pimasertib (AS703026) / EMD Serono, Day One Biopharma - LARVOL DELTA

Long-term functional drug and immunotherapy screening in immune-competent patient-derived microtissues across brain tumors (SNO 2025) - "Glioma cell line-based screens revealed inter-model variability in drug sensitivity, with only a few agents, including Pimasertib, Etoposide, Buparlisib, and Volasertib, demonstrating consistent efficacy, underscoring the need for individualized profiling. Our long-term, dynamic screening system supports personalized oncology approaches by enabling functional analysis of both drug and immune responses. Further validation in prospective clinical trials is required to determine its translational impact."

Clinical • Brain Cancer • Glioblastoma • Glioma • Meningioma • Oncology • Solid Tumor

Long-term functional drug and immunotherapy screening in immune-competent patient-derived microtissues across brain tumors (WFNOS 2025) - "Glioma cell line-based screens revealed inter-model variability in drug sensitivity, with only a few agents, including Pimasertib, Etoposide, Buparlisib, and Volasertib, demonstrating consistent efficacy, underscoring the need for individualized profiling. Our long-term, dynamic screening system supports personalized oncology approaches by enabling functional analysis of both drug and immune responses. Further validation in prospective clinical trials is required to determine its translational impact."

Clinical • Brain Cancer • Glioblastoma • Glioma • Meningioma • Solid Tumor

Identification of novel therapeutic options for the treatment of glioblastoma using a high-throughput live-imaging-based drug screening platform (EANO 2025) - "In all tested cells, at least one treatment was identified with higher efficacy than standard-of-care agents temozolomide and lomustine. Notably, a BRAF/MEK inhibitor combination (tovorafenib/pimasertib) consistently demonstrated strong activity across several microtumors, suggesting potential broad applicability. This study demonstrates the feasibility and indicates the potential of dynamic drug sensitivity testing platforms to identify personalized treatment strategies for glioblastoma. Further evaluation in clinical trials is required to validate these findings."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy. (PubMed, Int J Mol Sci) - "Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management."

Journal • Melanoma • Oncology • Solid Tumor • BRAF • GLS1

Changes in Melanoma Cell Morphology Following Inhibition of Cell Invasion by Third-Generation mTOR Kinase Inhibitors. (PubMed, Int J Mol Sci) - "The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026...The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • MMP2 • MMP9

Tovorafenib (DAY101) or in Combination With Pimasertib for Participants With Melanoma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=44 | Terminated | Sponsor: Day One Biopharmaceuticals, Inc.

New P1 trial • Astrocytoma • Brain Cancer • Colorectal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pilocytic Astrocytoma • Solid Tumor

Drug sensitivity patterns across FAB subtypes and molecular mutations in AML. (ASCO 2025) - "M1 samples (n=22 patients) demonstrated higher sensitivity to Navitoclax (σsDSS = 15.89), while combinations with mTOR inhibitors like Navitoclax + PF-04691502 (σsDSS = 13.97) and Navitoclax + Vistusertib (σsDSS = 13.72) showed promise...M4 subtypes (n=2 patients) were most sensitive to BAY 87-2243 (σsDSS = 15.98), with dual combinations like BAY 87-2243 + Cerdulatinib (σsDSS = 14.21) and BAY 87-2243 + Pevonedistat (σsDSS = 14.13) maintaining strong responses...In M4 eos (n=9 patients), Pimasertib demonstrated notable effectiveness (σsDSS = 14.43), with dual-agent combination such as Pimasertib + SCH772984 (σsDSS = 14.24) supporting RAS/ERK pathway inhibition. Despite rare M4/M5 subtypes (n=2 patients) showing limited Refametinib sensitivity (σsDSS = 8.75), their minimal sample size precludes definitive conclusions...Likewise, mutation analysis revealed that NPM1-mutated samples showed increased sensitivity to Venetoclax (σsDSS = 13.28) and PF-04691502 (σsDSS =..."

Acute Myelogenous Leukemia • FLT3 • NPM1

Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or an NF1-loss of function mutation. (PubMed, Cancer Res Commun) - "In NF1-LOF tumor cells treated with tovorafenib, increase in phosphorylated-ERK (pERK) was observed at low concentrations, with inhibition of pERK at higher concentrations. When tovorafenib was combined with pimasertib in vitro, synergy was observed in a NF1-LOF embryonal rhabdomyosarcoma PDX model ex vivo and a NF1-LOF MPNST cell line in vitro, suggesting that vertical pathway inhibition is needed in the NF1-LOF mutant setting."

