sapanisertib (CB-228) / Calithera - LARVOL DELTA

Results of a phase 1b study of osimertinib plus sapanisertib or alisertib for osimertinib-resistant, EGFR-mutant non–small cell lung cancer (NSCLC). (ASCO 2022) - P1 | "Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib."

P1 data • Anemia • Dental Disorders • Diabetes • Hematological Disorders • Leukopenia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • AURKA • EGFR

Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors. (PubMed, Cancer Med) - "The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies."

Combination therapy • Journal • Metastases • P1 data • Anorexia • Cardiovascular • Dyslipidemia • Fatigue • Hypertension • Hypertriglyceridemia • Mucositis • Oncology • Sarcoma • Solid Tumor • HIF1A

Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies. (PubMed, Cancer Res Commun) - "The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with anti-tumor activity observed in patients with advanced malignancies harboring PTEN/ AKT/mTOR pathway alterations."

Combination therapy • Journal • Metastases • P1 data • Breast Cancer • Diabetes • Dyslipidemia • Fatigue • Hypertriglyceridemia • Leiomyosarcoma • Metabolic Disorders • Oncology • Sarcoma • Solid Tumor • PIK3CA • STK11 • TSC1

Sapanisertib and serabelisib (PIKTOR) with paclitaxel, and an insulin-suppressing diet (ISD) substudy, in patients with advanced/recurrent endometrial cancer (EC): GOG-3111 (SGO 2026) - No abstract available

Clinical • Metastases • Endometrial Cancer • Oncology • Solid Tumor

A Mouse Model of Busulfan-Induced Ovarian Toxicity and Evidence for Attenuation with mTOR Inhibition. (PubMed, Reprod Toxicol) - "We established a time-resolved in vivo model of busulfan-induced ovarian injury and tested whether sapanisertib, an mTOR inhibitor, mitigates damage. These findings are consistent with premature activation of primordial follicles as a proximate contributor to busulfan-induced loss of ovarian reserve and suggest that mTOR inhibition may mitigate this process. A two-time-point assay (24hours for proliferation, 7 days for morphology) provides a practical framework for future studies and translation."

Journal • Preclinical • Bone Marrow Transplantation • Transplantation

Combining brigatinib with mTOR inhibition to effectively treat NF2-SWN-associated and sporadic NF2-deficient meningiomas. (PubMed, Cancer Res Commun) - "We previously generated an orthotopic, NF2-deficient meningioma model using the luciferase-expressing Ben-Men-1 cell line established from a sporadic tumor and identified the multi-kinase inhibitor brigatinib and the mTOR kinase inhibitor INK128 to potently impede tumor growth. As the first NF2-SWN-related meningioma cell line, AG-NF2-Men is a unique reagent for investigating meningioma biology and therapeutics. A clinical trial to evaluate the combination of brigatinib with an mTOR inhibitor in NF2-deficient meningiomas is warranted."

Journal • Brain Cancer • Meningioma • Oncology • Solid Tumor • EGFR • ERBB3 • NF2

Genomic and transcriptomic characterization of acute myeloid leukemia with CD123 overexpression (ASH 2025) - "Pharmaco-transcriptomic analysis revealed that IL3RA -high AML exhibited selective therapeutic vulnerabilities for venetoclax and INK-128 (sapanisertib). In conclusion, IL3RA overexpression defines a biologically and clinically distinct subgroup of AML. Continued translational research efforts are warranted to refine patient selection and integrate CD123-directed therapeutic modalities into the standard AML treatment protocols."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD123 • FUS • IL3RA • KMT2A • NPM1 • NUP214

Tumor Microenvironmental NRG1 Drives Resistance to PI3K Pathway Inhibition in Prostate Cancer (SUO 2025) - "Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor...In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone ( Figure 1D )... The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME, activates HER3 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting HER3 in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome NRG1-mediated resistance mechanisms in advanced prostate cancer."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NRG1

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (SNO 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

Macropinocytosis and Vascularization Determine Response to mTOR Inhibitors in Lung Squamous Cell Carcinoma. (PubMed, Cancer Res) - "Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

TORC1/2 Inhibitor MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Brain Cancer • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Fallopian Tube Cancer • Glioblastoma • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Uterine Cancer • BRAF

Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations (clinicaltrials.gov) - P2 | N=17 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2025 ➔ Nov 2026

Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • TSC1 • TSC2

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (WFNOS 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=85 ➔ 22 | Trial completion date: Jun 2026 ➔ Nov 2026 | Trial primary completion date: Jun 2026 ➔ Nov 2025

Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • KEAP1 • KRAS • NFE2L2 • ROS1

Genomic and transcriptomic characterization of acute myeloid leukaemia with IL3RA overexpression: Prognostic and therapeutic implications revisited. (PubMed, Br J Haematol) - "Pharmaco-transcriptomic analysis revealed that IL3RA-high AML exhibited selective sensitivity to venetoclax and sapanisertib, suggesting potential synergistic opportunities. In conclusion, IL3RA overexpression defines a clinically and biologically distinct subgroup of AML, with unique therapeutic vulnerabilities. Continued research efforts are warranted to integrate CD123-directed therapies into the upfront AML treatment paradigm."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • FUS • IL3RA • KMT2A • NPM1 • NUP214

DICE trial: An international multi-centre randomised phase II study to assess the efficacy of TAK228 in combination with intravenous weekly paclitaxel compared with weekly paclitaxel alone in women with advanced/recurrent epithelial ovarian or fallopian tube cancer (ESMO 2025) - P2 | "RR and OS analyses are ongoing along with translational research to identify predictive biomarkers. These data support the development of a larger phase III trial of TAK228 plus wP in PROC."

Clinical • Combination therapy • Late-breaking abstract • Metastases • P2 data • Carcinosarcoma • Clear Cell Carcinoma • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Sarcoma • PTEN

On the strength of DICE, we see sapanisertib plus paclitaxel as phase 3-ready in ovarian cancer, alongside our ongoing phase 2 in endometrial cancer and planned phase 1b/2 in breast cancer. (Businesswire)

New P1/2 trial • New P3 trial • Breast Cancer • Fallopian Tube Cancer • Ovarian Cancer

ESMO 2025: Faeth Therapeutics’ Phase 2 DICE Trial Shows 34% Reduction in Risk of Disease Progression with Oral Sapanisertib Plus Chemotherapy (Businesswire) - "The combination achieved mean progression-free survival (PFS) of 5.8 months compared to 4.0 months with paclitaxel alone, extending time to disease progress by approximately 45 percent. The addition of sapanisertib was associated with a 34% reduction in risk of progression compared to paclitaxel alone (HR=0.66; 90% CI: 0.45–0.96; p=0.07), meeting the trial's prespecified hazard ratio target of 0.66."

P2 data • Platinum resistant • Fallopian Tube Cancer • Ovarian Cancer

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights. (PubMed, Drug Dev Res) - "Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology."

Journal • Review • Genito-urinary Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Renal Cell Carcinoma • Solid Tumor

Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations. (PubMed, Biomed Pharmacother) - "Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • HLA-B • JAK1 • JAK2 • MUC4 • TP53

Efficacy and safety of systemic therapies following progression on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer: a systematic review and network meta-analysis. (PubMed, EClinicalMedicine) - "Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR)."

Journal • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Up next in our Article Showcase is a featured selection from Eileen M. O’Reilly, Senior Editor of Clinical Research and Trials: “Sapanisertib plus Metformin in Metastatic Solid Tumors” https://aacrjournals.org/cancerrescommun/article/4/2/378/734232/Phase-I-Study-of-mTORC1-2-Inhibitor-Sapanisertib @EileenMOReilly

Faeth Therapeutics Announces Late-Breaking Presentation of Positive Phase 2 Data in Ovarian Cancer at ESMO 2025 (Businesswire)

Late-breaking abstract • P2 data • Platinum resistant • Ovarian Cancer

Advanced Thyroid Cancer with Brain Metastases: A Case Series. (ATA 2025) - "Despite multiple treatments—including chemotherapy (docetaxel and doxorubicin), pembrolizumab, trametenib, everolimus, lenvatinib, and eventually starting sapanisertib, he passed away shortly after.One patient with PDTC had progression of disease, complicated with intracranial bleeding while on lenvatinib. Another with BRAFV600E-mutated PTC, failed multiple therapeutic targets including lenvatinib, sorafenib, dabrafenib, trametinib and pembrolizumab. With ongoing disease progression, initiated therapy with encorafenib and binimetinib...The other patient with NRAS-mutated FTC initially did not tolerate naporafenib, showed stable disease after redifferentiation therapy with trametinib...Radiation, including stereotactic surgery, has a pivotal role in managing brain metastasis and achieving local control2. Little is known about the evolution of mutations in brain metastases in the context of advanced thyroid carcinoma3, and therefore more data is needed to understand the..."

Clinical • Late-breaking abstract • Metastases • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • AXIN1 • MSH2 • NF1 • NRAS • PTEN • RB1 • SETD2 • TP53