vistusertib (AZD2014) / AstraZeneca - LARVOL DELTA

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma: The OCTOPUS Multicenter, Phase 2, Randomized Clinical Trial. (PubMed, JAMA Oncol) - "In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. isrctn.org Identifier: ISRCTN16426935."

Clinical • Journal • P2 data • Gynecologic Cancers • Oncology • Solid Tumor

The role of mTORC2/RICTOR in immune cells and inflammatory diseases. (PubMed, Inflamm Res) - "mTORC2 controls Th1/Th2 differentiation, Treg stability, and memory T cell formation; regulates BCR signaling and plasma cell survival; and modulates macrophage M2 polarization, DC maturation, and NK cell function. In tissue inflammation, mTORC2 plays context-dependent roles-exacerbating osteoarthritis and pancreatitis but restraining pro-inflammatory polarization in colorectal cancer. Dual mTORC1/2 inhibitors (e.g., AZD2014) have shown early promise, though challenges remain regarding efficacy, toxicity, and immunomodulatory complexity."

Journal • Review • Colorectal Cancer • Immunology • Inflammation • Oncology • Osteoarthritis • Pain • Pancreatitis • Rheumatology • Solid Tumor • RICTOR

The effectiveness of targeted therapy in the treatment of patients with neurofibromatosis type 2-related schwannomatosis and vestibular schwannomas: A systematic review. (PubMed, Neurooncol Pract) - "Bevacizumab was the most extensively studied agent, demonstrating durable tumor stabilization, hearing preservation, and sustained QoL with manageable long-term toxicity. Mammalian target of rapamycin inhibitors (everolimus, vistusertib) and TKIs (brigatinib, anlotinib) primarily achieved cytostatic disease control, while an early phase VEGFR peptide vaccine showed partial radiologic responses and improved subjective well-being...Targeted systemic therapy offers a disease-modifying, function-preserving alternative to surgery or radiotherapy in NF2-SWN. Although current evidence supports safety and efficacy, larger multicenter randomized trials with standardized outcome measures are required to refine dosing strategies and confirm long-term benefit."

Journal • Review • Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF2

Mapping Resistance and Pre-Sensitization to FLT3 Inhibitors in Acute Myeloid Leukemia Using Single-Cell Lineage Tracing (EACR 2026) - "The objective of this study was to elucidate mechanisms underlying primed resistance to FLT3 inhibitors driven by intrinsic transcriptional heterogeneity and to identify novel agents capable of pre-sensitizing AML cells to FLT3-targeted therapy.Material and To identify pre-existing resistant states to FLT3 inhibitors midostaurin and quizartinib, we applied our single-cell lineage-tracing platform, ReSisTrace, in an FLT3-ITD–positive MOLM-13 AML cell line. Our lineage-tracing approach enables the identification of transcriptional states that precede primed resistance to FLT3 inhibitors in FLT3-ITD–mutated AML. Targeting the pre-resistance gene GSPT1 with the molecular degrader CC-90009 produces robust synergistic effects with FLT3 inhibitors both in vitro and in vivo, highlighting a promising strategy to enhance therapeutic efficacy in FLT3-ITD–positive AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • CRBN • FLT3 • GSPT1 • IR

mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial and Ovarian (clinicaltrials.gov) - P1 | N=159 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jun 2026 ➔ Jun 2028 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Breast Cancer • Endometrial Adenocarcinoma • Endometrial Cancer • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • Uterine Cancer • BRCA • ER • MUC16 • PGR

Phenformin-Induced Apoptosis: A Potential Mechanism for Cervical Cancer Cell Inhibition. (PubMed, Int J Mol Sci) - "Additionally, the ability of phenformin to potentiate the antitumor effect of resveratrol and vistusertib was assessed...Our findings demonstrate that phenformin decreases the proliferation of various cancer cell lines in a dose-dependent manner and may have an ability to increase the autophagic flux in cervical cancer cells. Our findings demonstrate that phenformin decreases the proliferation of various cancer cell lines in a dose-dependent manner potentially by inducing apoptosis."

