apitolisib (GDC-0980) / Roche - LARVOL DELTA

Antibody-drug conjugates with novel payloads are enabled by an ultra-high DAR platform (AACR 2025) - "These HER2-targeted biomolecules combined with payloads inhibiting PI3K/mTOR (apitolisib) or MEK (cobimetinib) demonstrate the use of ADCs as precision medicine to selectively target cancer cells via antibody and payload. As shown in Table 1, PI3K pathway mutations can increase the sensitivity to ADCs with apitolisib as a payload, in some cases surpassing the potency of the exatecan derivative DXd in trastuzumab-DXd (DAR8). We will also present data supporting the in vivo safety and efficacy of these ADCs which may provide a novel solution to expand the therapeutic landscape, particularly for HER2-positive cancers."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CTSC • HER-2

The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic GBM tumors. (PubMed, Neuro Oncol) - "Radiation had no meaningful impact of drug delivery into brain or brain tumors for the drugs tested."

Journal • Preclinical • Brain Cancer • CNS Disorders • Oncology • Solid Tumor

A Multi-Omics Analysis of an Exhausted T Cells' Molecular Signature in Pan-Cancer. (PubMed, J Pers Med) - "Drug sensitivity analysis identified numerous correlations, with CXCL13 and HAVCR2 expressions influencing sensitivity to several drugs, including Apitolisib, Belinostat, and Docetaxel. Overall, these findings highlight the importance of reviving exhausted T cells to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes."

IO biomarker • Journal • Pan tumor • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CXCL13 • HAVCR2 • LAG3 • LAYN • TIGIT

Targeting the RAS upstream and downstream signaling pathway for Cancer treatment. (PubMed, Eur J Pharmacol) - "For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins..."

Journal • Review • Breast Cancer • Colorectal Cancer • Endocrine Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • PIK3CA • PTEN

Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor. (PubMed, Drugs R D) - P1 | "These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development."

Journal • PK/PD data • Retrospective data • Oncology • Renal Cell Carcinoma • Solid Tumor

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor). (PubMed, J Clin Pharmacol) - "Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy."

Journal • Metastases • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance. (PubMed, Acta Pharm Sin B) - "Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models...A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Development of Next Generation Antibody-Polymer-Drug Conjugates for Treatment of Multiple Myeloma (ASH 2023) - "CD38 upregulation was done by incubating with 10 or 25 nM panobinostat for 24 h and the apoptosis detection employed Annexin V and Propidium Iodide staining followed by flow cytometry analysis...Among them, we firstly prepared Epirubicin (EPI)-based pADCs, such as DARA-P-EPI, ISA-P-EPI and DRO-P-EPI (Fig.1A)...Notably, co-treatment of RPMI8226 cells with anti-CD38 and GDC0980, a PI3k/mTOR inhibitor, significantly improved cytotoxicity, suggesting DARA's potential for chemo sensitization (Fig.1G)... pADC's innovative design offers a high likelihood of successful clinical development and holds significant promise for MM therapy. Moreover, the unique mechanism provides potential to effectively overcome mAb and multiple drug resistance. Its facile nature allows for easy incorporation of multiple types of payloads into the ADC, making its synthesis highly scalable."

IO biomarker • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • ANXA5 • CALR • CTSB

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2 | N=273 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway. (PubMed, Mol Carcinog) - "These findings were further validated via rescue experiments using a small molecule inhibitor of PI3K/mTOR (GDC-0980). Our findings suggest that SLC4A7 promotes EMT and metastasis of HNSCC through the PI3K/AKT/mTOR signaling pathway, which may be a valuable predictive biomarker and potential therapeutic target in HNSCC."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SLC4A7

Oncogenic pathways of tumor cells signal to stem-ness in TNBC: Relationship between stem cell markers and PI3K-DDR pathway targeted drugs (SABCS 2022) - "CD44 was identified primarily in the membrane and to a lesser extent in the cytosol of tumor cells of BC patients (TMA and Avera cohort), TNBC cell lines, and xenograft-tumors. Apitolisib, in combination with Veliparib plus carboplatin, blocked the growth of established xenograft tumors by 80-90%, with a concomitant decrease in Ki67 levels. Membrane expression of CD44 inversely correlated to tumor sizes which significantly reduced in response to drug combinations."

