Tango Therapeutics Advances Lead Oncology Program: TNG462 Shows Durable Response Across Multiple Cancers, Strategic Pivot Underway

Tango Therapeutics has announced significant progress in its PRMT5 inhibitor pipeline, with clinical data supporting aggressive development of TNG462 while redirecting resources away from earlier candidates. The biotech company disclosed that TNG462 demonstrated sustained tumor activity and favorable tolerability in an ongoing phase 1/2 study, prompting a strategic shift in its cancer therapy portfolio.

TNG462 Emerges as Development Priority

The lead candidate TNG462 has shown clinical activity across multiple solid tumor types, with patients maintaining treatment for a median of 24 weeks—a duration that continues to extend. Among the 39 evaluable patients treated at therapeutic doses (160-300 mg daily), the drug proved active and well-tolerated in non-small cell lung cancer and pancreatic cancer cohorts.

Notably, cholangiocarcinoma patients demonstrated a 43% response rate, with 3 out of 7 patients achieving confirmed partial responses. A significant proportion of responders (approximately 60%) were initially classified as having stable disease before tumor shrinkage became apparent, highlighting the delayed-onset benefit pattern characteristic of this drug class. Median time to first response measured 16 weeks, ranging from 8 to 32 weeks.

The safety profile remained manageable across evaluated doses, with thrombocytopenia as the primary dose-limiting toxicity. Grade 1 adverse events like nausea, vomiting, diarrhea, and fatigue occurred in less than 20% of patients. Notably, dysgeusia—an adverse effect observed in the drug class—was absent at the doses being studied.

Combination Strategy Accelerates Development Path

The company has initiated multiple planned combination studies beginning in the first half of 2025, designed to explore TNG462 alongside targeted therapies and standard chemotherapy regimens. A clinical collaboration with Revolution Medicines will evaluate TNG462 combined with two RAS inhibitor molecules: RMC-6236 (multi-selective RAS(ON) inhibitor) and RMC-9805 (G12D-selective variant).

This partnership strategy targets pancreatic cancer specifically, where nearly all MTAP-deleted tumors harbor concurrent RAS mutations. Additional combination trials will pair TNG462 with osimertinib and pembrolizumab, positioning the agent for potential first-line treatment consideration in NSCLC and pancreatic cancer indications.

TNG908 Development Halted; TNG456 Enters Clinic

The company discontinued enrollment in TNG908, its earlier blood-brain barrier-penetrant PRMT5 inhibitor, to concentrate resources on TNG462. While TNG908 demonstrated clinical activity in non-CNS solid tumors (16-week median time on study, partial responses in pancreatic cancer and NSCLC), it failed to achieve adequate central nervous system exposure for glioblastoma efficacy. Cerebral spinal fluid concentrations reached only approximately 30% of plasma levels—below the threshold required for meaningful clinical benefit.

Replacing TNG908 in the glioblastoma indication is TNG456, an optimized brain-penetrant molecule entering phase 1/2 evaluation in the first half of 2025. Preclinical data supports enhanced CNS penetration (50-110% of plasma exposure) combined with 55-fold selectivity for MTAP deletion and substantially increased potency (20 nM GI50 versus TNG908’s 120 nM). The compound will undergo evaluation as monotherapy and in combination with abemaciclib, a brain-penetrant CDK4/6 inhibitor, leveraging the co-deletion pattern of CDKN2A and MTAP observed across MTAP-deleted cancers.

Clinical Development Roadmap

The 59-patient cohort enrolled across 13 tumor histologies provides the foundation for TNG462’s accelerated development. The company plans to initiate conversations with regulatory authorities regarding multiple registrational pathways while building internal capabilities to support broad patient access. Clinical data updates are anticipated during 2025, with the cash runway extending into third quarter 2026.