New ADC Data Underscore Progress and Highlight Challenges in HER2+ Breast Cancer and TNBC Management – OncLive

Report on Advances in Antibody-Drug Conjugates for Breast Cancer and Alignment with Sustainable Development Goals

Recent clinical trial data on antibody-drug conjugates (ADCs) are refining treatment paradigms for HER2-positive and triple-negative breast cancer (TNBC). These advancements represent significant progress toward achieving Sustainable Development Goal 3 (SDG 3): Good Health and Well-being, by improving therapeutic outcomes and reducing premature mortality from non-communicable diseases. The ongoing innovation in oncology also reflects advancements in SDG 9: Industry, Innovation, and Infrastructure, while highlighting the need to address disparities in care, a core tenet of SDG 10: Reduced Inequalities.

Advancements in HER2-Positive Breast Cancer Treatment

The development and expanded application of ADCs like fam-trastuzumab deruxtecan-nxki (T-DXd) are enhancing treatment efficacy across various stages of HER2-positive breast cancer, directly contributing to the targets of SDG 3.

Role of Trastuzumab Deruxtecan (T-DXd) in Early-Stage Disease

Data from recent phase 3 trials underscore the evolving role of T-DXd in neoadjuvant and adjuvant settings, offering improved patient outcomes but also necessitating careful management of toxicities to ensure patient well-being.

• DESTINY-Breast11 Trial (Neoadjuvant): This trial demonstrated that a neoadjuvant T-DXd-based regimen resulted in a superior pathologic complete response (pCR) rate compared to a standard regimen.
  1. T-DXd Regimen pCR: 67.3%
  2. Standard ddAC-THP Regimen pCR: 56.3%
  3. This improvement supports SDG 3 by increasing the effectiveness of early-stage treatment. However, the incidence of adverse effects (AEs), including interstitial lung disease (ILD), highlights the ongoing need for research into treatment de-escalation strategies to improve quality of life.
• DESTINY-Breast05 Trial (Adjuvant): Interim findings showed T-DXd significantly improved invasive disease-free survival (IDFS) compared to ado-trastuzumab emtansine (T-DM1) for patients with residual disease after neoadjuvant therapy.
  1. 3-Year IDFS with T-DXd: 92.4%
  2. 3-Year IDFS with T-DM1: 83.7%
  3. The 53% reduction in the risk of invasive disease or death with T-DXd is a substantial step toward achieving the health targets of SDG 3.

Novel Antibody-Drug Conjugates (ADCs) in Advanced Disease

Continued research into both established and novel ADCs for metastatic HER2-positive breast cancer is expanding therapeutic options, aligning with the innovation targets of SDG 9 and the health goals of SDG 3.

• DESTINY-Breast09 Trial: The primary analysis revealed that first-line T-DXd plus pertuzumab extended median progression-free survival (PFS) significantly compared to the standard THP regimen in patients with unresectable or metastatic disease.
  1. Median PFS with T-DXd plus Pertuzumab: 40.7 months
  2. Median PFS with THP: 26.9 months
  3. Subgroup analyses confirmed this benefit across patient populations, including those with de novo disease, reinforcing its potential as a new standard of care.
• Trastuzumab Botidotin Phase 3 Trial: This study demonstrated the efficacy of a novel ADC, trastuzumab botidotin, which showed a superior median PFS compared to T-DM1.
  1. Median PFS with Trastuzumab Botidotin: 11.1 months
  2. Median PFS with T-DM1: 4.4 months
  3. The agent’s favorable safety profile, with lower rates of specific toxicities like ILD and hepatotoxicity, contributes to SDG 3 by aiming to improve both survival and patient quality of life.

Emerging Therapies for Triple-Negative Breast Cancer (TNBC)

Advancements in TROP2-targeted ADCs are poised to change the first-line treatment landscape for TNBC. This is particularly crucial for advancing SDG 5 (Gender Equality) and SDG 10 (Reduced Inequalities), as TNBC disproportionately affects younger women and specific underrepresented ethnic groups.

Comparative Efficacy of TROP2-Targeted ADCs

Two major clinical trials have presented positive results for different TROP2-targeted ADCs, creating a more complex but promising decision-making framework for clinicians.

• ASCENT-03 Trial (Sacituzumab Govitecan): For patients with untreated metastatic TNBC ineligible for PD-1/PD-L1 inhibitors, sacituzumab govitecan demonstrated a statistically significant improvement in PFS over standard chemotherapy.
  1. Median PFS with Sacituzumab Govitecan: 9.7 months
  2. Median PFS with Chemotherapy: 6.9 months
  3. Combined with positive results from the ASCENT-04 trial in the PD-L1 positive population, these findings position sacituzumab govitecan as a key frontline option.
• TROPION-Breast02 Trial (Datopotamab Deruxtecan – Dato-DXd): In a similar patient population, Dato-DXd also showed superior PFS and overall survival (OS) compared to chemotherapy.
  1. Median PFS with Dato-DXd: 10.8 months
  2. Median PFS with Chemotherapy: 5.6 months
  3. The notably high overall response rate (62.5%) suggests this agent may be particularly beneficial for high-risk patients, furthering the goals of SDG 3.

The availability of multiple effective agents necessitates nuanced clinical application and further research to identify optimal sequencing and patient selection, while cautioning against potential cross-resistance due to similar drug payloads.

Future Directions and Addressing Health Inequalities

While recent progress is significant, addressing remaining unmet needs is critical for achieving equitable health outcomes and fulfilling the promise of the Sustainable Development Goals.

