How Dato-DXd and the TROPION Trials Are Transforming Solid Tumor Research – CancerNetwork

Report on the Clinical Advancement of Datopotamab Deruxtecan (Dato-DXd) and its Contribution to Sustainable Development Goals

Introduction: Advancing SDG 3 – Good Health and Well-being

Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate (ADC), has demonstrated significant clinical efficacy across multiple solid tumors, including breast, lung, and bladder cancers. The development and application of this therapeutic agent directly support the United Nations Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all at all ages, particularly Target 3.4, focused on reducing premature mortality from non-communicable diseases like cancer. This report outlines the mechanism, clinical trial data, and broad therapeutic potential of Dato-DXd, highlighting its role in advancing global health outcomes.

Mechanism of Action and Innovation (SDG 9)

The design of Dato-DXd represents a significant contribution to SDG 9 (Industry, Innovation, and Infrastructure) by advancing scientific research and technological capabilities in oncology. Its targeted delivery system is an innovation designed to improve treatment efficacy while potentially mitigating systemic toxicity.

Composition of Dato-DXd

• A humanized anti-TROP2 immunoglobulin 1 monoclonal antibody, which targets the TROP2 protein highly expressed in various solid tumors.
• A tetrapeptide-based cleavable linker, ensuring stable delivery.
• A topoisomerase I inhibitor payload, a potent cytotoxic agent delivered directly to cancer cells.

Clinical Trial Evidence and Impact on Global Health (SDG 3)

An extensive clinical trial program has evaluated the safety and efficacy of Dato-DXd, providing crucial data that supports its role in improving cancer treatment paradigms and contributing to better health outcomes globally.

TROPION-Breast01 Trial: HR-Positive/HER2-Negative Breast Cancer

This Phase 3 trial assessed Dato-DXd against the investigator’s choice of chemotherapy (ICC) in patients with previously treated HR-positive/HER2-negative breast cancer.

1. Efficacy Outcomes:
   • Progression-Free Survival (PFS): The trial met its primary endpoint, showing a median PFS of 6.9 months for Dato-DXd versus 4.9 months for ICC (HR, 0.63; P <.0001 a statistically significant and clinically meaningful improvement.>
   • Overall Survival (OS): The dual primary endpoint of OS was not met, with a median OS of 18.6 months for Dato-DXd versus 18.3 months for ICC (HR, 1.01). This outcome may have been influenced by subsequent ADC therapy in the control arm.
   • Overall Response Rate (ORR): The ORR was 36.4% in the Dato-DXd arm compared to 22.9% in the ICC arm.
2. Safety Profile:
   • Grade 3 or higher adverse effects (AEs) were less frequent with Dato-DXd (22%) compared to ICC (46%).
   • Common treatment-related AEs (TRAEs) included nausea, stomatitis, and alopecia.

BEGONIA Trial: Triple-Negative Breast Cancer (TNBC)

This Phase 1/2 trial evaluated Dato-DXd in combination with durvalumab for patients with advanced/metastatic TNBC, addressing a critical unmet need and contributing to SDG 3.

1. Efficacy in Arm 7 (Any PD-L1 Expression):
   • Confirmed ORR was 79.0%, demonstrating robust antitumor activity.
2. Efficacy in Arm 8 (PD-L1 High Expression):
   • Confirmed ORR was 81.8%.
3. Safety Profile:
   • Common treatment-emergent AEs (TEAEs) included stomatitis and nausea. Serious AEs occurred in 29.0% of patients in Arm 7 and 15.2% in Arm 8.

TROPION-Breast02 Trial: First-Line TNBC

This Phase 3 trial compared Dato-DXd to ICC in patients with locally recurrent inoperable or metastatic TNBC, including populations often excluded from clinical trials, thereby addressing health equity in line with SDG 10 (Reduced Inequalities).

1. Efficacy Outcomes:
   • PFS: Median PFS was 10.8 months with Dato-DXd versus 5.6 months with ICC (HR, 0.57; P <.0001>
   • OS: Median OS was 23.7 months with Dato-DXd versus 18.7 months with ICC (HR, 0.79; P = .0291).
   • ORR: The ORR was 62.5% in the Dato-DXd arm versus 29.3% in the ICC arm.
2. Safety Profile:
   • Common TRAEs included stomatitis, nausea, and dry eye. The safety profile was manageable.

Expanding Therapeutic Applications and Reducing Health Inequalities (SDG 3 & SDG 10)

The investigation of Dato-DXd extends beyond breast cancer, with promising results in lung and bladder cancers. This broad applicability is crucial for addressing different non-communicable diseases and reducing global health inequalities.

Lung Cancer Applications

Based on positive results from the TROPION-Lung05 trial, the FDA granted accelerated approval for Dato-DXd in patients with EGFR-mutated non-small cell lung cancer (NSCLC), expanding treatment options for this patient population.

Bladder Cancer Applications

• TROPION-PanTumor01 Trial: In a cohort of patients with locally advanced/metastatic urothelial cancer, Dato-DXd monotherapy demonstrated an ORR of 25.0% and a disease control rate of 77.5%. The median PFS was 6.9 months.
• TROPION-PanTumor03 Trial: This Phase 2 study assessed Dato-DXd plus rilvegostomig in patients with urothelial carcinoma.
  • First-Line (Platinum Ineligible): The combination showed a confirmed ORR of 68.2% and a 12-month PFS rate of 73.5%.
  • Second-Line: The confirmed ORR was 38.9%, with a median PFS of 12.5 months.