Breast Cancer • Oncology • Triple Negative Breast Cancer • ALDH1A1 • CD24 • CD44

Integrative genomic analysis facilitates precision strategies for glioblastoma treatment. (PubMed, iScience) - "NVP-BEZ235, GDC-0980, dasatinib and XL765 were ultimately identified to have subclass-specific efficacy targeting patients with a high risk of poor prognosis. Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells. (PubMed, Int J Mol Sci) - "On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2; N=273; Active, not recruiting; Sponsor: Genentech, Inc.; Trial completion date: Apr 2021 ➔ Jul 2022

Clinical • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Mild chronic hypoxia-induced HIF-2α interacts with c-MYC through competition with HIF-1α to induce hepatocellular carcinoma cell proliferation. (PubMed, Cell Oncol (Dordr)) - "Our data highlight a role of HIF-2α in activating and binding c-MYC, thereby inducing HCC cell proliferation during mild chronic hypoxia. The PI3K/mTORC2/HIF-2α/c-MYC axis may play a key role in this process. The PI3K inhibitor apitolisib may serve as a potential treatment option for patients suffering from HCC, especially in cases with rapidly growing tumors under mild chronic hypoxic conditions."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • EPAS1 • HIF1A • MYC

A tipping-point for apoptosis following dual inhibition of HER2 signaling network by T-DM1 plus GDC-0980 maximizes anti-tumor efficacy. (PubMed, Am J Cancer Res) - "Such complexity has been clinically evident from the limited efficacy of data in the BOLERO-1 and BOLERO-3 trials, which tested combinations of trastuzumab (T), everolimus, and chemotherapy in women with HER2+ advanced BC. In the following MARIANNE trial also, a combination of T-DM1 plus pertuzumab delivered a non-inferior but yet not superior PFS compared to trastuzumab plus a taxane...Interestingly, both trastuzumab and T-DM1 induce PD-L1 expression in HER2 amplified BC cells. Our data provide evidence that an oncogenic mutation of PIK3CA and HER2-amplification may represent biomarkers to identify patients who may benefit most from the use of GDC-0980 and an opportunity to include immunotherapy in the combination of anti-HER2 therapy."

Clinical • IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • CASP3 • CD31 • EIF4EBP1 • PD-L1 • PIK3CA • PTEN

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC. (PubMed, Cancers (Basel)) - "It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues...Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot...A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC."

Journal • Immunology • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EIF4EBP1 • IL6 • MIR17 • MIR206 • MYC • PIM1

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P2; N=262; Recruiting; Sponsor: Genentech

Clinical • New P2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2; N=273; Active, not recruiting; Sponsor: Genentech, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2; N=273; Active, not recruiting; Sponsor: Genentech, Inc.; Trial completion date: Jun 2018 ➔ Jul 2019

Clinical • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P2; N=262; Recruiting; Sponsor: Genentech; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2; N=281; Active, not recruiting; Sponsor: Genentech, Inc.; Phase classification: P2 ➔ P1/2; Trial primary completion date: Jun 2015 ➔ Sep 2015

Clinical • Phase classification • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P2; N=272; Active, not recruiting; Sponsor: Genentech, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P2; N=262; Recruiting; Sponsor: Genentech; N=21 ➔ 262

Clinical • Enrollment change • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2; N=295; Recruiting; Sponsor: Genentech, Inc.; Active, not recruiting ➔ Recruiting; Trial completion date: Jul 2019 ➔ Apr 2021; Trial primary completion date: Sep 2015 ➔ Apr 2021

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN