On September 10, 2024 Telix Pharmaceuticals Limited reported that primary results from its Phase III ZIRCON[1] trial have been published in The Lancet Oncology, reporting that Telix’s first-in-class investigational PET[2] agent, TLX250-CDx (Zircaix[3], 89Zr-girentuximab), is highly accurate in detecting and characterising clear cell renal cell carcinoma (ccRCC) in patients with indeterminate renal masses (IRMs) (Press release, Telix Pharmaceuticals, SEP 10, 2024, View Source [SID1234646489]).

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In this peer-reviewed manuscript, Professor Brian Shuch (University of California, Los Angeles, UCLA) and colleagues report results from this prospective, open-label, multicentre, Phase III trial in which 300 patients with an IRM ≤7cm (cT1) received TLX250-CDx. Authors conclude that TLX250-CDx "has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of ccRCC, which has the potential to be practice changing."

Authors explain that small masses in the kidney are increasingly being detected incidentally when patients undergo abdominal imaging, often for other health conditions, contributing to "an era of gross overtreatment". Diagnosis and treatment are limited by current imaging techniques, and renal mass biopsy is invasive, which can often lead to complications. Up to 30% of patients undergo unnecessary surgery, removing masses that are later determined to be benign[4]. If confirmed, however, ccRCC is the most common and aggressive form of kidney cancer, and delays in diagnosis can significantly reduce survival rates.

Professor Brian Shuch, MD, Director of the Kidney Cancer Program and the Alvin & Carrie Meinhardt Endowed Chair in Kidney Cancer Research at UCLA Institute of Urologic Oncology, and a ZIRCON principal investigator, said, "Until now, assessing whether renal masses are cancerous has been difficult and often involves invasive surgery or percutaneous biopsy. This is because standard imaging technology – either a CT or MRI scan – cannot reliably differentiate between benign or malignant renal lesions or provide information about disease biology.

"The challenges and uncertainty in diagnosing ccRCC underscore a critical unmet need for a new, non-invasive technique that accurately detects and differentiates ccRCC from other renal masses in patients, to inform clinical decision making. The ZIRCON trial has shown that TLX250-CDx is a breakthrough technology that can address this need."

TLX250-CDx is a zirconium-89 (89Zr) radiolabelled monoclonal antibody that targets carbonic anhydrase IX (CAIX), a tumour-associated antigen highly expressed in ccRCC. Following successful Phase I and II trials to establish safety and preliminary efficacy, the ZIRCON trial was designed to assess sensitivity and specificity of TLX250-CDx PET/CT imaging to non-invasively detect ccRCC in patients with cT1 IRMs (≤7 cm in diameter) who underwent nephrectomy, using central histological confirmation as standard of truth.

Key findings of the ZIRCON trial, outlined in the paper, include:

89Zr-girentuximab PET/CT imaging accurately detected ccRCC in patients with cT1 IRM (≤7cm), demonstrating a mean sensitivity of 86%, specificity of 87% and positive predictive value of 93%
89Zr-girentuximab PET/CT imaging has high diagnostic performance for detection and characterisation of small and very small renal masses
The primary and secondary endpoints were met by all three radiology readers and exceeded pre-specified thresholds. Inter-reader variability indicated robust agreement among the readers and intra-reader variability was 100%, indicating perfect agreement
No safety concerns associated with the administration of 89Zr-girentuximab were revealed
Imaging performed 5±2 days after administration is sufficient to visualise and assess ccRCC lesions, with the flexible imaging window offering several advantages for patient management
The non-invasive nature of this technique may be especially beneficial to those at risk of complications from a surgical renal mass biopsy.
Dr David N. Cade, Chief Medical Officer at Telix said, "The results of the ZIRCON trial make a compelling case for TLX250-CDx as a breakthrough product for kidney cancer imaging, and validate CAIX as a novel target to accurately identify renal cell carcinoma.

"Professor Shuch and his co-investigators, at 36 sites worldwide, found that its high diagnostic performance, including for very small lesions, may support early and accurate diagnosis, inform patient risk stratification and clinical decision making, and reduce over- and under-treatment. We believe this result will lead to improved patient outcomes".

If approved by the United States (U.S.) Food and Drug Administration (FDA), TLX250-CDx will be the first and only targeted PET agent specifically for kidney cancer to be commercially available in the U.S.

The full paper can be found at: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00402-9/fulltext

About TLX250-CDx (Zircaix3)

TLX250-CDx (Zircaix3) is an investigational radiodiagnostic PET agent that is under development to characterise IRMs as ccRCC or non-ccRCC in a non-invasive manner. Telix’s pivotal Phase III ZIRCON trial evaluating TLX250-CDx in 300 patients, of which 284 were evaluable, was completed in 2022 and met all primary and secondary endpoints[5].

