NASDAQ: TNGX

We are focused on evaluating the combination of vopimetostat with RAS inhibitors, given the overlap in patient populations, robust preclinical data supporting potential strong combination effect in clinical trials, and favorable clinical efficacy, durability, and safety profiles observed with each drug individually. We believe this approach may enable a development path for chemotherapy-free first-line and potentially second-line therapies for MTAP-deleted/RAS-mutated patients with pancreatic and lung cancer. In June 2025, we treated the first patient in our combination clinical trial evaluating vopimetostat with the RAS(ON) multi-selective inhibitor, daraxonrasib, and RAS(ON) G12D-selective inhibitor, zoldonrasib (Revolution Medicines), which enrolled 30 patients as of December 24, 2025. Both combinations have been well-tolerated to date with exposures in the active range for all compounds with encouraging early efficacy data. We anticipate providing a safety and efficacy update from this trial in 2026. Given the differentiated profile of vopimetostat enabling the potential for efficacious and tolerable RAS inhibitor combinations, in March 2026, we entered into a clinical trial collaboration and supply agreement (CTCSA) with Erasca, Inc., or Erasca, to evaluate vopimetostat in combination with Erasca’s pan-RAS molecular glue, ERAS-0015. Under the terms of the agreement, Tango is the sponsor of the trial and Erasca is supplying ERAS-0015 at no cost.

TNG456 is a brain-penetrant PRMT5 inhibitor. In May 2025, the first patient was treated with TNG456 in the dose escalation portion of the Phase 1/2 clinical trial to evaluate the safety, pharmacokinetics, pharmacodynamics and antitumor activity of TNG456 as a monotherapy. The trial is currently enrolling patients with MTAP-deleted solid tumors, with a focus on GBM. We anticipate providing a safety and efficacy update from this trial in 2026.

TNG961 is a novel, potent and selective molecular glue development candidate targeting HBS1L for degradation in solid tumors in FOCAD-deleted/MTAP-deleted cancers. FOCAD deletion occurs in 20-40% of all MTAP-deleted cancers due to the collateral loss with the tumor suppressor gene CDKN2A/B on chromosome 9p21. Cancers with FOCAD loss are dependent on HBS1L for mRNA processing, thus protein synthesis. By degrading HBS1L and disrupting the HBS1L/PELO complex, TNG961 causes tumor regression in FOCAD-deleted preclinical models of multiple histologies. TNG961 is in the IND-enabling phase of development.

TNG260 is a first-in-class CoREST inhibitor. In November 2025, we announced that patients with checkpoint inhibitor resistant STK11 mutant/KRAS wild-type NSCLC receiving clinically active doses of TNG260 plus pembrolizumab had a mPFS of 29 weeks (n=5), more than double the standard of care PFS of ~10 weeks. 80 mg QD of TNG260 was selected for dose expansion, which is ongoing for patients.

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Our Pipeline

We are leveraging the power and productivity of our discovery engine to discover and validate multiple novel targets each year. Our growing pipeline consists of discovery programs for multiple cancer types that currently have limited treatment options, as summarized in Figure 1.

Figure 1. Tango Therapeutics' product pipeline

Our Strategy

We are pioneering novel approaches to the discovery and development of innovative targeted oncology therapies. We leverage the following core strategic components, enabling the pursuit of transformative therapies for patients with cancer:

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Advance the clinical development of vopimetostat as a monotherapy and in combination with other therapies, including RAS inhibitors, in clinical trials to enable multiple registration paths for markets with large addressable patient populations and high unmet need

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Advance the clinical development of TNG456 in the ongoing Phase 1/2 clinical trial, focused on GBM

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Develop the next generation of precision oncology targets to continue to grow our pipeline

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Opportunistically evaluate our pipeline assets and maximize the value through strategic collaborations and licensing deals to bring more medicines to patients, accelerate development timelines and explore combination therapy approaches for our product candidates

BACKGROUND

Unmet need in precision oncology

Many genetic drivers of cancer are well-characterized but remain difficult to target directly, either because their molecular structure resists conventional inhibition (“undruggable” targets) or because the alteration results in loss of the gene’s normal function. As a result, a substantial portion of oncogenic biology remains a largely unaddressed target space. We are applying precision-oncology strategies, including the concept of synthetic lethality, to address the unmet medical need of large patient groups defined by actionable molecular alterations (e.g., specific mutation, deletions, copy-number changes, or immune contextures).

