akoya’s standardization and compression of data generated on the company’s platforms. Spatial data generated by the PhenoCycler-Fusion and PhenoImager HT platforms are compressed into a manageable size and a standardized file format, termed QPTIFF, for downstream storage and analysis. This is done in real time on the instrument and utilizes a proprietary algorithm that reduces file sizes from terabytes to gigabytes. By reducing file sizes, researchers can easily manage their data and eliminate lengthy post-processing steps, allowing them to confidently scale-up spatial discovery efforts with larger panels and study sizes. With this suite of software partners, Akoya meets the diverse data analysis needs of discovery, translational, and clinical researchers.

Instrument Enhancements for Higher Throughput and Automation – New enhancements to the PhenoCycler-Fusion system enable a doubling of the platform’s throughput. The PhenoCycler-Fusion 2.0 workflow includes a multi-slide carrier which enables labs to process twice as many samples per week and will be available in 1H 2023. The upgrade also enables automation of Bio-Techne’s RNAscope assay for visualization and spatial detection of single RNA molecules.

On December 15, 2022 Targovax ASA (OSE: TRVX), a clinical-stage immuno-oncology company developing immune activators to target hard-to-treat solid tumors, reported that it has entered into a collaboration agreement with The University of Kansas Cancer Center (KU Cancer Center) and Agenus Inc. to run a clinical trial testing mutant RAS vaccine TG01 in combination with PD-1 CPI balstilimab in pancreatic cancer following surgery and standard-of-care (SoC) chemotherapy (Press release, Targovax, DEC 15, 2022, View Source [SID1234625291]).

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Pancreatic cancer is the third leading cause of cancer-related deaths with less than 10% 5-year survival from diagnosis. Chemotherapy remains the standard-of-care (SoC) therapy, and clinical trials with CPIs or targeted agents have to date been largely unsuccessful and not led to any new product approvals. As such, there is a major unmet medical need for novel, effective agents to improve outcomes for pancreatic cancer patients.

Mutations in the RAS genes are found in over 90% of pancreatic cancers, and therefore represent a particularly attractive target in this disease. Targovax´s RAS immunotherapy TG01 targets all of the most common RAS mutations observed in pancreatic cancer and has previously demonstrated promising immune responses and survival benefit after surgery in a phase 1 trial.

The planned study will be led by gastrointestinal cancer expert Dr. Anup Kasi in a three-way clinical collaboration between KU Cancer Center, Agenus and Targovax testing TG01 vaccination combined with Agenus´ immune-stimulatory adjuvant QS-21 STIMULON and PD-1 CPI balstilimab. TG01 vaccination +/- balstilimab will be tested in 24 pancreatic cancer patients who have detectable disease by circulating tumor DNA analysis of blood samples1 following surgery and SoC. The aim is to evaluate whether mutant RAS T-cell responses generated by TG01, and further boosted by QS-21 STIMULON and balstilimab, may have the potential to eliminate remaining cancer cells to prolong time to relapse and extend patient survival.

Dr Anup Kasi, Associate Professor at The University of Kansas Cancer Center, said: "Targovax has demonstrated encouraging early data for their mutant KRAS immunotherapy, and I am very excited about the opportunity to test the enhanced TG01 vaccine at our center using ctDNA as a blood-based biomarker to track efficacy in real-time. The core aim of the study is to assess whether the expected synergy between TG01 and PD-1 checkpoint inhibitor balstilimab may prolong time to relapse in a therapeutic window where we have nothing available today."

Dr Erik Digman Wiklund, Chief Executive Officer of Targovax ASA, added: "We are continuing to execute on our strategy of bringing the TG-program forward in cost-efficient, collaborative set-ups. This study is a major milestone as our first US-based RAS vaccine trial and the first time we combine TG01 with checkpoint blockade. Dr. Kasi has developed an innovative study design deploying cutting-edge ctDNA technology to track patient responses. The scientific rationale behind the concept is solid, and we believe post-surgery pancreatic cancer is the ideal setting to test it. If successful, this can provide the first RAS-targeted immunotherapy to address this major unmet medical need."

As previously communicated, Targovax has been awarded two prestigious research grants from Innovation Norway (IN) and the Norwegian Research Council (NRC) to advance the TG program in several clinical studies. This Phase 1/2 trial at KU Cancer Center will be the first randomized study to test TG01 both as a monotherapy and in combination with PD-1 CPI. Targovax will be responsible for TG01 drug supply, scientific support and will provide a financial contribution to KU Cancer Center through the IN and NRC research grants. Agenus will provide drug supply and scientific support. The Investigational New Drug (IND) Application for TG01 has been authorized and the trial has been given the approval to move ahead by the US FDA. The study is set to be activated at KU Cancer Center on December 15.

