On April 29, 2025 AstraZeneca reported that a fixed-duration regimen of Calquence (acalabrutinib) in combination with venetoclax, with or without obinutuzumab, has been recommended for approval in the European Union (EU) for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, AstraZeneca, APR 29, 2025, View Source [SID1234652259]).

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the AMPLIFY Phase III trial, which were presented at the American Society of Haematology (ASH) (Free ASH Whitepaper) 2024 Annual Meeting and published in The New England Journal of Medicine.1

Results showed Calquence plus venetoclax reduced the risk of disease progression or death by 35% compared to standard-of-care chemoimmunotherapy (investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab; hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.49-0.87; p=0.0038). Calquence plus venetoclax with obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death compared to standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p<0.0001).2

At three years, 77% of patients treated with Calquence plus venetoclax and 83% of patients treated with Calquence plus venetoclax and obinutuzumab were progression free, versus 67% of patients treated with chemoimmunotherapy.1 Median progression-free survival (PFS) was not reached for either experimental arm versus 47.6 months for chemoimmunotherapy.1

Wojciech Jurczak, MD, Maria Sklodowska-Curie National Institute of Oncology, Kraków, Poland and investigator for the trial, said: "Chronic lymphocytic leukaemia is an incurable cancer which means patients live with the disease and stay on treatment for many years, which can have long-term effects. The fixed-duration Calquence regimens will allow patients to take breaks from their treatment, reducing the risk of long-term adverse events and drug resistance."

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "With this recommendation, Calquence plus venetoclax can potentially be the only all-oral second-generation BTK inhibitor option approved in Europe for patients with previously untreated chronic lymphocytic leukaemia. Calquence has demonstrated efficacy and safety in fixed-duration and treat-to-progression regimens providing patients and their doctors more treatment flexibility."

CLL is the most common type of leukaemia in adults, with an estimated 27,000 patients diagnosed in the UK, France, Germany, Spain and Italy in 2024.3

The safety and tolerability of Calquence was consistent with its known safety profile, and no new safety signals were identified.

Regulatory applications for Calquence plus venetoclax, with or without obinutuzumab, in this setting are currently under review in several countries based on the AMPLIFY results.

Notes

Chronic lymphocytic leukaemia (CLL)
CLL is the most prevalent type of leukaemia in adults, with over 117,000 new cases globally in 2021.4 Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.5 In CLL, there is an accumulation of abnormal lymphocytes within the blood, bone marrow and lymph nodes. As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets.6 This could result in infection, anaemia and bleeding. B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

AMPLIFY
AMPLIFY is a randomised, global, multi-centre, open-label Phase III trial evaluating the efficacy and safety of Calquence in combination with venetoclax, with or without obinutuzumab, compared to investigator’s choice of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in adult patients with previously untreated CLL without del(17p) or TP53 mutation.7 Patients were randomised 1:1:1 to receive either Calquence plus venetoclax, Calquence plus venetoclax with obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy.7 Both the Calquence containing arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was for 6 cycles.7

The primary endpoint is PFS in the Calquence and venetoclax arm as assessed by an Independent Review Committee and PFS in the Calquence plus venetoclax with obinutuzumab is a key secondary endpoint.7 Other key secondary endpoints include OS and undetectable measurable residual disease.7 The trial includes 27 countries across North and South America, Europe, Asia and Oceania.7

The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic.7 Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalisation and death compared to the general population.8

Calquence
Calquence (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.9 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

Calquence is approved for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in the US, Japan and China, approved for CLL in the EU and many other countries worldwide. Calquence is also approved for the treatment of adult patients with previously untreated MCL in the US and other countries. It is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in China and several other countries. Calquence is not currently approved for the treatment of MCL in Japan.

As part of an extensive clinical development programme, Calquence is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma.

On April 29, 2025 Nouscom, a clinical-stage biotech company developing next-generation neoantigen-targeted off-the-shelf and personalized cancer immunotherapies, reported complete safety and immunogenicity results from a Phase Ib/II study evaluating NOUS-209 in individuals with Lynch Syndrome (LS) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, NousCom, APR 29, 2025, View Source;utm_medium=rss&utm_campaign=nouscom-presents-positive-final-results-from-completed-phase-ib-ii-study-of-neoantigen-immunotherapy-nous-209-at-aacr-2025-demonstrating-a-highly-potent-and-durable-immune-response-in-lynch-syndrome [SID1234652315]). The study found that NOUS-209 monotherapy was safe, well-tolerated and induced potent, broad and durable immune responses in all LS carriers evaluated.

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LS is a common inherited condition that significantly increases a person’s risk of developing microsatellite instability (MSI)-associated cancers over their lifetime. Managing LS is limited to frequent screenings or elective organ removal surgery. NOUS-209 is an investigational off-the-shelf cancer immunotherapy that targets tumors with mismatch repair deficiency (dMMR) and/or MSI. These tumors produce markers known as frameshift peptide neoantigens (FSPs). NOUS-209 is a pioneering approach to cancer interception comprising two proprietary viral vectors that deliver 209 shared FSP neoantigens and train the immune system to recognize and attack cancerous and pre-cancerous cells before tumors can fully develop.