Conclusion: Fostering Partnerships for Health and Innovation (SDG 17)

The comprehensive clinical development of Datopotamab deruxtecan exemplifies SDG 17 (Partnerships for the Goals), reflecting a global, multi-stakeholder effort to advance cancer therapy. The positive results across multiple tumor types underscore its potential to significantly impact the achievement of SDG 3 by providing a new, effective treatment that can reduce premature mortality from cancer. Continued research and collaboration are warranted to fully realize the potential of this innovative therapy in improving global health and promoting well-being for all.

Which SDGs are addressed or connected to the issues highlighted in the article?

SDG 3: Good Health and Well-being

• The article focuses entirely on the development and clinical trials of a new cancer drug, Datopotamab deruxtecan-dlnk (Dato-DXd). This directly relates to improving health outcomes and well-being for individuals suffering from non-communicable diseases like breast, lung, and bladder cancer.
• It details efforts to find more effective treatments to extend life and improve the quality of life for patients, which is a core component of SDG 3.

SDG 9: Industry, Innovation, and Infrastructure

• The development of Dato-DXd, described as a “TROP2-directed antibody drug conjugate (ADC) with a stable linker,” represents significant scientific research and technological innovation within the pharmaceutical industry.
• The article highlights the complex infrastructure required for medical advancement, including numerous large-scale clinical trials (e.g., TROPION-Breast01, BEGONIA) and the regulatory approval process by bodies like the FDA.

SDG 17: Partnerships for the Goals

• The article implicitly points to partnerships. The FDA approval process for Dato-DXd is a public-private partnership between the pharmaceutical company (Daiichi Sankyo) and a government regulatory agency.
• The presentation of trial results at the “16th Annual World Antibody Drug Conjugate Conference” demonstrates knowledge-sharing and collaboration within the global scientific community, which is essential for advancing medical science.

What specific targets under those SDGs can be identified based on the article’s content?

SDG 3: Good Health and Well-being

1. Target 3.4: By 2030, reduce by one-third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
   • The article directly addresses this target by discussing a new treatment for cancer, a primary non-communicable disease. The clinical trials, such as TROPION-Breast01, aim to demonstrate the drug’s effectiveness in improving survival rates and reducing mortality. For example, it notes an improvement in median progression-free survival (PFS) from 4.9 months to 6.9 months.
2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases.
   • The entire article is a case study of this target in action. It details the research journey of Dato-DXd, from its mechanism of action to its assessment in multiple phase 1, 2, and 3 clinical trials (TROPION-PanTumor01, TROPION-Breast02, etc.) for various cancers, culminating in FDA approval.

SDG 9: Industry, Innovation, and Infrastructure

1. Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors… encouraging innovation and substantially increasing the number of research and development workers.
   • The development of Dato-DXd as a novel TROP2-directed antibody-drug conjugate is a clear example of enhancing scientific research and technological capability in the biopharmaceutical sector. The article showcases the work of specialized professionals like “Federico Nasroulah, MD, executive director, Global Clinical Lead of Oncology Clinical Development at Daiichi Sankyo,” representing the R&D workforce driving this innovation.

SDG 17: Partnerships for the Goals

1. Target 17.17: Encourage and promote effective public, public-private and civil society partnerships.
   • The article mentions the FDA’s approval of Dato-DXd for breast and lung cancer. This approval is the result of a critical public-private partnership between the drug’s developer (a private entity) and the FDA (a public regulatory body), which evaluates the drug’s safety and efficacy for public benefit.

Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

SDG 3: Good Health and Well-being

• Implied Indicator for Target 3.4 (Mortality from NCDs): The article provides specific clinical metrics that serve as direct indicators of treatment efficacy and survival. These include:
  • Progression-Free Survival (PFS): Mentioned in TROPION-Breast01 (“median progression-free survival (PFS) was 6.9 months… vs 4.9 months”) and TROPION-Breast02.
  • Overall Survival (OS): A primary endpoint in TROPION-Breast01 and TROPION-Breast02.
  • Overall Response Rate (ORR): Reported for multiple trials, such as BEGONIA (“confirmed ORR was 79.0%”) and TROPION-PanTumor01.
  • Adverse Effects (AEs) and Treatment-Related Deaths: Safety data, including “TEAEs leading to death,” are reported, which are crucial for assessing the net benefit of a treatment.

SDG 9: Industry, Innovation, and Infrastructure

• Implied Indicator for Target 9.5 (R&D Activity): While not providing financial figures, the article implies significant R&D investment and activity through:
  • Number and Phase of Clinical Trials: The article lists numerous advanced-stage trials (TROPION-Breast01, TROPION-Lung05, BEGONIA, etc.), indicating a robust and well-funded R&D pipeline.
  • FDA Approvals: The successful navigation of the FDA approval process for multiple indications is a key outcome indicator of successful R&D.

SDG 17: Partnerships for the Goals

• Implied Indicator for Target 17.17 (Public-Private Partnerships): The article provides qualitative evidence of partnerships through:
  • Regulatory Submissions and Approvals: The mention of “FDA approved Dato-DXd” is a direct outcome and indicator of a functioning partnership between the industry and a public health authority.
  • Knowledge Sharing Platforms: The presentation of findings at the “16th Annual World Antibody Drug Conjugate Conference” serves as an indicator of collaboration and knowledge dissemination within the global scientific community.

SDGs, Targets, and Indicators Analysis

Source: cancernetwork.com