Background
DESTINY-PanTumor02 was a phase II open-label, multicenter, single-arm basket trial evaluating trastuzumab deruxtecan (T-DXd, 5.4 mg/kg q3w) in seven HER2-expressing (IHC 2+ or 3+) advanced solid tumor types that lacked established HER2-targeted therapies. For gynecologic oncology, it enrolled distinct cohorts for endometrial, cervical, and ovarian cancers, providing the first prospective data for T-DXd in HER2-expressing gyn/onc tumors.
Interventions and follow up
Regimen: Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV q3w until progression or unacceptable toxicity in HER2-expressing (IHC 2+ or 3+) advanced solid tumors (seven cohorts)
Primary endpoint: Confirmed ORR by BICR per RECIST v1.1 in each tumor cohort
mFollow-up: 12.75 months
Primary endpoint: Confirmed ORR by BICR per RECIST v1.1 in each tumor cohort
mFollow-up: 12.75 months
Results
Overall ORR: 37.1% (99/267); IHC 3+ 61.3%, IHC 2+ 27.3%
Gyn cohorts: endometrial (n=40) ORR 57.5%; cervical (n=40) ORR 50.0%; ovarian (n=40) ORR 35.0%
Other cohorts: biliary (n=41) 22.0%; bladder (n=41) 39.0%; gastric (n=25) 32.5%
DoR: median not reached in most cohorts
Gyn cohorts: endometrial (n=40) ORR 57.5%; cervical (n=40) ORR 50.0%; ovarian (n=40) ORR 35.0%
Other cohorts: biliary (n=41) 22.0%; bladder (n=41) 39.0%; gastric (n=25) 32.5%
DoR: median not reached in most cohorts
Adverse events
Overall: Grade ≥3 treatment-emergent AEs 53.6%; most common Grade ≥3 — anemia (7.1%), fatigue (4.9%), nausea (2.2%); dose reductions 23%
Pulmonary (ILD/pneumonitis): any grade 10.5% (n=28), Grade 3–4 0.7%, Grade 5 (fatal) 1.9% (n=5); ILD adjudication committee used
Pulmonary (ILD/pneumonitis): any grade 10.5% (n=28), Grade 3–4 0.7%, Grade 5 (fatal) 1.9% (n=5); ILD adjudication committee used
Conclusions
T-DXd demonstrated clinically meaningful ORR across HER2-expressing solid tumors, with particularly notable activity in endometrial (57.5%) and cervical (50.0%) cancers at IHC 2+/3+, supporting HER2 as a pan-tumor actionable target and establishing T-DXd as a tissue-agnostic option in HER2-expressing pretreated cancers.
Key Limitations
Single-arm design — no comparator; n=40 per cohort limits confidence intervals; IHC 2+ vs 3+ heterogeneity (IHC 3+ dramatically higher ORR); ILD/pneumonitis fatal events (1.9% Grade 5) require rigorous monitoring; tumor-type-specific HER2 biology differs (amplification vs overexpression); ovarian ORR (35%) lower than endometrial/cervical; cross-cohort aggregation of heterogeneous tumors; exploratory statistical design with no formal hypothesis testing per cohort.
Clinical Context
DESTINY-PanTumor02 supported the FDA tissue-agnostic approval of T-DXd for HER2-expressing (IHC 3+) unresectable/metastatic solid tumors after prior systemic therapy (April 2024). For gyn/onc specifically, endometrial (ORR 57.5%) and cervical (ORR 50%) data are practice-informing given the high unmet need in these settings. HER2 IHC 3+ is required for the tissue-agnostic indication; IHC 2+ data are supportive but not sufficient for all approvals. DESTINY-Cervical01 and DESTINY-PanTumor03 are further investigating these signals.