The completed Phase Ib/II trial evaluated safety and immunogenicity in 45 LS carriers demonstrated;

Favorable Safety Profile: NOUS-209 was well tolerated, with no serious treatment-related adverse events across the entire study population.
Potent and Durable Immunogenicity Profile: Neoantigen-specific T cell responses were reported in 100% of evaluable participants (n=37). Responses were robust, reaching a mean of ~1100 interferon-gamma (IFN-γ) spot forming cells (SFC) per million of Peripheral Blood Mononuclear Cells (PBMCs). Immune responses were durable, with tumor-specific T cells detected after 1 year in >85% of participants (n=33).
Broad, Polyspecific T Cell Response: Immune responses were confirmed against 115 different FSP neoantigens to date, validating the ability of NOUS-209 to elicit broad polyspecific immune responses.
Desired T Cell Phenotype: NOUS-209 induced neoantigen-specific CD8 and CD4 T cells, exhibiting an effector memory phenotype associated with long-lived immunity critical for sustained surveillance and ability to eliminate emerging tumor cells.
Demonstration of Tumor Cell Killing: T cells induced by NOUS-209 were shown to directly kill tumor cells ex vivo, confirming functional anti-cancer activity.
Target Validation in LS-Associated Premalignant and Cancer Lesions: The vast majority of the immunogenic FSP neoantigens were shown to be present in both pre-cancerous as well as cancer lesions from independent cohorts of LS carriers.
These data support the further clinical development of NOUS-209 as a monotherapy in LS carriers. Following positive Type B and C meetings with the US Food and Drug Administration (FDA), Nouscom has a clear path forward for the advancement of NOUS-209 to a potentially registration-enabling Phase 2/3 clinical study for cancer interception in those living with LS.

"Currently, individuals with Lynch Syndrome rely on frequent screenings, such as colonoscopies, to manage their markedly increased risk of developing cancer. These latest data are a step toward a completely new approach – leveraging the immune system for cancer interception," said the study’s principal investigator, Eduardo Vilar-Sanchez, M.D., Ph.D., Professor of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center. "NOUS-209 has shown clear evidence that the T cells it activates can persist over time, effectively target and kill tumor cells and develop into memory cells that support long-term immune protection. These findings support NOUS-209’s potential as a cancer interception strategy."

"Nouscom’s proprietary viral vector platform is uniquely positioned to deliver rapid, potent and broad immune activation against a large number of shared neoantigens, with minimal reactogenicity and durable immune responses," said Dr. Elisa Scarselli, Chief Scientific Officer of Nouscom. "These compelling Phase Ib/II data further reinforce our confidence in NOUS-209 monotherapy to safely and effectively prime the immune system to recognize and intercept pre-malignant and cancer lesions before they progress into tumors in LS carriers."

Dr. Marina Udier, Chief Executive Officer of Nouscom, added: "We are enormously pleased with these robust Phase Ib/II data and look to progress toward a potentially registration-enabling Phase 2/3 clinical study for cancer interception in LS. We remain deeply committed to advancing NOUS-209 and bring better solutions for people living with LS who urgently need and deserve a better way to manage their cancer risk."

The study was led by researchers at MD Anderson, in collaboration with the Cancer Prevention Clinical Trials Network and sponsored by the National Cancer Institute (grant # UG1CA242609) of the National Institutes of Health. These data were presented during the Hot Topics in Cancer Prevention session, and the abstract is available on the AACR (Free AACR Whitepaper) website here.

On April 29, 2025 SOTIO Biotech, a clinical-stage biopharmaceutical company owned by PPF Group, this week reported preclinical data on two of its leading antibody-drug conjugate (ADC) candidates, SOT109 and SOT106, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, IL (Press release, SOTIO, APR 29, 2025, View Source [SID1234652336]).

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Preclinical data on SOT109 (anti-CDH17 ADC) and SOT106 (anti-LRRC15 ADC) demonstrate strong anti-tumor activity and favorable tolerability profiles across multiple tumor models, supporting their potential as groundbreaking ADC therapies for various solid tumor types.

SOT109 is tailored to be a best-in-class ADC exploiting the highly promising target of CDH17 for treatment of gastrointestinal cancers including colorectal cancer (CRC), where unmet need remains very high. ADCs have shown limited clinical success in CRC to date largely due to a lack of ideal target antigens. CDH17 is a highly promising target antigen homogenously overexpressed in more than 90% of CRC and abundantly expressed in other GI cancers. Its expression in normal adult tissues is largely restricted to the GI tract, reducing the risk of off-target toxicity. SOT109 utilizes a proprietary, highly internalizing and fully human antibody combined with Synaffix B.V.’s leading ADC technology platform. Both the antibody and the epitope it is targeting, as well as the linker/payload design, have been selected to maximize its efficacy and safety.