Synthetic lethality as a precision oncology strategy

Synthetic lethal cancer therapies exploit pairs of genes or pathways in which one is inactivated by a tumor-specific alteration and the other is inhibited pharmacologically. While genetic alterations drive the development of cancer, they also

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create unique vulnerabilities that can be targeted therapeutically. Biologically, these vulnerabilities may include an inability of cancer cells to respond to a specific signal, such as DNA damage or cell-cycle arrest, or the inability to remodel chromatin or to maintain cellular homeostasis. A key advantage of the synthetic lethal approach is selectivity: normal cells are not dependent on the same compensatory pathway and are therefore largely unaffected at drug-dose levels that selectively kill alteration-bearing cancer cells, as noted in Figure 2 below. The success of PARP inhibitors in BRCA-mutant breast, ovarian and prostate cancers is the first clinical example of using synthetic lethality to target tumors deficient in DNA-repair mechanism.

Figure 2. In cancer cells, specific molecular alterations create a dependency that allows an inhibitor to target a synthetic-lethal partner gene, causing tumor-cell death. This selective killing only occurs in tumors harboring the defined alteration (e.g. tumor suppressor gene), thereby largely sparing normal tissues offering a wide therapeutic index.

Biomarker driven patient selection

Across our clinical programs, we use molecular biomarkers as the basis for patient selection to enroll those patients most likely to benefit from each new drug candidate. This patient-centric, molecular approach is designed to enable efficient clinical development, increase the probability of success, and deliver the greatest clinical benefit to patients.

OUR CLINICAL STAGE PROGRAMS

PRMT5 inhibitors

PRMT5 has long been a therapeutic target of interest for cancer given its role in regulating proteins involved in multiple essential cellular functions, including RNA splicing, cell cycling, cell death, and metabolic signaling. PRMT5 is a protein arginine methyltransferase that modifies the activity of these proteins, which are critical for growth and viability of both normal and cancer cells. The first generation of PRMT5 inhibitors did not advance in clinical development because they were either SAM-cooperative or SAM-competitive (and not MTA-cooperative), and as a result, they killed rapidly growing normal cells, particularly bone marrow, as effectively as cancer cells. Therefore, on-target, dose-limiting bone marrow toxicity prevented adequate target inhibition in cancer cells. To address this problem, we designed vopimetostat and TNG456 to be MTA-cooperative and thus selectively active (synthetic lethal) in cancer cells that have a homozygous deletion of MTAP, which is not deleted in normal cells.

This synthetic lethal interaction occurs when MTAP is co-deleted as a “passenger” with the frequently-deleted tumor suppressor gene CDKN2A. Synthetic lethality occurs because MTAP-deleted cells accumulate the PRMT5 inhibitory factor MTA. As a result, PRMT5 is partially inhibited in MTAP-deleted cells, making those cells more sensitive than normal cells to further inhibition of PRMT5 activity. Taking advantage of this unique interaction between PRMT5 inhibition and MTAP deletion requires that the inhibitors have a specific binding mechanism called MTA cooperativity. Vopimetostat and TNG456 bind cooperatively with MTA to inhibit PRMT5 function by blocking access to the PRMT5 active site for both protein substrates and the activating PRMT5 co-factor SAM, specifically in tumor cells which are MTAP deleted. This MTA-cooperative binding mechanism allows selective inhibition of PRMT5 in tumor cells that have lost MTAP while being relatively inert in normal cells without MTAP deletion.

MTAP-deletion frequency in multiple solid tumor types

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A partial deletion of chromosome 9p21, driven by loss of the tumor suppressor gene CDKN2A, is the most common homozygous deletion in human cancer. MTAP is adjacent to CDKN2A and is lost along with it in 80-90% of CDKN2A-deleted tumors, thus MTAP is one of the most commonly deleted genes across all cancer types. Based on The Cancer Genome Atlas, SEER, Kantar and other sources, there are at least 15 cancer types where MTAP loss occurs in more than 10% of patients, including approximately 15% of NSCLC, 25% of bladder cancers, 40% of pancreatic cancers, and 45% of GBM. Our development program for vopimetostat is focusing on patients with pancreatic cancer, lung cancer, and histology selective cancers, and we estimate that the annual addressable patient population in the U.S. for these indications totals approximately 60,000 patients. Our development program for TNG456 will focus primarily on patients with GBM, which has an annual addressable U.S. patient population of approximately 7,000 patients.