About TG01 mutant RAS vaccine
TG01 is a RAS neoantigen therapeutic cancer vaccine adjuvanted by QS-21 STIMULON, which targets the seven most commonly found RAS mutations in pancreatic cancer. The vaccine is formulated as a polyvalent peptide mixture and covers 99% of RAS-mutated pancreatic cancer patients. TG01 has previously demonstrated robust immune responses and clear signal of clinical activity in resected pancreatic cancer in in the adjuvant setting combined with standard of care chemotherapy.

On December 15, 2022 AstraZeneca and MSD reported that the US Food and Drug Administration (FDA) has informed AstraZeneca that it will extend the Prescription Drug User Fee Act (PDUFA) date by three months to provide further time for a full review of the supplementary new drug application (sNDA) for Lynparza (olaparib) in combination with abiraterone and prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, DEC 15, 2022, View Source [SID1234625278]). The companies will continue to work with the FDA to facilitate the completion of the agency’s review.

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The sNDA is based on results from the pivotal PROpel Phase III trial, which were published in June 2022 in NEJM Evidence. In August 2022, the sNDA was granted Priority Review and AstraZeneca and MSD are committed to working with the FDA to bring this treatment option to patients with mCRPC.

In November, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion recommending approval of Lynparza in combination with abiraterone and prednisone or prednisolone in the EU for the treatment of adult patients with mCRPC for whom chemotherapy is not clinically indicated. This combination is also undergoing regulatory reviews in other countries.

Lynparza is approved in the US based on results from the PROfound Phase III trial as monotherapy for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone; and in the EU, Japan, and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent.

Notes

Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.11 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.12

In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.6 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.6 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.5

Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is high unmet need in this population.6,8,9,13

PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting.

Men in both treatment groups also received either prednisone or prednisolone twice daily. The primary endpoint is investigator-assessed rPFS, with sensitivity analyses by BICR, and secondary endpoints include overall survival, time to secondary progression or death, time to first subsequent therapy, and quality of life measures.

In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway.

AR signalling engages a transcriptional programme that is critical for tumour cell growth and survival in prostate cancer.14,15 Preclinical models have identified interactions between PARP signalling and the AR pathway which support the observation of a combined anti-tumour effect of Lynparza and NHAs, like abiraterone, in both HRR deficient and HRR proficient prostate cancer.16-18

The PARP1 protein has been reported to be required for the transcriptional activity of androgen receptors; therefore, inhibiting PARP with Lynparza may impair the expression of androgen receptor target genes and enhance the activity of NHAs.14,17,19 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficiency and increase sensitivity to PARP inhibition.16,18,20,21

For more information about the trial please visit ClinicalTrials.gov.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for gBRCAm, HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; and HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On December 14, 2022 Carina Biotech files its first IND application for a CAR-T cell therapy targeting a solid cancer (Press release, Carina Biotech, DEC 15, 2022, View Source [SID1234625251]). The IND application is directed at a first-in-human Phase 1/2a clinical trial in advanced colorectal cancer patients.

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has submitted an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) for first-in-human Phase 1/2a clinical trial of CNA3103, its LGR5-targeted chimeric antigen receptor T cell (CAR-T) therapy candidate, in patients with advanced colorectal cancer.

"We are delighted to achieve the major milestone of submitting this first IND to the FDA for our lead LGR5 CAR-T cell therapy candidate as our team continues to advance Carina’s vision to create a future that defeats cancer," said Deborah Rathjen, PhD, Carina’s Chief Executive Officer.

"Colorectal cancer is a lethal cancer, and a clear need exists for more effective treatment options. CAR-T cell therapy is a revolutionary and targeted cancer treatment option that harnesses a patient’s own immune system to fight their cancer. We are targeting the recruitment of the first patients in the Phase 1/2a trial in early 2023."

"Carina’s CAR-T cell therapy candidate, CNA3103, is targeted at LGR5, a cancer stem cell marker that is highly expressed on advanced colorectal cancer and some other cancers," stated José Iglesias, MD, Carina’s Chief Medical Officer. "In colorectal cancer patients, LGR5 expression has been correlated with a particularly poor prognosis and by targeting cancer stem
cells, this therapy may potentially reduce the tumor’s ability to generate new cancer cells, resulting in enhanced tumor suppression and preventing the relapses that are very common in patients with this disease."

Dr Iglesias added, "Colorectal cancer is the third most common cancer worldwide and the third most common cancer diagnosed in the United States, excluding skin cancers. Colorectal cancer is the deadliest cancer for young Australians and the second deadliest cancer for all Australians with its incidence rising in people under 50. Many younger people, who are often
diagnosed when their cancer is in its later stages, are given a very poor prognosis with very limited treatment options."