Journal • Preclinical • Melanoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • AGK • BRAF • NF1

Analysis of nitrogen metabolism-related gene expression in hepatocellular carcinoma to establish relevant indicators for prediction of prognosis and guidance of immunotherapy. (PubMed, Comput Methods Biomech Biomed Engin) - "This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1 • YARS1

Common diagnostic biomarkers and molecular mechanisms of Helicobacter pylori infection and inflammatory bowel disease. (PubMed, Front Immunol) - "Additionally, the CMap database identified the top 11 small molecule compounds across 10 cell types, including TPCA-1, AS-703026 and memantine, etc. Our study revealed the co-pathogenic mechanism between H. pylori and IBD and identified 10 Hub genes related to cellular immune regulation and signal transduction. The expression of MMP-9 is significantly upregulated in both H. pylori infection and IBD. This study provides a new perspective for exploring the prevention and treatment of H. pylori infection and IBD."

Biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • CCL2 • CXCL8 • CXCR2 • IL10 • IL1B • IL6 • MMP9 • TLR2 • TLR4

A novel, glutathione-activated prodrug of pimasertib loaded in liposomes for targeted cancer therapy. (PubMed, RSC Med Chem) - "The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug."

Journal • Melanoma • Oncology • Solid Tumor

FIRELIGHT-1: Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors (clinicaltrials.gov) - P1/2 | N=168 | Active, not recruiting | Sponsor: Day One Biopharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Monotherapy • Astrocytoma • Bladder Cancer • Brain Cancer • Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • Urothelial Cancer • BRAF • NF1 • RAF1

Type II RAF inhibitor tovorafenib in recurrent/refractory (R/R) melanoma or other solid tumors with RAF fusions and/or RAF1 amplification (ESMO 2024) - P1/2 | "Tovorafenib was generally well tolerated and showed activity in adults with r/r melanoma and encouraging anti-tumor activity in other solid tumors with activating RAF fusions and/or RAF1 amplification. Enrollment continues in FIRELIGHT-1 sub-study DAY101-102b of tovorafenib + the MEK inhibitor, pimasertib."

Astrocytoma • Brain Cancer • CNS Tumor • Colorectal Adenocarcinoma • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Glioblastoma • Glioma • Melanoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • Spindle Cell Sarcoma • BRAF • NRAS

Optimal Precision TherapIes to CustoMISE Care in Childhood and Adolescent Cancer (clinicaltrials.gov) - P1/2 | N=82 | Recruiting | Sponsor: Australian & New Zealand Children's Haematology/Oncology Group | Not yet recruiting ➔ Recruiting | Initiation date: Mar 2024 ➔ Jul 2024

Enrollment open • Trial initiation date • Brain Cancer • Oncology • Solid Tumor

Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or a NF1-LOF mutation (AACR 2024) - P1/2, P2 | "Tovorafenib is currently being evaluated as a monotherapy in relapsed or progressive pediatric low-grade glioma (pLGG) harboring RAF alterations (NCT04775485) and in combination with pimasertib in patients ≥12 years of age with recurrent, progressive, or refractory solid tumors harboring MAPK pathway alterations (NCT04985604). Ongoing preclinical translational work will continue to explore potential biomarker-defined tumor indications for these agents."

Preclinical • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Melanoma • Neurofibrosarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • AGK • BRAF • KIAA1549 • NF1

Day One Reports Fourth Quarter and Full Year 2023 Financial Results and Corporate Progress (GlobeNewswire) - "Patient enrollment continues in the Phase 1b/2 substudy (102b) of the FIRELIGHT-1 trial evaluating the combination of tovorafenib with the Company’s investigational MEK inhibitor, pimasertib....The recommended Phase 2 dose and schedule in the FIRELIGHT-1 clinical trial is expected in 2H 2024."

Enrollment status • P1/2 data • Solid Tumor

FIRELIGHT-1: Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors (clinicaltrials.gov) - P1/2 | N=168 | Recruiting | Sponsor: Day One Biopharmaceuticals, Inc. | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Monotherapy • Phase classification • Astrocytoma • Bladder Cancer • Brain Cancer • Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • Urothelial Cancer • BRAF • NF1 • RAF1

Optimal Precision TherapIes to CustoMISE Care in Childhood and Adolescent Cancer (clinicaltrials.gov) - P1/2 | N=82 | Not yet recruiting | Sponsor: Australian & New Zealand Children's Haematology/Oncology Group

New P1/2 trial • Brain Cancer • Oncology • Solid Tumor

Bintrafusp Alfa and Pimasertib for the Treatment of Patients With Brain Metastases (clinicaltrials.gov) - P1/2 | N=8 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: May 2025 ➔ Dec 2023 | Trial primary completion date: May 2025 ➔ Dec 2023

Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Cutaneous Melanoma • Hematological Malignancies • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Proteomic and phosphoproteomic analysis of responses to enterovirus A71 infection reveals novel targets for antiviral and viral replication. (PubMed, Antiviral Res) - "Notably, based on the prediction of upregulated kinases during EV-A71 infection, we identified specific kinase inhibitors approved by the FDA, with ceralasertib, bosutinib, flavin mononucleotide, minocycline, pimasertib and acetylcysteine inhibiting EV-A71 infection. Finally, EV-A71 proteins were found to be phosphorylated during infection, with one site (S184 on 3D polymerase) observed to be crucial for viral replication because a S184A mutation knocked out viral replication. The results improve our understanding of the host response to EV-A71 infection of neuroblastoma cells and provide potential targets for developing anti-EV-A71 strategies."

