Daiichi Sankyo has submitted a supplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for trastuzumab deruxtecan in patients with HER2-expressing advanced or recurrent uterine carcinosarcoma, a rare and aggressive cancer with limited treatment options.
The application covers patients whose tumors demonstrate HER2 expression at immunohistochemistry (IHC) levels of 3+, 2+, or 1+, potentially expanding access to HER2-directed treatment beyond populations traditionally classified as HER2-positive.
The submission is supported by results from the Phase 2 STATICE trial, which demonstrated antitumor activity in previously treated patients, including those with low HER2 expression.
If approved, trastuzumab deruxtecan could provide a new biomarker-directed treatment option for patients with this difficult-to-treat gynecologic malignancy.
Uterine Carcinosarcoma: An Aggressive Cancer with Limited Treatment Options
Uterine carcinosarcoma accounts for fewer than 5% of endometrial cancer cases in Japan but is estimated to contribute to approximately 15% of endometrial cancer-related deaths.
The disease is characterized by aggressive behavior, a high risk of recurrence, and poor outcomes following progression. For patients with advanced or recurrent disease, systemic treatment has traditionally relied on chemotherapy, particularly carboplatin combined with paclitaxel.
Although chemotherapy can provide disease control, recurrence remains common, and effective treatment options after progression are limited.
HER2 has emerged as a potential therapeutic target in this population. Studies have identified varying degrees of HER2 expression in uterine carcinosarcoma, with one analysis cited by Daiichi Sankyo reporting HER2 IHC 1+, 2+, or 3+ expression in approximately 72% of cases.
This creates an opportunity to investigate whether HER2-directed therapies can provide meaningful benefit in a disease that has historically lacked established molecularly targeted treatment options.
STATICE Trial: Trastuzumab Deruxtecan Demonstrates Responses Across HER2 Expression Levels
The regulatory submission is based on the investigator-initiated, multicenter, open-label, single-arm Phase 2 STATICE trial (NCCH1615), conducted across seven institutions in Japan.
The study evaluated trastuzumab deruxtecan in patients with advanced or recurrent uterine carcinosarcoma who had previously received chemotherapy, including treatment administered in the adjuvant setting.
A total of 34 patients were enrolled, 33 received treatment, and 32 were evaluable for efficacy.
Patients were divided into two groups according to HER2 expression:
- HER2-high: IHC 2+ or 3+ (22 patients).
- HER2-low: IHC 1+ (10 patients).
Trastuzumab deruxtecan was administered intravenously every three weeks.
Treatment initially began at 6.4 mg/kg, but the protocol was subsequently modified to use 5.4 mg/kg following a reassessment of the benefit-risk profile. The lower dose became the preferred regimen.
The primary endpoint was objective response rate (ORR) by independent central review in the HER2-high population.
More Than Half of Patients Responded to Trastuzumab Deruxtecan
Results published in the Journal of Clinical Oncology demonstrated antitumor activity across both HER2-expression groups.
In the HER2-high population:
- Objective response rate: 54.5% (12 of 22 patients).
- Median duration of response: 6.9 months.
- Median progression-free survival: 6.2 months.
- Median overall survival: 13.3 months.
In the exploratory HER2-low population:
- Objective response rate: 70.0% (7 of 10 patients).
- Median duration of response: 8.1 months.
- Median progression-free survival: 6.7 months.
- Median overall survival: Not reached at the time of analysis.
Across the entire efficacy population, median progression-free survival was 6.7 months, while median overall survival reached 15.8 months.
These findings are particularly relevant because responses were observed even in patients whose tumors expressed HER2 at the IHC 1+ level.
However, the HER2-low group included only 10 patients, and its analysis was exploratory. The numerically higher response rate should therefore not be interpreted as evidence that HER2-low tumors respond better than HER2-high tumors.
Additionally, the published efficacy results include patients treated at both dose levels rather than exclusively at the proposed 5.4 mg/kg dose.
Safety Findings: Interstitial Lung Disease Remains an Important Consideration
The STATICE trial also evaluated the safety of trastuzumab deruxtecan in this previously treated population.