On September 10, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, cardiovascular and metabolic, ophthalmology and other major diseases, reported the presentation of Phase 1 clinical data (ClinicalTrials.gov, NCT04085185) for IBI363 (first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein) in advanced non-small cell lung cancer at the 2024 World Conference on Lung Cancer (WCLC) (Press release, Innovent Biologics, SEP 10, 2024, View Source [SID1234646488]). Currently, Innovent is conducting Phase 1/2 clinical trials in China, U.S. and Australia to evaluate the safety, tolerability and efficacy of IBI363 in subjects with advanced solid tumors.

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First-in-class PD-1/IL-2α-bias bispecific antibody IBI363 in patients with advanced non-small cell lung cancer in a Phase 1 study

This update on previously reported Phase 1 results focuses on the safety and efficacy of IBI363 in advanced non-small cell lung cancer (NSCLC). As of the follow-up data cutoff date of August 2, 2024, 134 patients were enrolled and received IBI363 monotherapy (up to 3 mg/kg Q3W), with 95.5% having received prior PD-(L)1 immunotherapy. The median duration of IBI363 exposure was 10 weeks, and 77.6% remained on treatment. In the group of 125 patients having at least one post-baseline tumor assessment, the overall ORR was 20.8% and DCR was 74.4%.
IBI363 demonstrated encouraging efficacy signals in IO-treated squamous NSCLC, with a trend toward relatively higher ORR and DCR in the 3 mg/kg Q3W group (n=29）compared to the 1/1.5 mg/kg Q2W/Q3W group (n=27) (see table below). Despite relatively short follow-up time for the 3mg/kg Q3W subgroup, among the 18 patients who had at least 12 weeks of follow-up or end of study, the ORR and DCR were 50% and 88.9%, respectively.
Patients with at least 1
tumor assessment

sqNSCLC

1/1.5 mg/kg
(N=27)

3 mg/kg
(N=29)

3 mg/kg

with at least 12 weeks of follow-up
(N=18)

Best overall response, n (%)

Partial Response (PR)

6*

10**

9***

Stable Disease (SD)

13

16

7

Progressive Disease (PD)

8

2

2

Not Evaluable (NE)

0

1

0

ORR, % (95% CI)

22.2% (8.6, 42.3)

34.5% (17.9, 54.3)

50.0% (26.0, 74.0)

DCR, % (95% CI)

70.4% (49.8, 86.2)

89.7% (72.6, 97.8)

88.9% (65.3, 98.6)

*6 patients had confirmed PR; **9 out 10 patients had confirmed PR; ***8 of 9 patients had confirmed PR.

As of the data cutoff date, for patients with squamous NSCLC who were treated with IBI363 at 1/1.5 mg/kg, the median follow up time was 7.5 months, and the median PFS was 5.5 months (95% CI, 1.5-8.3); currently, the 12-month PFS rate is 30.7%, showing a long-term benefit advantage of immunotherapy. The median PFS was not reached for subjects who received 3mg/kg Q3W.
Similar responses were observed among squamous NSCLC patients with PD-L1 TPS<1% (n=22) and TPS≥1% (n=22) treated across the 1/1.5 mg/kg and 3 mg/kg doses, with ORRs of 36.4% and 31.8% respectively, suggesting IBI363 has efficacy regardless of PD-L1 expression.
IBI363 has a manageable safety profile. The most common treatment related adverse events (TRAEs) included arthralgia, anemia, hyperthyroidism, hypothyroidism and rash. Overall, 20.1% of patients experienced TRAEs ≥ grade 3 and 6.0% experienced TRAE leading to treatment discontinuation. In the 3 mg/kg Q3W subgroup (n=57), 17.5% experienced TRAEs ≥ grade 3 and 5.3% experienced TRAEs leading to treatment discontinuation. The safety profile was consistent with the overall population. No new safety signals were identified.
Given that IBI363 has shown encouraging efficacy signals and good tolerability, this study continues to investigate the long-term efficacy and safety and to determine the RP2D in NSCLC. Additional studies are also underway to evaluate IBI363 in combination with other therapies and in other solid tumors. Relevant data and analyses will be shared in future academic conferences or publications.

Professor Jianya Zhou, The First Affiliated Hospital, School of Medicine, Zhejiang University, stated: "Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer accounting for approximately 80% of cases[1]. While PD-1/PD-L1 inhibitors have shown promising efficacy in non-small cell lung cancer, most patients eventually develop primary or secondary resistance to these immune checkpoint inhibitors. For NSCLC patients who fail IO therapy, effective treatment options are limited, with chemotherapy, such as docetaxel, achieving only about an ORR of 10% and a median PFS of under 4 months[2]. As a key cytokine that activates tumor-specific CD8+T cells, IL-2 complements immune checkpoint inhibitors in its MOA. Combining PD-1 with IL-2 may reverse the exhaustion of tumor-specific CD8+ T cells and help overcome immune resistance. As a PD-1/IL-2α-bias bispecific molecule, IBI363 has demonstrated promising antitumor activity in IO-resistant, driver gene wild-type NSCLC, with clinical benefits shown in both ORR and PFS. Additionally, its manageable safety profile, even at higher doses, provides confidence in its therapeutic potential."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to present the latest data on IBI363 in lung cancer at WCLC. The data highlights the promising trend of IBI363 showing better ORR and DCR at higher doses, alongside a manageable safety profile. Although the follow-up period for the 3 mg/kg dose group is still relatively short, we anticipate more mature data from longer-term follow-up and expect to see its potential as an immunotherapy for long-term survival benefits to patients. Meanwhile, in non-small cell lung cancer, particularly in IO-treated squamous NSCLC, IBI363 has demonstrated potent anti-tumor effects regardless of PD-L1 expression levels. This indicates that IBI363 could potentially offer breakthroughs in treating cold tumors with low or absent PD-L1 expression. We will continue to advance the clinical exploration of IBI363 in squamous NSCLC and other tumor types."

About IBI363 (First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein)

IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein developed independently by Innovent Biologics. It functions by both blocking the PD-1/PD-L1 pathway and activating the IL-2 pathway. The IL-2 arm of IBI363 is designed to maintain its affinity for IL-2Rα while reducing binding to IL-2Rβ and IL-2Rγ, thereby minimizing toxicity. The PD-1 binding arm not only blocks PD-1 but also selectively delivers IL-2. This approach targets and activates tumor-specific T cells that express both PD-1 and IL-2Rα, leading to more precise and effective activation of this T cell subpopulation. IBI363 has demonstrated robust antitumor activity in various tumor-bearing pharmacological models, including those resistant to PD-1 resistance and models of metastasis. In response to urgent clinical needs, Innovent is conducting clinical studies in China, the United States and Australia to further explore the efficacy and safety of IBI363 in advanced tumors.

On September 10, 2024 Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported the expansion of its in vivo chimeric antigen receptor macrophage and monocyte (together, "CAR-M") collaboration with Moderna, Inc. (Nasdaq: MRNA) to include the nomination of two targets for the treatment of autoimmune diseases (Press release, Carisma Therapeutics, SEP 10, 2024, View Source [SID1234646487]). Carisma retains all rights in autoimmune disease beyond the two nominated targets, which will be exclusively partnered with Moderna.

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Under this expanded collaboration, Carisma and Moderna will leverage Carisma’s proprietary CAR-M technology and Moderna’s mRNA/LNP platform to develop novel in vivo macrophage engineering approaches in the nominated autoimmune disease targets. Carisma will receive research funding and is eligible to receive development, regulatory, and commercial milestone payments, plus royalties on net sales of any products that are commercialized under the collaboration agreement. Carisma will be responsible for the discovery and optimization of development candidates, while Moderna will lead the clinical development and commercialization of therapeutics resulting from the agreement.

"We are excited to expand our collaboration with Moderna into the realm of autoimmune diseases," said Steven Kelly, President and Chief Executive Officer of Carisma. "The nomination of the two autoimmune targets is a significant milestone in our mission to harness the power of macrophages to treat a broader range of diseases. Our innovative CAR-M technology has the potential to revolutionize the treatment landscape for patients suffering from these debilitating conditions."

"We are excited to build on the progress of advancing in vivo CAR-M therapies with Carisma by expanding beyond oncology," said Lin Guey, PhD, CSO of Therapeutic Research Ventures, Moderna. "We continue to believe that the combination of our platform and Carisma’s deep myeloid biology expertise could lead to innovative treatments for patients."

The expanded collaboration between Carisma and Moderna underscores the potential of CAR-M technology to impact a diverse range of disease areas. The expansion will aim to bring transformative therapies to patients with cancer and autoimmune diseases, advancing the frontier of immunotherapy.

On September 10, 2024 Lunit (KRX:328130.KQ), a leading provider of AI-powered solutions for cancer diagnostics and therapeutics, reported the presentation of a significant study at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain, from September 13-17 (Press release, Lunit, SEP 10, 2024, View Source [SID1234646486]).

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While Nivolumab plus chemotherapy has recently been approved as a standard first-line treatment for advanced gastric cancer (AGC), its efficacy varies among patients. This variability underscores the critical need for reliable biomarkers to predict treatment response. Lunit’s study addresses this pressing need, potentially offering a new tool to optimize patient care and treatment decisions.

Conducted in collaboration with leading Korean medical institutions, the research showcases the potential of Lunit’s AI-powered histopathology analyzer, Lunit SCOPE IO, in predicting treatment response and guiding treatment decisions for AGC via assessment of immune phenotype.