Journal • CNS Tumor • Infectious Disease • Neuroblastoma • Oncology • Solid Tumor

In Silico Screening and Validation of Achyranthes aspera as a Potential Inhibitor of BRAF and NRAS in Controlling Thyroid Cancer. (PubMed, Anticancer Agents Med Chem) - "The outcomes of docking experiments conducted on BRAF and NRAS provide insight into natural compounds with pharmacological characteristics. These findings indicate that natural compounds derived from plants as a more promising cancer treatment option. Thus, the results of docking investigations conducted on BRAF and NRAS substantiate the conclusions that the molecule possesses the most suited drug-like qualities. Compared to other compounds, natural compounds are superior, and they are also druggable. This demonstrates that natural plant compounds can be an excellent source of potential anti-cancer agents. The preclinical research will pave the road for a possible anti-cancer agent."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • EIF1AX • HRAS • MUC16 • NRAS • SFTPA1 • SPTA1 • ZFHX3

Three generations of mTOR kinase inhibitors in the activation of the apoptosis process in melanoma cells. (PubMed, J Cell Commun Signal) - "The following inhibitors were used: protein kinase inhibitors such as AKT-MK-2206, MEK-AS-703026, mTOR-everolimus and Torkinib, as well as dual PI3K and mTOR inhibitor-BEZ-235 and Omipalisib, and mTOR1/2-OSI-027 inhibitor in single-mode and their combinations with MEK1/2 kinase inhibitor AS-703026. There is a need for research on the search for new therapeutic strategies aimed at particular groups of patients. Effect of three generations of mTOR kinase inhibitors on caspase-3 activity, apoptosis and proliferation in melanoma cell lines."

Journal • Melanoma • Oncology • Solid Tumor • CASP3 • MAP2K1

E6201, a novel MEK1 inhibitor, suppresses the metastatic capability of triple-negative breast cancer cells (AACR 2018) - P1; "Background: Triple-negative breast cancer (TNBC) lacks the receptor targets ER, PR, and HER2 and thus it does not respond to receptor-targeted treatments such as hormonal therapy and trastuzumab, leaving chemotherapy as the mainstay of treatment...Two BRAF inhibitors (vemurafenib and dabrafenib) and two MEK inhibitors (trametinib and cobimetinib) have received U.S. Food and Drug Administration approval for treatment of melanoma, clinically validating the potential of MAPK pathway inhibition to meaningfully benefit patients with TNBC...To evaluate the anti-metastatic activity of E6201 in vitro and in vivo, a migration/invasion assay and an experimental/spontaneous metastasis assay were performed, respectively. In vitro cell proliferation data demonstrated that E6201 inhibited growth more effectively (half maximal inhibitory concentration [IC50] range: 0.05-5 M) than did other MEK inhibitors (selumetinib, pimasertib, and trametinib)... Taken together,

IO biomarker • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Triple Negative Breast Cancer

Immune landscape-based machine-learning-assisted subclassification, prognosis, and immunotherapy prediction for glioblastoma. (PubMed, Front Immunol) - "Finally, the MES subtype is proved to be more sensitive to 17-AAG, docetaxel, and erlotinib using drug sensitivity analysis and three compounds of AS-703026, PD-0325901, and MEK1-2-inhibitor might be potential therapeutic agents. Overall, the findings of this research could help enhance our understanding of the tumor immune microenvironment and provide new insights for improving the prognosis and immunotherapy of GBM patients."

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

CD73/NT5E is a Potential Biomarker for Cancer Prognosis and Immunotherapy for Multiple Types of Cancers. (PubMed, Adv Biol (Weinh)) - "Last, specific inhibitor molecules, like NORNICOTINE, AS-703026, and FOSTAMATINIB, which inhibit the expression of NT5E in various types of cancers, are screened with the CMap. Thus, it is proposed that NT5E can be utilized as a potential biomarker for predicting the prognosis of cancer patients and determining the infiltration of various immune cells in different types of cancers."

Biomarker • IO biomarker • Journal • Immune Modulation • Inflammation • Oncology • NT5E