Strong preclinical data demonstrated with our MTA-cooperative PRMT5 inhibitors in MTAP-deleted cancers

Since PRMT5 is an essential enzyme for all cell types, we designed our PRMT5 inhibitors to be selectively active in cancer cells that have a homozygous deletion of MTAP, which is not deleted in normal cells.

In normal cells with MTAP, MTA is rapidly degraded by MTAP and therefore does not inhibit PRMT5. When MTAP is deleted in cancer cells, intracellular MTA is markedly elevated compared to normal cells (Figures 3 and 4 below) and partially inhibits PRMT5. Our inhibitors preferentially bind PRMT5 in the presence of MTA and “lock” the enzyme into the inactive state which further inhibits PRMT5 and prevents it from methylating target proteins critical for cell survival. As a result, our inhibitors selectively kill MTAP-deleted tumor cells with elevated MTA levels while sparing normal cells.

Figure 3. Schematic of PRMT5 and MTAP functions

Figure 4. Vopimetostat and TNG456 have an MTA-cooperative mechanism of action that is selective for MTAP-deleted cancer cells

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In preclinical studies, our PRMT5 inhibitors drive dose-dependent, on-target, anti-tumor activity including deep and durable regressions in MTAP-null xenograft models regardless of histology. These preclinical results are driven by vopimetostat has 4nM potency and 45X selectivity for MTAP-deleted cancer cells versus normal cells. Additionally, TNG456 demonstrated 20nM potency and 55X MTAP deletion selectivity.

Preclinical and clinical combination data

We plan to develop vopimetostat and TNG456 as monotherapy agents and in combination with other agents. Based on strong preclinical data showing significant in vivo combination benefit, clinical combinations that are currently being executed, planned or are of potential interest for the future with our PRMT5 inhibitors include RAS, CDK4/6, and MAT2A inhibitors and potentially other oncogene-targeted therapies.

The RAS combinations are a key focus due to the overlap in patient populations with MTAP deletion in pancreatic and lung cancer as well as the anticipated postitive safety profile of both therapies. More than 90% of MTAP-deleted pancreatic adenocarcinomas are RAS-mutant and approximately 40% of RAS mutations are G12D. Additionally, approximately 30% of MTAP-deleted lung adenocarcinomas are also RAS-mutant. Additionally, preclinical in vivo studies showed their combination leads to significant tumor reductions, supporting further clinical testing. We have an ongoing clinical collaboration with Revolution Medicines, Inc., or RevMed, and are currently combining vopimetostat with daraxonrasib, a RAS(ON) multi-selective inhibitor, and separately with zoldonrasib, a RAS(ON) G12D-selective inhibitor, in MTAP-deleted, RAS-mutant pancreatic and lung cancer in a Phase 1/2 clinical trial. We anticipate providing a safety and efficacy update from that study in 2026.

Given the our belief that the differentiated profile of vopimetostat could enable the potential for efficacious and tolerable RAS inhibitor combinations, we have entered into a CTCSA with Erasca to evaluate vopimetostat in combination with Erasca’s pan-RAS molecular glue, ERAS-0015. Under the terms of the agreement, Tango is the sponsor of the trial and Erasca is supplying ERAS-0015 at no cost.

Essentially all MTAP-deleted tumors also harbor a CDKN2A deletion, which may sensitize cancers to CDK4/6 inhibition. We have observed the expected efficacy of this combination in preclinical in vivo studies. We have a clinical collaboration agreement with Eli Lilly and Company, or Lilly, that will supply Verzenio® (abemaciclib), a CDK4/6 inhibitor, for use in combination with TNG456 in our ongoing Phase 1/2 clinical trial focused on MTAP-deleted GBM. We anticipate treating patients with that combination upon confirmation of single-agent TNG456 activity in patients with GBM.

Strong synergy has been demonstrated preclinically with sub-therapeutic doses of vopimetostat and MAT2A inhibition, suggesting the combination of vopimetostat with MAT2A inhibitors may be clinically beneficial in MTAP-deleted tumors.

In preparation for potential first-line pivotal studies and to inform future clinical development opportunities, we are also conducting combination studies to assess tolerability with various agents, including pembrolizumab and chemotherapy.

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Clinical trials

Vopimetostat Phase 1/2 monotherapy

The vopimetostat Phase 1/2 clinical trial is evaluating the safety and efficacy of vopimetostat as a monotherapy in patients with MTAP-deleted solid tumors and is focused on pancreatic and lung cancer. The first patient was dosed in July 2023 and we are currently enrolling patients at 250 mg QD.

In October 2025, we reported positive data from the ongoing Phase 1/2 clinical trial of vopimetostat in patients with MTAP-deleted cancers, demonstrating clinical activity across multiple cancer types with a favorable safety and tolerability profile to date. The cutoff date for the analysis was September 1, 2025 and included all evaluable patients at active doses (200 mg QD and above). Based on our observations of other PRMT5 inhibitors, we believe that the objective response rate, or ORR, improves over time in PRMT5 inhibitors. When all evaluable patients as of September 1, 2025, regardless of duration of follow-up, were assessed for response, the ORR was 20%. At greater than 6 months of follow-up as of September 1, 2025, the ORR increased to 27%. The ORR analyses presented were thus derived from patients enrolled more than 6 months before the data cutoff regardless of outcome, to avoid under-reporting response rates. Therefore, the ORRs were calculated in all tumor-evaluable patients enrolled more than 6 months prior to the efficacy analysis. mPFS was calculated in all patients who received a first scan (~8 weeks).

Across all MTAP-deleted tumor types, there were 94 tumor evaluable patients. We observed an ORR 27% and mPFS of 6.4 months in these patients.

Figure 5: Vopimetostat 27% ORR across cancer types

Figure 6: Durable disease control with vopimetostat across cancer types

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In the 29 patients with second line (2L) MTAP-deleted pancreatic cancer, mPFS was 7.2 months. In patients with 2L pancreatic cancer who were tumor evaluable (n=8), the ORR was 25%, more than double that observed in historical chemotherapy studies (~10%), supporting the planned initiation of a 2L pivotal trial in this patient population in 2026.

Figure 7: Vopimetostat mPFS is 7.2 months in 2L pancreatic cancer

In the histology selective cohort with 37 evaluable patients, we observed a 49% ORR and mPFS of 9.1 months. The histology selective cohort excludes pancreatic and lung cancer patients, as those indications were enrolled in separate cohorts and are being developed independently. Sarcoma patients are also excluded from this analysis, as no activity was observed in this indication (ORR 0%), which will not be pursued in future development. We are evaluating the development path for the histology selective cohort, as well as for selected indications as stand-alone development opportunities.

Figure 8: Vopimetostat 49% ORR in histology selective cohort and mPFS of 9.1 months

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As of September 1, 2025, 41 patients with 2L+ lung cancer were enrolled in the Phase 1/2 clinical trial at active doses, 12 of whom were enrolled more than 6 months prior to the analysis. Emerging data from the lung cohort are consistent with expectations, and we anticipate providing a safety and efficacy update in 2026.

Figure 9: Vopimetostat 250mg QD has a potentially best-in-class safety profile

Vopimetostat demonstrated a favorable safety and tolerability profile with no drug-related dose discontinuations and ~8% dose reduction in patients dosed at 250 mg QD as of the data cutoff date of September 1, 2025. These data support our view that vopimetostat has the potential to be a best-in-class molecule and we believe support the initiation of a registrational trial in 2026 to evaluate 2L MTAP-deleted pancreatic cancer as a single agent.

Vopimetostat Phase 1/2 combination with RAS(ON) inhibitors

We are focused on evaluating the combination of vopimetostat with RAS inhibitors, given the overlap in patient populations, robust preclinical data supporting potential strong combination effect in clinical trials, and favorable clinical efficacy, durability, and safety profiles observed with each drug individually. This approach may enable a development path for chemotheraphy-free first-line and potentially second-line therapies for MTAP-deleted/RAS-mutated patients with pancreatic and lung cancer. We have a collaboration with RevMed to support the ongoing Phase 1/2 combination trial.

In June 2025, the first patient was treated in the combination clinical trial that is evaluating vopimetostat with the RAS(ON) multi-selective inhibitor, daraxonrasib, and RAS(ON) G12D-selective inhibitor, zoldonrasib (RevMed). As of December 24, 2025, we had enrolled 30 patients in the trial, and both combinations were well-tolerated to date with exposures

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in the active range for all compounds. Early efficacy data are encouraging. We anticipate providing a safety and efficacy update from this trial in 2026.

TNG456 Phase 1/2

TNG456 is a brain-penetrant PRMT5 inhibitor being evaluated in an ongoing Phase 1/2 trial enrolling patients with MTAP-deleted solid tumors, with a focus on GBM. In May 2025, we began enrolling patients in the TNG456 Phase 1/2 clinical trial, in which we plan to evaluate patients with TNG456 monotherapy as well as in combination with abemaciclib. The trial is currently in dose escalation and we anticipate providing a safety and efficacy update from this trial in 2026.

