Positive Phase 1/2 Data for IDE397 and Trodelvy Combination in MTAP-Deletion Urothelial Cancer
Breakthrough Clinical Results
IDEAYA Biosciences announced positive data from a Phase 1/2 trial evaluating the combination of IDE397, a MAT2A inhibitor, and Trodelvy (sacituzumab govitecan-hziy) in patients with late-line MTAP-deletion urothelial cancer. The trial showed an overall response rate (ORR) of 57% in one dose cohort and 33% in another. A manageable safety profile was observed. The company plans to select a recommended Phase 2 dose by the end of 2025 and provide an update at a medical conference in the first half of 2026. The combination is also being investigated in non-small cell lung cancer.
Key Highlights
- 57% overall response rate (ORR) observed in one dose cohort of IDE397 and Trodelvy combination in MTAP-deletion urothelial cancer.
- Manageable safety profile with no treatment-related serious adverse events at the highest dose.
- Recommended Phase 2 dose selection targeted by end of 2025.
- Trial expansion into non-small cell lung cancer underway.
Drug used in other indications
Indications for Trodelvy Beyond Urothelial Cancer
Based on the provided information, sacituzumab govitecan (Trodelvy) is currently indicated for:
- Triple-negative breast cancer (TNBC), specifically for patients with metastatic TNBC who have received 2-3 previous lines of therapy
- It is positioned as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer
Mechanism of Action
Trodelvy functions as an antibody drug conjugate that: - Targets the Trop-2 antigen present in solid epithelial tumors - Is linked to the active metabolite SN-38 (similar to irinotecan) - Specifically targets cancer cells while minimizing damage to healthy cells
Clinical Evidence
- Trodelvy is the first antibody drug conjugate demonstrating significant improvement in overall survival and progression free survival in metastatic TNBC patients
- Efficacy results showed significantly greater clinical benefit compared to standard chemotherapy
- The drug's preference is supported by clinical evidence and consensus across international clinical guidelines
- It is expected to become a treatment of substantial impact in future treatment guidelines for triple-negative breast cancer
Note: The provided information does not contain specific details about IDE397 clinical trials or intervention models for either medication beyond what is mentioned above.
Incidence and Prevalence
Global Epidemiology of Urothelial Cancer
Bladder cancer accounts for more than 200,000 deaths annually on a global level, with an age-standardized mortality rate of 2.9 per 100,000 individuals.
Urothelial carcinoma (UC) is the most common malignancy of the urinary tract, with urothelial bladder cancer accounting for approximately 90% of cases. This high prevalence makes it a significant global health concern.
Demographic Distribution
Men are more likely to suffer from bladder cancer than women, and it mostly affects the elderly. This gender disparity is evident in epidemiological studies:
- In a study from Johannesburg, South Africa (2010-2020), the incidence rate was highest among patients with a mean age of 60.7 ± 14.9
- Males constituted 60.9% of the cases, resulting in a male-to-female ratio of 1.6:1
Risk Factors
The most common risk factors associated with bladder cancer complications include: - Smoking - Being male - Black ethnicity - Increasing age
Histological Patterns
Transitional cell carcinoma remains the most prevalent histological subtype compared to squamous cell carcinoma (SCC). Patients with transitional cell carcinoma (TCC) were more likely to be: - Older (odds ratio: 1.03, 95% CI: 1.01-1.06, p = 0.029) - Male (OR: 2.60, 95% CI: 1.10-6.04, p = 0.030)
Most TCC cases were among black patients, though white patients were four times more likely to present with TCC compared to SCC (OR: 4.22, 95% CI: 1.43-12.48, p = 0.009).
Regional Trends
China
From 1990 to 2021, the number of deaths and DALYs due to smoking-attributable bladder cancer significantly increased. However, age-standardized mortality rates (ASMR) and age-standardized DALY rates (ASDR) decreased for both sexes, with males experiencing a higher burden.
By 2036, ASDR and ASMR for smoking-related bladder cancer in China are expected to continue decreasing, with this trend being more pronounced in males.
Montenegro
There was a consistent increase in mortality rates due to bladder cancer from 1990 to 2021, with an average annual percent change (AAPC) of 1.5% (95% CI: 0.5-2.9) overall and 1.6% (95% CI: 0.4-3.3) for males.
The majority of bladder cancer deaths in Montenegro occurred in the age groups of 65-74 (35.8%), 75-84 (33.6%), and 55-64 (16.8%).
Study Design Parameters
Study Design Parameters and Endpoints in Key Urothelial Cancer Trials
Immune Checkpoint Inhibitor Trials
Five immune checkpoint inhibitors have received FDA approval for advanced bladder cancer management. Key trials include:
- KEYNOTE-052: A single-arm phase II trial evaluating first-line pembrolizumab (200 mg every 3 weeks)
- KEYNOTE-045: A randomized phase III trial comparing salvage pembrolizumab versus chemotherapy (paclitaxel/docetaxel/vinflunine)
- KEYNOTE-361: A phase 3 study comparing pembrolizumab with/without chemotherapy versus chemotherapy alone
- JAVELIN Bladder 100: Assessed avelumab maintenance treatment plus best supportive care (BSC) versus BSC alone
- DANUBE: A phase 3 trial evaluating durvalumab with/without tremelimumab as first-line treatment
A real-world retrospective study of tislelizumab (200-mg monotherapy intravenously every 3 weeks) enrolled 33 patients with 10.17 months median follow-up.
Common Endpoints
Most trials assessed multiple endpoints including:
- Objective response rate (ORR)
- Progression-free survival (PFS)
- Overall survival (OS)
- Disease control rate (DCR)
- Safety and tolerability
- Quality-adjusted life years (QALY) in economic evaluations
The DANUBE trial had coprimary endpoints of OS for durvalumab monotherapy versus chemotherapy in high PD-L1 expression patients, and durvalumab plus tremelimumab versus chemotherapy in the intention-to-treat population.
Biomarker Studies
Trials frequently evaluated biomarkers including: - PD-L1 expression - Tumor mutational burden (TMB) - T-cell-inflamed gene expression profile (TcellinfGEP) - Stromal signature
A study of tumor-associated trypsin inhibitor (TATI), CYFRA 21-1, and urinary bladder carcinoma antigen (UBC) enrolled 160 individuals including 80 patients with high-grade urothelial bladder cancer.
Targeted Therapy Trials
RC48 (disitamab vedotin) was evaluated in a real-world study with endpoints including PFS, OS, ORR, DCR, and adverse events. In this study, median PFS was 5.4 months, and ORR was 38.9%.
A real-world study of Enfortumab vedotin (EV) monotherapy identified 416 advanced urothelial cancer patients, with 55.3% receiving EV as later-line therapy and 44.7% as earlier line therapy. EV dosing per label is 1.25 mg/kg on Days 1, 8, 15 of a 28-day cycle, though real-world dosing averaged 1.1 mg/kg.
Surgical Intervention Studies
A literature review included 21 studies on surgery in metastatic UC, with 17 retrospective reviews, 2 prospective phase II trials, and 2 meta-analyses. 15 of 17 studies showed improved survival with chemotherapy followed by radical cystectomy (RC) in patients with nodal involvement.
Trial Design Trends
A review of 48 randomized controlled trials (RCTs) in advanced/metastatic urothelial cancer found that 27 (56.3%) were phase II trials with a median sample size of 107 (range, 30-626).
Switch-maintenance therapy using immune checkpoint inhibitors following platinum-based chemotherapy has shown significant OS improvement (21.4 vs. 14.3 months, hazard ratio, 0.69).
