TROP2-Directed ADCs Show Promise in Recurrent Gynecological Cancers
核心洞察
Datopotamab deruxtecan (Dato-DXd) demonstrated promising outcomes in recurrent endometrial and ovarian cancers (搜索) after platinum-based chemotherapy, with manageable safety profiles.
In endometrial cancer (搜索), Dato-DXd showed an ORR of 27.5% and a DCR of 85%, while in ovarian cancer, the ORR was 42.9% and the DCR was 91.4%.
Sacituzumab govitecan (Sac-TMT), another TROP2 (搜索)-directed ADC, showed comparable efficacy, with TROP2 expression potentially influencing treatment outcomes, particularly in ovarian cancer.
Platinum-based therapies remain the standard of care for endometrial cancer (搜索) (EC) and ovarian cancer (OC), but recurrence and platinum resistance are common, highlighting a critical unmet need. Antibody-drug conjugates (ADCs) are emerging as transformative treatments, exemplified by the approval of mirvetuximab soravtansine for platinum-resistant OC.
Datopotamab Deruxtecan (Dato-DXd) in Recurrent Gynecological Cancers
New data from the Phase II TROPION-PanTumor03 trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024, evaluated Daiichi Sankyo and AstraZeneca’s datopotamab deruxtecan (Dato-DXd) as a monotherapy in patients with recurrent EC and OC who had progressed after one to two lines of platinum-based chemotherapy. The results indicated a trend towards improved outcomes with a manageable safety profile, warranting further investigation.
Dato-DXd is a TROP2 (搜索)-directed monoclonal antibody linked to a deruxtecan-based topoisomerase I inhibitor via a cleavable tetra-peptide linker, utilizing Daiichi Sankyo’s DXd technology. TROP2 overexpression is associated with accelerated tumor growth and poor prognosis in various solid tumors, including gynecological cancers.
Efficacy Data from TROPION-PanTumor03 Trial
In the EC cohort, with a median of one prior line of therapy, Dato-DXd achieved an overall response rate (ORR) of 27.5% and a disease control rate (DCR) of 85%. The median duration of response (DoR) was 16.4 months, and the median progression-free survival (PFS) was 6.3 months (95% CI: 2.8-not yet reached). The OC cohort, with a median of two prior lines of therapy, showed an ORR of 42.9% and a DCR of 91.4%. The median DoR was 5.7 months, and the median PFS was 5.6 months (95% CI: 4.1–7.1). Notably, platinum-sensitive OC patients (n=9) had an ORR of 66.7%, DCR of 100%, and median DoR of 8.5 months, while platinum-resistant patients (n=26) had an ORR of 34.6%, DCR of 80.8%, and median DoR of 5.6 months. These results suggest that platinum status may impact treatment outcomes.
The trial did not select patients based on TROP2 (搜索) expression, raising the question of whether TROP2 expression levels correlate with outcomes. Retrospective analysis of TROP2 expression may provide insights into the necessity of assessing TROP2 levels for personalized treatment in OC.
Safety Profile
Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 42.5% of EC and 45.7% of OC patients. The most common TRAEs included stomatitis (52.5% in EC, 62.9% in OC) and nausea (37.5% in EC, 48.6% in OC), mostly grade 1 and 2. There were low rates of grade 3 adjudicated drug-related interstitial lung disease (one case per cohort). No grade 4 or 5 events or treatment-related deaths occurred, although two patients in the OC cohort and three patients in the EC cohort discontinued treatment due to TRAEs.
Competition: Sacituzumab Govitecan (Sac-TMT)
Merck (搜索)’s sacituzumab govitecan (Sac-TMT), another TROP2 (搜索)-directed ADC, is a strong competitor. In a Phase II trial presented at ESMO, Sac-TMT was evaluated as a monotherapy in heavily pretreated EC and OC patients, showing comparable efficacy. Sac-TMT was dosed at 5mg/kg every two weeks, while Dato-DXd was dosed at 6mg/kg every three weeks. The EC cohort had an ORR of 34.1%, a DCR of 75%, a median DoR of 5.7 months, and a median PFS of 5.7 months (95% CI: 3.7–9.4). The OC cohort exhibited an ORR of 40%, a DCR of 75%, a median DoR of 5.3 months, and a median PFS of 6.0 months (95% CI: 3.9–7.3). Importantly, Sac-TMT’s trial incorporated TROP2 expression assessment via immunohistochemistry (IHC). Patients with a TROP2 IHC H-score ≥200 demonstrated higher response rates than patients with a low TROP2 IHC H-score (41.7% vs. 35.7% in EC, 61.5% vs. 27.3% in OC), suggesting that TROP2 expression may play a role in treatment efficacy, particularly in OC.
In terms of safety, 72.7% of the EC cohort and 67.5% of the OC cohort experienced grade 3 or higher TRAEs, with the most common hematological toxicities including neutropenia and anemia, and gastrointestinal toxicities including stomatitis, vomiting, and nausea.
Market Outlook
According to GlobalData’s analyst consensus forecast, Dato-DXd could generate global annual sales of $6.1 billion by 2030. Sac-TMT is projected to achieve $431 million in annual sales by 2030. Dato-DXd offers a more convenient dosing schedule and a similar efficacy and safety profile, potentially making it a preferred option, pending further analyses and head-to-head studies. Overall, TROP2 (搜索)-directed ADC agents like Dato-DXd and Sac-TMT show significant promise in recurrent EC and OC, offering hope for patients with these challenging cancers.