Strategic Imperatives for Future Research

• Brain Metastases: A significant unmet need, particularly in TNBC, is the development of agents that effectively cross the blood-brain barrier. Progress in this area is essential for improving survival and quality of life, directly aligning with SDG 3.
• Novel Immune-Targeted Therapies: Exploration of new immunotherapies and combination strategies beyond existing agents is a key area for future research to further improve outcomes.

Enhancing Equity in Clinical Research

A critical challenge remains in ensuring clinical trial participation is inclusive and representative of the patient populations most affected by diseases like TNBC. Addressing this issue is fundamental to achieving SDG 10 (Reduced Inequalities).

• It is imperative to focus on understanding the efficacy and safety of novel therapies in underrepresented groups who are disproportionately affected by aggressive breast cancer subtypes.
• Making clinical research more accessible and inclusive will ensure that advancements in treatment are effective and beneficial for all patients, thereby creating a more equitable global health landscape.

Analysis of Sustainable Development Goals in the Article

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

The article on advancements in breast cancer treatment connects to several Sustainable Development Goals (SDGs) by focusing on health, scientific innovation, and social equity in medical research.

• SDG 3: Good Health and Well-being: The core theme of the article is the improvement of treatments for non-communicable diseases, specifically HER2-positive and triple-negative breast cancer. It details clinical trials for new drugs aimed at increasing survival rates and improving patient outcomes, which is central to ensuring healthy lives.
• SDG 9: Industry, Innovation, and Infrastructure: The article is fundamentally about scientific research and innovation. It discusses numerous phase 3 clinical trials (DESTINY-Breast11, DESTINY-Breast09, ASCENT-03, TROPION-Breast02), the development of novel antibody-drug conjugates (ADCs), and the continuous effort by the medical community to refine treatment paradigms. This highlights the role of research and development in advancing healthcare.
• SDG 10: Reduced Inequalities: The article concludes by addressing a critical issue of inequality in healthcare. It explicitly mentions that “TNBC disproportionately affects underrepresented groups, and yet, we consistently see these groups continue to be underrepresented in our clinical trials.” This points to the need for more inclusive research to ensure that medical advancements benefit all segments of the population equally.

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

Based on the issues discussed, the following specific SDG targets are relevant:

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 entire article focuses on improving treatment for breast cancer, a major non-communicable disease. The discussion of new drugs like T-DXd and Dato-DXd and their superior efficacy in clinical trials—demonstrated by improved survival rates—directly contributes to this target of reducing premature mortality.
2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases…
   • The article is a testament to ongoing research and development. It details the findings from multiple clinical trials for new medicines (ADCs) and mentions the “FDA breakthrough therapy designation” for one treatment, showcasing the process of developing and providing access to new, effective therapies.
3. Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries… encouraging innovation and substantially increasing the number of research and development workers…
   • The article highlights the intensive scientific research being conducted in oncology. The presentation of data at major international conferences like the ESMO Congress and ASCO Annual Meeting, along with insights from leading medical oncologists from various prestigious institutions, reflects a strong commitment to enhancing scientific research and fostering innovation in the medical field.
4. Target 10.2: By 2030, empower and promote the social, economic and political inclusion of all, irrespective of… race, ethnicity… or other status.
   • The article’s conclusion directly addresses this target in the context of healthcare. The call to action to make “clinical research participation more inclusive and accessible for patients” and to address the underrepresentation of groups disproportionately affected by TNBC is a clear effort to promote inclusion and ensure new therapies are effective for all.

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

Yes, the article contains several quantitative and qualitative indicators that can measure progress towards the identified targets:

• For Target 3.4 (Reduce mortality from NCDs): The article provides specific quantitative data from clinical trials that serve as direct indicators of treatment efficacy.
  • Invasive Disease–Free Survival (IDFS) Rate: The DESTINY-Breast05 trial showed a 3-year IDFS rate of 92.4% with T-DXd compared to 83.7% with T-DM1.
  • Progression-Free Survival (PFS): The DESTINY-Breast09 trial reported a median PFS of 40.7 months with T-DXd plus pertuzumab versus 26.9 months with standard therapy. The TROPION-Breast02 trial showed a median PFS of 10.8 months with Dato-DXd versus 5.6 months with chemotherapy.
  • Overall Survival (OS): The TROPION-Breast02 trial noted a median OS of 23.7 months with Dato-DXd compared to 18.7 months with chemotherapy.
  • Pathologic Complete Response (pCR) Rate: The DESTINY-Breast11 trial showed a pCR rate of 67.3% in the T-DXd arm versus 56.3% in the standard therapy arm.
• For Target 9.5 (Enhance scientific research): Progress is implied through the description of the research ecosystem.
  • Number and Phase of Clinical Trials: The article details multiple large-scale, international, phase 3 clinical trials (e.g., DESTINY-Breast11, DESTINY-Breast05, ASCENT-03), indicating a high level of research activity and investment.
  • Development of Novel Therapies: The focus on “newer antibody-drug conjugates (ADCs)” and specific agents like trastuzumab botidotin and datopotamab deruxtecan indicates ongoing innovation.
• For Target 10.2 (Promote inclusion): The article provides a qualitative baseline indicator and suggests a path for measurement.
  • Representation in Clinical Trials: The statement that underrepresented groups “consistently see these groups continue to be underrepresented in our clinical trials” serves as a baseline indicator of inequality. Progress could be measured by tracking the demographic data of participants in future clinical trials to ensure they reflect the populations most affected by the disease.

4. Table of SDGs, Targets, and Indicators

Source: onclive.com