vopimetostat (TNG462) / Tango Therap - LARVOL DELTA

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=183 | Recruiting | Sponsor: Tango Therapeutics, Inc. | N=133 ➔ 183

Enrollment change • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (SNO 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

MTA-Cooperative PRMT5 Inhibitors Demonstrate Efficacy in MTAP-Deleted MPNST Models and Enhance Chemotherapy Response (SNO 2025) - "Furthermore, the combination of a PRMT5 inhibitor with doxorubicin or trabectedin had additive antiproliferative effects. In vivo, TNG908 and TNG462 demonstrated dose-dependent antitumor activity in MTAP-null MPNST PDX models WU-356 and WU-386, inducing tumor regressions at well-tolerated doses.CONCLUSIONTNG908 and TNG462 selectively inhibited MTAP-deleted MPNST cell growth in vitro and induced tumor regressions in vivo through PRMT5 inhibition and apoptosis induction. These findings support the therapeutic potential of MTA-cooperative PRMT5 inhibitors as a targeted treatment strategy for patients with MTAP-deleted MPNST."

Clinical • Brain Cancer • Neurofibrosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CASP3 • CDKN2A • MTAP

MTA-Cooperative PRMT5 Inhibitors Demonstrate Efficacy in MTAP-Deleted MPNST Models and Enhance Chemotherapy Response (WFNOS 2025) - "Furthermore, the combination of a PRMT5 inhibitor with doxorubicin or trabectedin had additive antiproliferative effects. In vivo, TNG908 and TNG462 demonstrated dose-dependent antitumor activity in MTAP-null MPNST PDX models WU-356 and WU-386, inducing tumor regressions at well-tolerated doses.CONCLUSIONTNG908 and TNG462 selectively inhibited MTAP-deleted MPNST cell growth in vitro and induced tumor regressions in vivo through PRMT5 inhibition and apoptosis induction. These findings support the therapeutic potential of MTA-cooperative PRMT5 inhibitors as a targeted treatment strategy for patients with MTAP-deleted MPNST."

Clinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • CASP3 • CDKN2A • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (WFNOS 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • MTAP

Tango Therapeutics…Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: (i) Combination trial with vopimetostat + daraxonrasib, and vopimetostat + zoldonrasib (Revolution Medicines), phase 1/2 initial safety and efficacy data 2026; (ii) Vopimetostat monotherapy Phase 1/2 clinical data lung cancer update in 2026; (iii) Vopimetostat monotherapy 2L pancreatic cancer pivotal study start 2026; (iv) TNG456 monotherapy phase 1/2 trial initial safety and efficacy data 2026."

New trial • P1/2 data • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

The phase 1/2 combination study of vopimetostat with RAS(ON) multi-selective inhibitor daraxonrasib, and RAS(ON) G12D-selective inhibitor zoldonrasib (both from Revolution Medicines, RVMD), is ongoing with robust enrollment in previously treated MTAP-del/RAS mut pancreatic and lung cancer. (The Manila Times) - "The first dose escalation cohort of this study has been fully enrolled (n=7) and backfill is ongoing. Vopimetostat in combination with both daraxonrasib and zoldonrasib have been well-tolerated to date with exposures in the active range for each compound. The second cohort was initiated in early October. A cohort of 1L patients is expected to begin enrolling after go-forward doses have been selected. The data from this study have the potential to support a pivotal study in 1L MTAP-del/RAS mut pancreatic cancer. Initial data from the Phase 1/2 study are anticipated in 2026."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Epigenetic silencing of MTAP defines a distinct class of PRMT5-inhibitor-sensitive cancers (AACR-NCI-EORTC 2025) - "This metabolic vulnerability renders MTAP-deficient tumors selectively sensitive to PRMT5 inhibitors such as TNG-462 and TNG-908. We identify promoter hypermethylation as a distinct mechanism of MTAP silencing, broadening the spectrum of MTAP-low tumors beyond genomic loss. These findings support integration of epigenetic biomarkers to refine patient selection and enhance response rates in PRMT5-targeted clinical trials."

Bladder Cancer • Brain Cancer • Glioblastoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Urothelial Cancer • MTAP

Tango Therapeutics Reports Positive Data from Ongoing Phase 1/2 Study with Vopimetostat (TNG462) in Patients with MTAP-deleted Cancers (The Manila Times) - "Across the 16 cancer types enrolled in the trial, the ORR is 27% in patients with a median follow-up of 9.4 months, which supports the potential for vopimetostat as the best-in-class PRMT5 inhibitor. In 2L MTAP-deleted pancreatic cancer, the median PFS is 7.2 months and the ORR is 25%, more than double that observed in historical control studies, supporting our decision to initiate a pivotal trial in this patient population in 2026. With FDA alignment on the go-forward dose of 250 mg QD, we anticipate that this study will enroll rapidly..."

New trial • P1/2 data • Pancreatic Cancer

Enrollment in Lung Cancer (The Manila Times) - "As of September 1, 2025, 41 patients with 2L+ lung cancer were enrolled, 12 of whom had received active doses and were enrolled more than 6 months prior to the analysis; Emerging data are consistent with expectations, and the company anticipates providing a safety and efficacy update in 2026."

P1/2 data • Non Small Cell Lung Cancer

Tango Therapeutics Announces First Patient Dosed in Phase 1/2 Trial of TNG462 plus Revolution Medicines’ Daraxonrasib or Zoldonrasib in Patients with RAS-Mutant MTAP-deleted Pancreatic or Lung Cancer (GlobeNewswire) - "Tango Therapeutics...announced that the first patient has been dosed in the Phase 1/2 trial of TNG462 and Revolution Medicines’ daraxonrasib (RAS(ON) multi-selective inhibitor) or zoldonrasib (RAS(ON) G12D-selective inhibitor) in patients with MTAP-deleted and RAS mutant metastatic pancreatic or lung cancer....The Phase 1/2 combination trial (NCT06922591) is evaluating safety, pharmacokinetics, pharmacodynamics and antitumor activity in TNG462 in combination with daraxonrasib and TNG462 in combination with zoldonrasib in pancreatic and lung cancer patients with an MTAP deletion and a co-occurring RAS mutation. TNG462...is currently being evaluated as monotherapy in a Phase 1/2 trial, with data expected in the second half of 2025. This upcoming monotherapy data update is anticipated to provide sufficient information to inform a registrational trial in pancreatic cancer next year and advance the development plan for lung cancer."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

MTA-Cooperative PRMT5 Inhibitors are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models. (PubMed, Clin Cancer Res) - "Clinical stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 are efficacious in MPNST models in vitro and in vivo; therefore MTA-cooperative PRMT5 inhibitors are promising therapeutic agents for patients with MTAP-deleted MPNST."

Journal • Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • MTAP

S095035 as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of MTAP (clinicaltrials.gov) - P1/2 | N=308 | Recruiting | Sponsor: Servier Bio-Innovation LLC | Phase classification: P1 ➔ P1/2 | N=27 ➔ 308 | Trial completion date: May 2026 ➔ Oct 2031 | Trial primary completion date: May 2026 ➔ Oct 2031

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=133 | Recruiting | Sponsor: Tango Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Tango Therapeutics Reports First Quarter 2025 Financial Results and Provides Business Highlights (GlobeNewswire) - "TNG462: Enrollment in dose expansion is ongoing and a clinical data update on the TNG462 Phase 1/2 trial is expected in the second half of this year. This update is anticipated to provide sufficient information to inform a registrational trial in pancreatic cancer next year and determine the next steps for the development path in NSCLC; Based on promising preclinical data, the Company is on track to initiate a combination trial with TNG462, including RAS(ON) multi-selective inhibitor, daraxonrasib, and RAS(ON) G12D-selective inhibitor, zoldonrasib (Revolution Medicines). This trial is expected to begin enrolling in the second quarter of 2025."

New trial • P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors (AACR 2025) - "To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors."

Clinical • Oncology • CDKN2A • MTAP

TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models (AACR 2025) - "This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca...Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib...However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss."

Combination therapy • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • MAT2A • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss (AACR 2025) - "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases."

Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=133 | Not yet recruiting | Sponsor: Tango Therapeutics, Inc.

New P1/2 trial • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Tango Therapeutics to Highlight Preclinical Data on Precision Oncology Pipeline with Five Posters at the American Association for Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "Tango Therapeutics...announced that five abstracts have been accepted as poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025....'The data we are presenting at this year’s AACR meeting highlights important preclinical analyses of our PRMT5 programs that underscore the potential of these molecules as both standalone treatments and as key combination partners in MTAP-deleted cancers, including in combination with KRAS-inhibitors'..."

Preclinical • Solid Tumor

Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. (PubMed, J Med Chem) - "We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials."

Journal • Oncology • MTAP

Tango Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Highlights (GlobeNewswire) - "Investigational New Drug (IND) application for TNG456, a next-generation brain-penetrant MTA-cooperative PRMT5 inhibitor, cleared by FDA. Phase 1/2 enrollment expected to begin 1H 2025; Data update from ongoing TNG462 monotherapy trial expected in 2025 with focus on pancreatic and lung cancer."

P1/2 data • Trial status • Lung Cancer • Pancreatic Cancer

TNG462-C101: Safety and Tolerability of TNG462 in Patients With MTAP-deleted Solid Tumors (clinicaltrials.gov) - P1/2 | N=225 | Recruiting | Sponsor: Tango Therapeutics, Inc. | N=159 ➔ 225

Enrollment change • Metastases • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MTAP

Clinical collaboration with Revolution Medicines (Businesswire) - "In November 2024, the Company entered into a clinical collaboration with Revolution Medicines to evaluate the efficacy and safety of TNG462 in combination with RMC-6236, a RAS(ON) multi-selective inhibitor, and with RMC-9805, a RAS(ON) G12D-selective inhibitor. The agreement provides that Revolution Medicines will supply RMC-6236 and RMC-9805 to Tango and that Tango will be the sponsor of any combination trials. Each company will retain commercial rights to their respective compounds and the agreement is mutually non-exclusive."

Commercial • Oncology

Tango Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - P1/2 | N=159 | NCT05732831 | Sponsor: Tango Therapeutics, Inc. | "Data from the ongoing phase 1/2 clinical trial of TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor, demonstrate clinical activity across multiple tumor types, including NSCLC and pancreatic cancer. Of note, this includes an ORR of 43% in cholangiocarcinoma (n=7). Substantive durability and a good safety and tolerability profile also were observed in this ongoing trial. The next clinical update is expected in 2025. The Company plans to initiate multiple targeted and standard of care combinations with TNG462 including RAS(ON) multi-selective and RAS(ON) G12D-selective inhibitors (Revolution Medicines), osimertinib (AstraZeneca) and pembrolizumab (Merck). These studies are expected to begin enrolling in 1H 2025."

New trial • P1/2 data • Non Small Cell Lung Cancer • Pancreatic Cancer