Grade 3 or higher adverse events occurred in 61% of treated patients.
Interstitial lung disease (ILD) and pneumonitis, recognized risks associated with trastuzumab deruxtecan, were reported at the following severity levels:
- Grade 1–2: Eight patients (24%).
- Grade 3: One patient (3%).
These findings reinforce the importance of appropriate patient selection, respiratory monitoring, and early recognition of treatment-related pulmonary toxicity.
Although the study demonstrated encouraging antitumor activity, its small sample size, single-arm design, and inclusion of two dosing regimens limit definitive conclusions about comparative efficacy and safety.
Why HER2-Low Activity Could Change the Treatment Landscape
One of the most clinically relevant aspects of the Japanese submission is the inclusion of patients with HER2 IHC 1+ tumors.
HER2-directed treatments have traditionally focused on tumors with high HER2 expression or gene amplification. However, antibody-drug conjugates such as trastuzumab deruxtecan have demonstrated activity at lower HER2-expression levels in certain cancer types.
Trastuzumab deruxtecan combines a HER2-targeting monoclonal antibody with a topoisomerase I inhibitor payload, connected through a cleavable linker. This design enables targeted delivery of a cytotoxic agent to HER2-expressing cancer cells.
The STATICE results suggest that even relatively low levels of HER2 expression may be sufficient for clinically meaningful antitumor activity in some patients with uterine carcinosarcoma.
Importantly, HER2-low findings from one tumor type cannot automatically be generalized to other cancers. Further research is needed to identify which patients are most likely to benefit and how HER2 expression should guide treatment selection.
For rare tumors such as uterine carcinosarcoma, where therapeutic options are limited and large randomized trials can be challenging, this biomarker-directed approach represents a potentially important development.
Trastuzumab Deruxtecan’s Growing Role Beyond Breast Cancer
Trastuzumab deruxtecan, developed by Daiichi Sankyo in collaboration with AstraZeneca, is already approved across several cancer types, including HER2-positive and HER2-low breast cancer, HER2-mutant non-small cell lung cancer, and HER2-positive gastric cancer, depending on the jurisdiction and clinical setting.
It is also approved in more than 50 countries and regions for certain previously treated HER2-positive solid tumors, defined by IHC 3+ expression.
In Japan, trastuzumab deruxtecan can already be considered for selected patients with uterine carcinosarcoma characterized by HER2 gene amplification or IHC 3+ expression when standard treatment is inappropriate.
The new application is different because it specifically addresses uterine carcinosarcoma and includes tumors with HER2 IHC 1+ and 2+ expression.
The filing therefore represents a potential expansion of the population eligible for HER2-directed treatment.
Daiichi Sankyo is also pursuing additional regulatory indications for trastuzumab deruxtecan, including an application under review in Japan for adjuvant treatment of HER2-positive breast cancer with residual invasive disease following neoadjuvant therapy, based on the DESTINY-Breast05 trial.
What Comes Next for Trastuzumab Deruxtecan in Uterine Carcinosarcoma?
Japan’s regulatory authorities will now evaluate the submitted evidence to determine whether the efficacy and safety findings support approval of trastuzumab deruxtecan for HER2-expressing advanced or recurrent uterine carcinosarcoma.
The STATICE trial provides encouraging evidence of activity in a population with substantial unmet medical need.
However, important questions remain, including how trastuzumab deruxtecan compares with available treatment approaches, whether particular HER2-expression levels predict greater benefit, and how best to balance durable responses against pulmonary and other treatment-related toxicities.
For patients with this rare and aggressive cancer, the significance of the filing extends beyond another potential drug indication.
It reflects a growing effort to develop biomarker-directed therapies for malignancies that have historically received relatively little disease-specific therapeutic development.
If approved, trastuzumab deruxtecan could make HER2 expression a more actionable treatment biomarker in advanced or recurrent uterine carcinosarcoma in Japan.
Read further on OncoDaily: A New Chance to Prevent Recurrence: EU Approves Trastuzumab Deruxtecan for HER2-Positive Early Breast Cancer
