Breast cancer continues to be a leading cause of cancer death among women globally. However, the ongoing DESTINY breast cancer clinical trials have brought a wave of optimism, with novel therapies like trastuzumab deruxtecan offering unprecedented efficacy.

1. The Landscape of HER2-Targeted Therapy Before DESTINY

For decades, the management of breast cancer has relied heavily on classifying tumors based on their hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. HER2-positive cancers—once associated with aggressive disease—became more manageable with targeted therapies such as:

• Trastuzumab (Herceptin)

• Pertuzumab (Perjeta)

• T-DM1 (trastuzumab emtansine)

However, these therapies were limited to HER2-positive patients, typically defined by IHC 3+ or IHC 2+ with positive FISH. Those with HER2-low tumors (IHC 1+ or 2+ with negative FISH) were historically grouped with HER2-negative disease, receiving only chemotherapy or endocrine therapy.

This classification left a treatment void for HER2-low patients, who constitute nearly 50–60% of all breast cancer cases. Furthermore, in the metastatic setting, treatment options dwindled after progression on standard therapies, calling for more innovative solutions.

2. Introduction to the DESTINY Clinical Trial Program

The DESTINY (Drug Evaluation Study on Trastuzumab Deruxtecan In Breast Cancer) program is a series of global clinical trials led by Daiichi Sankyo and AstraZeneca, exploring the potential of a revolutionary drug: trastuzumab deruxtecan (T-DXd).

These trials aim to:

• Expand HER2-targeted therapy to HER2-low populations

• Improve outcomes in pretreated, metastatic, and resistant cancers

• Explore early-stage and combination regimens for broader applications

At the heart of this initiative is T-DXd, an antibody-drug conjugate (ADC) designed to enhance the specificity and potency of HER2 targeting beyond what previous agents could achieve.

Summary of DESTINY Trial Results

(*Interim data)

3. Mechanism of Action: How Trastuzumab Deruxtecan Works

T-DXd exemplifies a next-generation ADC, composed of three main elements:

• Trastuzumab: A monoclonal antibody that targets HER2

• Cleavable linker: Ensures the payload is only released inside tumor cells

• Payload: A potent topoisomerase I inhibitor, capable of inducing DNA damage

Key innovations in T-DXd's design include:

• High drug-to-antibody ratio (DAR) of ~8 (vs. ~3.5 in T-DM1)

• Bystander effect: The cytotoxic payload can diffuse into adjacent HER2-low or negative cells

• Efficient internalization and lysosomal cleavage, maximizing tumor-specific activity

This mechanism enables robust activity even in tumors with low HER2 expression, changing the traditional binary view of HER2 status.

4. Key DESTINY Trials and Their Findings

The DESTINY program encompasses multiple pivotal trials that have reshaped breast cancer therapy:

DESTINY-Breast01

• Population: Heavily pretreated HER2-positive metastatic breast cancer (mBC)

• Key Results:

• Objective response rate (ORR): 61.4%

• Median progression-free survival (PFS): 19.4 months

• Median overall survival (OS): 29.1 months

• Significance: T-DXd outperformed all prior options in patients who had received multiple lines of HER2 therapy.

DESTINY-Breast03

• Comparison: T-DXd vs. T-DM1 in second-line HER2+ mBC

• Key Results:

• PFS: 28.8 months (T-DXd) vs. 6.8 months (T-DM1)

• ORR: 78.5% (T-DXd) vs. 35.0% (T-DM1)

• HR for progression or death: 0.33

• Significance: Established T-DXd as the preferred second-line agent for HER2+ metastatic disease.

DESTINY-Breast04

• Population: HER2-low metastatic breast cancer (HR+ and HR−)

• Key Results (HR+ cohort):

• PFS: 10.1 months (T-DXd) vs. 5.4 months (chemotherapy)

• OS: 23.9 months vs. 17.5 months

• Significance: First therapy to successfully treat HER2-low tumors, leading to FDA approval of T-DXd for HER2-low mBC in 2022.

DESTINY-Breast06

• Interim results (ASCO 2023) suggest benefit in HR+/HER2-low and even HER2-ultralow disease

• Ongoing to determine impact in earlier settings and first-line use

5. Safety and Tolerability Profile of T-DXd

T-DXd's potency brings considerable efficacy, but it also necessitates careful management of side effects:

Common Adverse Events:

• Nausea and vomiting (most frequent; manageable with antiemetics)

• Neutropenia and anemia

• Alopecia and fatigue

Interstitial Lung Disease (ILD) is the most serious concern, with rates of 10–15% (mostly low-grade).

• Grade 5 ILD (fatal) reported in ~1–2% of patients

• Monitoring with regular CT scans and prompt corticosteroid treatment is recommended

• Trials now include ILD mitigation protocols, improving safety

Despite these concerns, dose reductions and supportive care allow most patients to continue treatment.

6. Impact on Clinical Practice and Treatment Guidelines

The success of DESTINY trials has led to rapid guideline revisions:

• NCCN and ASCO endorse T-DXd as standard of care for:

• Second-line therapy in HER2+ mBC

• First-line for HER2-low after prior chemo or endocrine therapy

• HER2-low is now a therapeutic category, requiring more refined IHC testing

• Emphasis on HER2 re-testing at metastasis, as HER2 expression may evolve

Clinicians now consider T-DXd early in treatment algorithms, particularly for patients progressing on traditional HER2-directed or endocrine therapies.

7. Comparison Table: T-DXd vs. T-DM1 vs. Chemotherapy in Key Trials

8. The Future of the DESTINY Program

The DESTINY program continues to expand its scope with multiple new trials:

• DESTINY-Breast07 & 08: Exploring T-DXd in combination with immunotherapy (e.g., durvalumab) and CDK4/6 inhibitors

• DESTINY-Breast09: Investigating neoadjuvant and adjuvant settings

• DESTINY-Gastric & DESTINY-Lung: Targeting HER2+ gastric and NSCLC tumors

There is also growing interest in:

• HER2-ultralow tumors (IHC 0–1+)

• Non-breast cancers with HER2 expression

• ADC sequencing and resistance mechanisms, to optimize duration and timing of therapy

These expansions will likely broaden eligibility, offering novel solutions for other solid tumors.

FAQs

Q1: What is the DESTINY trial program?
A: A series of clinical studies investigating trastuzumab deruxtecan in various breast cancer settings, particularly HER2+ and HER2-low disease.

Q2: Who qualifies for T-DXd treatment?
A: Patients with HER2-positive or HER2-low metastatic breast cancer who have received prior therapy. Trials are expanding to earlier lines and other cancers.

Q3: Is HER2-low the same as HER2-negative?
A: No. HER2-low (IHC 1+ or 2+/FISH−) expresses some HER2, making it eligible for T-DXd. HER2-negative (IHC 0) may not benefit—though this is under investigation.

Q4: What are the side effects of trastuzumab deruxtecan?
A: Common side effects include nausea, fatigue, and low blood counts. ILD is the most serious but is manageable with early detection.

Q5: How does T-DXd compare to other HER2 therapies?
A: T-DXd offers superior efficacy in both HER2+ and HER2-low populations, with longer PFS and higher response rates than T-DM1 or chemotherapy.

Conclusion

The DESTINY breast cancer trials have significantly altered the landscape of HER2-targeted therapy. Trastuzumab deruxtecan has demonstrated groundbreaking results not only in traditional HER2-positive disease but also in HER2-low tumors—a population previously left without targeted options. These findings have transformed clinical guidelines, expanded the definition of HER2 relevance, and brought hope to thousands of patients worldwide. With further trials underway and new combinations on the horizon, the DESTINY program continues to redefine what is possible in breast cancer treatment.