SOTIO’s poster presentation on SOT109 showed the following:

SOT109 exhibited potent efficacy, producing significant and sustained tumor regressions in several in vivo colorectal tumor models, including cell-derived and patient-derived xenografts.
The doses tested in these studies were well tolerated in mice, with no dose-limiting toxicities observed. Subsequent studies in non-human primates confirmed a favorable pharmacokinetic and safety profile.
SOT106, leveraging LigaChem Biosciences’ clinically validated ConjuAll ADC platform for tumor-specific MMAE release, is a potentially best-in-class ADC for the clinically-validated target LRRC15. SOTIO’s oral presentation on SOT106 showed the following:

SOT106 demonstrated exceptional efficacy in an LRRC15 low-expressing patient-derived xenograft model of pediatric osteosarcoma, achieving significant tumor regression where a first-generation LRRC15-targeting ADC benchmark therapy was ineffective. This further supports its therapeutic potential across a broad range of target expression levels.
Complete responses and potent antitumor efficacy were also observed across a range of other models where LRRC15 is expressed directly on tumor cells, including multiple subtypes of soft tissue sarcoma, a therapy-resistant non-small-cell lung cancer model, and head and neck squamous cell carcinoma.
SOT106 displays a favorable pharmacokinetic and safety profile, good stability in vivo, and a high therapeutic index.
"The data we presented at AACR (Free AACR Whitepaper) this week highlights the strength of our next-generation ADCs by addressing areas of high unmet need in oncology," said Martin Steegmaier, Ph.D., chief scientific officer at SOTIO. "SOT109 continues to show excellent tolerability and strong anti-tumor activity across multiple preclinical models of colorectal cancer, while SOT106 offers a novel precision approach with broad applicability in LRRC15+ sarcomas and other solid tumors. These findings mark important progress in our pipeline and reinforce our commitment to developing highly differentiated ADCs for difficult to treat solid tumors."

Presentation materials will be available here after the presentation concludes.

On April 29, 2025 AstraZeneca reported first quarter financial results for the year 2025 (Press release, AstraZeneca, APR 29, 2025, View Source [SID1234653617]).

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On April 29, 2025 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which supports the rational molecular design of zidesamtinib, its novel and selective ROS1 inhibitor (Press release, Nuvalent, APR 29, 2025, https://investors.nuvalent.com/2025-04-29-Nuvalent-Announces-Publication-in-Molecular-Cancer-Therapeutics-Reinforcing-Rational-Molecular-Design-of-Zidesamtinib-as-a-Novel-ROS1-Selective-Inhibitor [SID1234652317]). Zidesamtinib is currently being evaluated in the ongoing ARROS-1 Phase 1/2 trial for patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors, which is designed with registrational intent for tyrosine kinase inhibitor (TKI) pre-treated and TKI-naïve patients with advanced ROS1-positive NSCLC.

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The publication, entitled "Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations," is published online and can be accessed here: View Source

"Zidesamtinib was specifically designed with the goal of addressing the combined medical needs of treating tumors that have developed resistance, treating brain metastases and avoiding off-target adverse events. Structural studies play a critical role in the development and optimization of novel therapeutics, particularly when aiming to solve for multiple, and at times competing, challenges. To date, structural studies for ROS1-positive cancers have been hindered by a lack of ROS1 G2032R crystal structures, despite G2032R being the most commonly occurring ROS1 resistance mutation," said first author Anupong Tangpeerachaikul, Ph.D., Director, Biology at Nuvalent. "With this publication in Molecular Cancer Therapeutics, we are pleased to have shared what is, to our knowledge, the first structure of ROS1 G2032R, or any ROS1 mutation, offering a framework for understanding ROS1 TKI activity against these important drivers of disease progression. This structure further illustrates the intentional design of zidesamtinib and adds to the growing body of preclinical data supporting its ROS1-selective and TRK-sparing design."

The manuscript explores the activity of zidesamtinib and other approved or investigational ROS1 TKIs at clinically relevant concentrations against ROS1 resistance mutations, including the most commonly occurring resistance mutation, ROS1 G2032R, in preclinical mutagenesis screens and an intracranial ROS1 G2032R xenograft model. Findings presented in the manuscript show that, at clinically relevant concentrations, zidesamtinib suppressed on-target resistance in ENU mutagenesis screens simulating first-line and later-line treatment and inhibited ROS1 G2032R brain tumors more effectively than the other ROS1 TKIs evaluated. This favorable preclinical activity suggests the potential for zidesamtinib to delay tumor progression, both peripherally and intracranially.

In addition, the manuscript details the first crystal structure of ROS1 G2032R in complex with zidesamtinib, which further supports zidesamtinib’s molecular design and provides structural insights into how the ROS1 G2032R mutation affects TKI binding. Zidesamtinib was designed with the goal of being active against ROS1 and ROS1 resistance mutations while avoiding the inhibition of the structurally related tropomyosin receptor kinase (TRK) family in the central nervous system (CNS), which has been associated with neurological adverse events that can be dose limiting. The crystal structure elucidates zidesamtinib’s preclinical affinity for ROS1 G2032R and selectivity for ROS1 over TRK.

The company expects to report pivotal clinical data for TKI pre-treated patients with advanced ROS1-positive NSCLC from the ARROS-1 Phase 1/2 trial in the first half of 2025 in support of an anticipated New Drug Application submission by mid-year 2025, with an initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC.

About Zidesamtinib
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.