Real-world activity of trastuzumab deruxtecan in heavily pretreated HER2-expressing ovarian cancer: focusing on HER2-low responses and CCNE1 amplification
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Background
Trastuzumab deruxtecan (T-DXd) is active in HER2-expressing solid tumours, but trials excluded HER2 immunohistochemistry (IHC) 1+ disease, and data in pretreated ovarian cancer are lacking. We evaluated real-world T-DXd activity and genomic correlates in pretreated ovarian cancer, predominantly high-grade serous (HGSOC).
Methods
HER2 expression was assessed in an unselected ovarian cancer cohort (N=74). Fifteen patients receiving off-label T-DXd (14 HGSOC, 1 clear cell; IHC 1+ to 3+) had HER2 status centrally confirmed using gastric-type criteria. Activity was assessed by intra-patient growth modulation index (GMI; progression-free survival [PFS] on T-DXd divided by PFS on the prior line; ≥ 1.33 considered meaningful). Patients on treatment at data cut-off were censored. Objective response (RECIST 1.1) was assessed centrally where imaging was available (n=8).
Results
Of the 40 HER2-expressing tumours, 15 received T-DXd, limited mainly by reimbursement. Among 14 evaluable patients (median 5 prior lines), 9 reached a GMI ≥ 1.33 (median 1.69); 8 remained on treatment at cut-off, making durability preliminary. Confirmed partial responses occurred across the HER2 spectrum. Benefit was independent of homologous-recombination (HR) status: one HR-proficient, CCNE1 -wild-type patient achieved prolonged control and was rendered disease-free after radiotherapy to an oligoprogressive lesion. Exploratory analysis showed all four evaluable CCNE1 -amplified tumours had reduced or non-durable benefit.
Conclusions
T-DXd shows preliminary, clinically meaningful activity in HER2 IHC 1+ ovarian cancer independent of HR status. CCNE1 amplification may attenuate benefit, a candidate biomarker for WEE1-inhibitor combinations. Approval restricted to IHC 3+ disease would exclude most responders in this cohort. Prospective validation is required.
Key message
In heavily pretreated, predominantly HER2-low (IHC 1+) high-grade serous ovarian cancer, trastuzumab deruxtecan showed preliminary, clinically meaningful and homologous-recombination-independent activity. In an exploratory analysis (n=4), CCNE1 amplification was associated with reduced or non-durable benefit, suggesting a candidate resistance mechanism and a rationale for WEE1-inhibitor combination strategies. Most HER2-expressing patients did not receive treatment, predominantly because of off-label reimbursement barriers rather than clinical ineligibility.