We plan to initiate the combination with abemaciclib with evidence of single agenda TNG456 activity in GBM.

We believe that the initial pharmacokinetics from the clinical trial support our hypothesis that TNG456 will reach efficacious exposures in the CNS at well-tolerated doses (Fig 10). In contrast, the results of the TNG908 Phase1/2 clinical trial determined that the TNG908 exposure in the brain of was subtherapeutic. TNG908 was discontinued in November 2024 due to insufficient brain exposure for clinical activity in GBM.

Figure 10. TNG908 (actual) and TNG456 (predicted based on clinical PK at 100mg BID) steady-state clinical exposure in plasma and brain

CoREST inhibition to reserve immune evasion

TNG260 is a first-in-class CoREST inhibitor targeting STK11 mutant/KRAS wild type NSCLC, representing ~10% of lung adenocarcinoma annually in the US (~10,000 patients). STK11 loss-of-function mutations suppress the immune microenvironment of lung cancers. As a result, immune checkpoint inhibitors, like anti-PD-1, are not sufficient to overcome the immune evasive environment of STK11-mutant tumors, leading to poor clinical responses in these patients. Inhibition of the CoREST complex by TNG260 has been shown in preclinical studies to lead to changes in expression of immune-related genes that favor a more active immune environment.

In a syngeneic mouse tumor model where STK11 loss drives resistance to immune checkpoint blockade, CoREST inhibition by TNG260 in combination with an anti-PD-1 antibody resulted in complete tumor regressions in five out of eight treated mice. Treatment was stopped on Day 48 and the five of eight mice that were completely tumor-free at that time remained tumor-free for 21 days with no further treatment. Furthermore, when tumor cells were re-implanted in these mice on day 69, they were rejected, compared to a treatment-naïve group of animals where tumors grew as expected. This demonstrated the induction of immune memory in the animals with complete responses to TNG260 with anti-PD-1 antibody (Figure 11).

Figure 11: Pharmacologic proof-of-concept for CoREST inhibition in STK11 mutant MC38 mouse tumors with TNG260 in combination with an anti-PD-1 antibody

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TNG260 Phase 1/2

In the first quarter of 2023, the FDA cleared the TNG260 IND and we announced the first patient in the Phase 1/2 clinical trial was dosed in July 2023. Data from the dose escalation portion of this study provided early clinical proof-of-concept in a pre-specified subgroup of patients with checkpoint inhibitor resistant STK11 mut/KRAS WT lung cancer. In this group (n=5), the mPFS was 29 weeks, more than double the standard of care PFS of ~10 weeks. There was no evidence of activity in STK11 mutant /KRAS mutant lung cancers or other cancer types. The trial is ongoing in the STK11mut/KRAS WT lung cancer cohort.

Manufacturing

Our lead investigational products are small molecule inhibitors that can be readily manufactured without requiring any specialized equipment or processes. We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We rely, and expect to continue to rely, on third-party Contract Development and Manufacturing Organizations, or CDMOs, for the manufacturing, packaging, labeling and distribution of our investigational products for preclinical and clinical testing, as well as for commercial manufacturing if any of our investigational products obtain marketing approval. A team of internal experts oversee activities at our contracted CDMOs with the goal of ensuring our investigational products are being manufactured under current good manufacturing practices, or cGMP. Currently, all manufacturing of the drug substance for our product candidates to be used in our clinical trials is conducted by one manufacturer and manufacturing of the drug product to be used in our clinical trials is conducted by two manufacturers. We believe that the contracted CDMOs have the capacity to support our potential registrational clinical studies, in addition to the first-in-human studies of our product candidates. The operations of one of these CDMOs are located outside the U.S. and the other CDMO conducts its operations for us in a single location in the United States. In addition to the risks related to having only two CDMOs (and only one manufacturer of drug substance), we may also encounter challenges related to supply chain, climate issues, pandemic and geopolitical risks. We plan to further expand and diversify our supply chain by identifying and contracting other CDMOs (beyond the two CDMOs that are currently conducting operations for us) with the capacity and expertise to support the drug substance and drug product for our product candidates and other investigational products in our pipeline and to manufacture commercial supply of our drugs (if those therapies obtain regulatory approval). For additional information and details on the risk related to manufacturing, see “