IO biomarker • Journal • Cervical Cancer • Diabetes • Hepatocellular Cancer • Melanoma • Metabolic Disorders • Oncology • Pancreatic Cancer • Solid Tumor • Type 2 Diabetes Mellitus • BAX • BCL2

Targeting mTOR with vistusertib attenuates metabolic steatohepatitis and prevents HCC development. (PubMed, Inflamm Res) - "Our findings identify vistusertib as a promising candidate for MASH, capable of mitigating disease progression and preventing MASH-to-HCC transition, highlighting its potential in managing metabolic liver disorders."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • TGFB1

National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=423 | Completed | Sponsor: University of Birmingham | Active, not recruiting ➔ Completed

IO biomarker • Trial completion • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NKX2-1 • TP63

Evaluation of mTOR, NFκB and BCL-2 Inhibitor Activity In Vitro in Karpas 1106P, a Primary Mediastinal B-Cell Lymphoma Cell Line. (PubMed, Hematol Rep) - "We administered three novel drugs: AZD2014 (vistusertib), an inhibitor of the serine-threonine kinase mTOR; IMD-0354, an NFκB inhibitor; and ABT-199 (venetoclax), a highly selective inhibitor for BCL-2. The combination of three drugs did not have a stronger effect than either a single drug used alone or any two-drug combination. These results provide preliminary in vitro evidence that targeting the BCL-2 and mTOR pathways may enhance pro-apoptotic activity in a PMBCL cell model; however, further validation in additional cell lines and in vivo models is needed before translational implications can be considered."

Journal • Preclinical • B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma

MTORC1/2 inhibition enhances STX-478, a PIK3CAH1047R mutant inhibitor, in PIK3CAH1047R mutant colorectal cancer (AACR 2026) - "The combination of STX-478 and AZD2014 enhanced response in both 2D and 3D PIK3CAH1047R mutant CRC models and shows promise for combining MTORC1/2 with PIK3CA inhibition for PIK3CA mutant CRC. Future work should investigate STX-478 and MTORC1/2 inhibition in PIK3CA mutant CRC in vivo."

Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • EIF4EBP1 • PIK3CA

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors (AACR 2024) - "Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer)...High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells...These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials."

Clinical • Combination therapy • B Cell Lymphoma • Brain Cancer • Breast Cancer • CNS Tumor • Gastrointestinal Cancer • Genito-urinary Cancer • Glioma • Hematological Malignancies • Liver Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor • EIF4EBP1

Targeting the PI3K/Akt/mTOR pathway in non-small cell lung cancer spheroids (AACR 2024) - "Having a more intricate cellular organization, this study alleviates the increased complexity of pharmacological responses in 3D spheroids when compared to 2D models. Further studies are being carried out to define the enhanced biomimetic ability of these NSCLC spheroids and the underlying mechanisms involved when targeting the PI3K/Akt/mTOR pathway using AZD2014 as mono-therapy or in combination with two novel anti-sense oligonucleotides (ASO)."

Late-breaking abstract • Large Cell Carcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Recruiting | Sponsor: UNICANCER | Trial completion date: Jun 2021 ➔ Dec 2022 | Trial primary completion date: Jun 2019 ➔ Dec 2021

IO biomarker • Trial completion date • Trial primary completion date

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2023 ➔ Dec 2024

IO biomarker • Trial completion date • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Recruiting ➔ Active, not recruiting

Enrollment closed • IO biomarker • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2022 ➔ Dec 2023

IO biomarker • Trial completion date • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Recruiting | Sponsor: UNICANCER | N=460 ➔ 1460 | Trial primary completion date: Oct 2016 ➔ Jun 2019

Enrollment change • IO biomarker • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=460 | Recruiting | Sponsor: UNICANCER

IO biomarker • New P2 trial • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2024 ➔ Dec 2025

IO biomarker • Trial completion date • Breast Cancer • Oncology • Solid Tumor

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial primary completion date: Dec 2021 ➔ Dec 2022

IO biomarker • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=531 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2024 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=320 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2021 ➔ Sep 2022 | Trial primary completion date: Jul 2021 ➔ Sep 2022

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: AstraZeneca

Biomarker • IO biomarker • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=420 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2023 ➔ Aug 2024 | Trial primary completion date: Oct 2023 ➔ Aug 2024

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor