Breakthrough Clinical Results
Atossa Therapeutics announced positive feedback from the FDA regarding its proposed dose optimization trial of (Z)-endoxifen for ER+/HER2- metastatic breast cancer. The FDA's constructive response eliminates the need for a pre-IND meeting and paves the way for a potential IND submission in Q4 2025. The FDA affirmed Atossa's dose optimization strategy, supported the combination of (Z)-endoxifen with standard-of-care therapies, and deemed the nonclinical safety data adequate. Atossa will finalize the trial design, including patient population and combination therapy details, in the coming weeks. (Z)-endoxifen is a potent SERM with potential activity even in tumors resistant to other endocrine therapies. Atossa is developing a proprietary oral formulation to ensure optimal bioavailability.
Key Highlights
- Positive FDA feedback received on (Z)-endoxifen dose optimization trial for metastatic breast cancer.
- FDA affirmed dose optimization strategy and supported combination with standard-of-care therapies.
- IND submission targeted for Q4 2025.
- Nonclinical safety data deemed adequate by the FDA.
Incidence and Prevalence
Latest Estimates of Metastatic Breast Cancer Incidence and Prevalence Globally
Breast cancer remains the most commonly diagnosed cancer in women and the leading cause of cancer-related mortality worldwide. Within this disease spectrum, Metastatic breast cancer (MBC) represents the main cause of cancer-related death among breast cancer patients, with distant metastasis being the primary cause of breast cancer-related deaths.
According to a 2025 systematic review of global breast cancer stage distribution that analyzed data from 2.4 million women across 81 countries, the proportion of breast cancer cases diagnosed with distant metastatic disease varies significantly by geographic region:
- In sub-Saharan Africa, metastatic disease at diagnosis ranges from 5.6% to 30.6% of cases
- In North America, the proportion is substantially lower, ranging from 0.0% to 6.0%
Encouragingly, the proportion of patients diagnosed with distant metastatic disease has decreased over the past two decades: - Early 2000s: Between 3.8% to 35.8% of cases - 2015 onwards: Between 3.2% to 11.6% of cases
However, some regions have shown stabilization or slight increases in metastatic disease at diagnosis.
Several demographic factors influence metastatic breast cancer diagnosis rates:
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Age: Older patients have higher proportions of metastatic disease at diagnosis
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Younger patients: 2.0% to 15.7%
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Oldest age group: 4.1% to 33.9%
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Socioeconomic status: Lower socioeconomic status correlates with higher rates of metastatic disease
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Least disadvantaged groups: 1.7% to 8.3%
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Most disadvantaged groups: 2.8% to 11.4%
Research on the tumor microenvironment has revealed important insights into metastatic breast cancer biology. A 2024 study analyzing microenvironment heterogeneity found that T-NK and B cells dominated breast cancer with lymphatic node metastasis, while fibroblasts were prevalent in brain metastases. Proliferative cancer-associated fibroblasts (pCAFs) were found to dominate breast cancer with lymphatic node, bone, and brain metastasis, with the proportion of pCAF increasing in advanced breast cancer and being associated with a poor prognosis.
Additionally, liver and lung metastases of human breast cancers tend to be highly fibrotic and exclude cytotoxic T lymphocytes (CTLs), unlike primary breast tumors.
A 2016 meta-analysis of 24 studies with 3701 MBC patients demonstrated that higher circulating tumor cell (CTC) numbers indicated worse treatment response, poorer progression-free survival (PFS), and poorer overall survival (OS) in MBC patients.
While these findings provide valuable insights into metastatic breast cancer's global distribution and biology, specific age-standardized incidence rates, point prevalence, or period prevalence metrics for stage IV breast cancer were not available in the current data.
Key Unmet Needs and Target Populations in Metastatic Breast Cancer
Major Unmet Needs
Metastasis remains the cause of over 90% of all breast cancer deaths, with a dismal 5-year survival rate of only 20% for metastatic disease, highlighting the urgent need for improved treatments.
Drug resistance represents a critical challenge, particularly for triple negative breast cancer patients after multiline treatment. Similarly, endocrine resistance is a major unmet need, as "essentially all HR-positive metastatic breast cancers will become resistant to these drugs."
Brain metastases remain a significant challenge, especially in HER2-positive metastatic breast cancer, with one real-world study showing 153 of 216 patients (71%) having brain metastases.
Poor drug delivery efficiency to tumors and unsatisfactory anti-metastasis efficacy of current nanomedicine approaches continue to limit treatment success.
Key Target Populations
HR+/HER2- Advanced Breast Cancer
This represents the largest breast cancer subgroup. Key developments include: - PI3K/AKT/mTOR pathway inhibitors, particularly alpelisib, for postmenopausal women after disease progression on first-line therapy - TSPAN1 inhibition as a potential strategy for ER+ breast cancer patients with poor prognosis - Elacestrant (oral selective estrogen receptor degrader) showing modest improvement in progression-free survival - PIK3CA mutation testing is justified upon diagnosis and can guide treatment decisions
HER2-Positive Metastatic Breast Cancer (15-20% of cases)
- Trastuzumab deruxtecan (T-DXd) significantly improved progression-free survival compared to T-DM1 in second-line therapy
- Tucatinib-based combination represents a suitable second-line option for patients with brain metastases
- Pyrotinib + capecitabine showed consistent PFS benefits in trastuzumab-resistant disease
Triple-Negative Breast Cancer
- Sacituzumab govitecan (SG) showed significant improvement over treatment of physician's choice in HR+/HER2- metastatic breast cancer
- Immunotherapy combined with chemotherapy demonstrated overall survival advantage in immune cells PD-L1-positive subgroups
Circulating Tumor Cell (CTC) Clusters
- Plexin-B2 (PB2) has been identified as a therapeutic target driving formation of both homotypic and heterotypic CTC clusters
- Neutrophil-CTC cluster formation is an urgent issue, as these clusters facilitate metastasis
- Novel approaches targeting simultaneous elimination of primary tumors and inhibition of CTC clusters are being developed
Emerging Approaches
Hypoxia-responsive drug delivery systems show promise in targeting the acute hypoxic environment of advanced breast tumors.
Advanced imaging techniques like DCE-MRI with radiomics-clinical models show promise for more accurate TNM staging.
Anti-angiogenic therapy has potential as angiogenesis plays a key role in the growth and metastasis of breast cancer.
PARP inhibitor therapy for HER2-negative patients with germline BRCA1/2 mutations has shown improved overall survival in specific subgroups.
Drug used in other indications
(Z)-Endoxifen Clinical Trials Beyond Metastatic Breast Cancer
Beyond its application in metastatic breast cancer, (Z)-endoxifen has been evaluated in clinical studies for several other indications, demonstrating its potential versatility as a therapeutic agent.
Additional Indications Under Investigation
(Z)-endoxifen, the active isomer of endoxifen, has been investigated in Phase 1/2 clinical studies for multiple conditions including:
- Gynecologic tumors
- Desmoid tumors
- Hormone-receptor positive solid tumors
These expanded applications highlight the compound's potential utility across a broader spectrum of oncologic conditions beyond its initial focus on breast cancer.
Intervention Models and Clinical Findings
While specific intervention models for these additional indications are not fully detailed in the available information, the studies have demonstrated that Z-endoxifen possesses substantial oral bioavailability and has shown promising antitumor activity across these various tumor types.
Emerging Non-Oncologic Applications
Interestingly, Z-endoxifen is also showing an emerging role as an antimanic agent in the treatment of bipolar disorder, suggesting potential applications in psychiatric conditions.
Comparative Advantages Over Tamoxifen
Z-endoxifen appears to offer certain advantages compared to tamoxifen:
- It results in similar or even greater bone agonistic effects compared with tamoxifen
- It produces little or no endometrial proliferative effects compared with tamoxifen, potentially offering an improved safety profile
Development Status
The current body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications. Its pharmacological properties and preliminary clinical results support continued investigation across these diverse therapeutic areas.
The expansion of Z-endoxifen trials beyond metastatic breast cancer represents an important development in maximizing the potential clinical utility of this selective estrogen receptor modulator across multiple disease states.