Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Abstract

PURPOSE Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. PATIENTS AND METHODS This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS). RESULTS primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3–43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6–17.8); median PFS, 6.9 months (95% CI, 5.6–8.0); median OS, 13.4 months (95% CI, 11.9–15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4–72.4); median DOR, 22.1 months (95% CI, 9.6–not reached); median PFS, 11.9 months (95% CI, 8.2–13.0); median OS, 21.1 months (95% CI, 15.3–29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Evolving standards and future directions for systemic therapies in cervical cancer

“…This is a human epidermal growth factor 2 (HER2)-directed ADC with a potent topoisomerase I inhibitor payload. The single-arm, multi-cohort phase II DESTINY-PanTumor02 basket trial evaluated trastuzumab deruxtecan (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ as per ASCO/CAP gastric cancer scoring) advanced cancers after at least 1 line of systemic treatment or without standard options [ 31 ]. Within the cohort of 40 aCC subjects, 5 patients with IHC 1+ status were included after a protocol-specified interim analysis.…”

Human Epidermal Growth Factor Receptor 2 Overexpression/Amplification in Primary Ovarian Endometrioid Carcinoma

“…Furthermore, the ongoing phase 2 trial DESTINY-PanTumor-02, with results expected in April 2027, shows that T-DXd has broad activity across many tumor types with positive HER2 status, including ovarian cancers. Initial findings presented during the 2023 American Society of Clinical Oncology Annual Meeting revealed that among enrolled patients with ovarian cancers, there was an overall response rate of 45% and a complete response rate of 10% 32 . Evaluating HER2 status including those classified as HER2 “low” in EOC introduces new options for experimentation with potential therapy to improve the overall survival of such patients.…”

Gastric-type adenocarcinoma of the uterine cervix: clinical features and future directions

“…A total of 120 patients with gynaecologic malignancies were included, in which objective response rate (ORR) among patients with cervical cancer was 50.0%. The ORR was particularly high in the HER2+ and HER3+ groups, suggesting that this treatment can be an option for HER2-positive GAS cases ( 54 ). This may offer a new treatment paradigm for this small subset of patients with GAS and should be explored further in prospective studies including antibody–drug conjugates as in non-small cell lung cancer or breast cancer.…”