The study analyzed H&E images from 585 AGC patients, with Lunit SCOPE IO classifying tumors into two immune phenotypes—inflamed (IIP) and non-inflamed—based on the presence and distribution of tumor-infiltrating lymphocytes (TILs) from hematoxylin and eosin (H&E) slides that are readily available from a standard clinical workup. This classification provided valuable insights into the tumor microenvironment and helped predict treatment response, particularly in cases where traditional biomarkers like PD-L1 may not provide a complete picture.

Key findings include:

1. Patients treated with Nivolumab+Chemotherapy showed significantly longer median progression-free survival (mPFS) compared to Chemotherapy alone (8.2 vs. 5.9 months).
2. The inflamed immune phenotype group, classified by Lunit SCOPE IO, was associated with more pronounced PFS benefits from Nivolumab+Chemotherapy:

IIP: 5.2 months longer PFS for Niv+Chemo (mPFS of 11.0 vs 5.8 months)
Non-IIP: only 1.4 months longer PFS for Niv+Chemo (mPFS of 7.3 vs 5.9 months)
3. The predictive value of IIP was consistent across different PD-L1 expression levels.
4. Multivariate analysis confirmed IIP as an independent factor for PFS in patients treated with Nivolumab+Chemotherapy.

"By demonstrating that our AI-powered immune phenotype analysis can predict treatment response independently of PD-L1 status, we’re opening new possibilities for tailoring treatments in AGC," said Brandon Suh, CEO of Lunit. "This is particularly significant because gastric cancer continues to be a leading cause of cancer-related deaths globally, representing 7.7% of all cancer cases. Our AI technology has the potential to enhance the precision of treatment decisions, potentially leading to more effective therapies and better quality of life for patients with AGC."

Please visit Lunit’s poster session at 1411P to discover more about our findings and the innovative capabilities of Lunit SCOPE IO.

Poster presentation featuring Lunit SCOPE IO at ESMO (Free ESMO Whitepaper) Congress 2024:

"AI-powered immune phenotype predicts favorable outcomes of nivolumab (niv) plus chemotherapy (chemo) in advanced gastric cancer (AGC): A multi-center real-world data analysis" (1411P, September 16, 12:00~13:00 PM)

On September 10, 2024 Pillar Biosciences, Inc. reported that it has entered into a strategic partnership with AstraZeneca to expand laboratory access to molecular testing, using rapid, Next Generation Sequencing (NGS)-based liquid biopsy tumor profiling panels for detection of genetic cancer variants, with an initial focus on European markets and the UK (Press release, Pillar Biosciences, SEP 10, 2024, View Source [SID1234646485]).

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The partnership aims to rapidly identify tumors with clinically actionable genomic alterations via liquid biopsy profiling and intends to support faster diagnostic testing by increasing the local availability of plasma-based tumor profiling at leading clinical laboratories.

The work will initially leverage Pillar Biosciences oncoRevealTM Core LBx, Essential LBx, and Fusion LBx research-use-only (RUO) liquid biopsy kitted NGS panels. Pillar’s oncoRevealTM Core LBx panel, which interrogates 104 genes in circulating cell-free tumor DNA (cfDNA), oncoRevealTM Essential LBx panel, which interrogates 34 genes in cfDNA,and oncoRevealTM Fusion LBx, which interrogates various fusion forms from 18 driver genes via circulating cell-free tumor RNA (cfRNA), can be performed by any laboratory, with a sample-to-report time in less than three days. Laboratories will be able to batch test both cfDNA and cfRNA samples from >22 patients on a single Illumina NextSeq run, enabling economic value and scale of sequencing needed to properly profile at extremely high levels of sensitivity and specificity.

"Access to cost effective, easy to use, distributed NGS kits for liquid biopsy testing are critical to support local laboratories in providing clinically actionable results to oncologists and supporting critical treatment decisions for cancer patients globally," said Dan Harma, Chief Commercial Officer, Pillar Biosciences. "Pillar Biosciences LBx panels, including oncoRevealTM Core LBx, oncoReveal EssentialTM LBx and oncoRevealTM Fusion LBx will help provide in-house results locally within a few days vs. several weeks to receive results from sending out their patient samples for most clinical laboratories."

"We are committed to expanding global patient access to biomarker testing, and decentralized NGS solutions are key to this strategy," said John Longshore, Head of Scientific Affairs, Global Oncology Diagnostics, AstraZeneca. "These kit-based methods allow a broad range of laboratories to perform high-quality NGS testing, which improves patient access to targeted therapies. Pillar Biosciences sequencing panels provide rapid, simplified NGS workflows and bioinformatics, which are ideal to supporting our global efforts."