Trastuzumab deruxtecan shows robust efficacy, durable clinical benefit, and safety consistent with the known profile in human epidermal growth factor receptor 2-expressing tumors in a phase II study.
Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate, is currently approved for treating HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer.
An open-label phase II study in the Journal of Clinical Oncology assessed the efficacy and safety of T-DXd in patients with locally advanced, metastatic, or unresectable HER2-expressing solid tumors.
Study Population
The study comprised 267 patients. The median age was 62 years. The patients had received a median of two lines of prior therapy, with 40.8% having received ≥ three lines, and 14.2% having received prior HER2 therapy. The median follow-up duration was 12.75 months.
Substantial Clinical Benefit in Patients With HER2-Expressing Solid Tumors
Of the 267 patients, 99 (37.1%) had a confirmed objective response. Investigator-assessed objective response rates (ORRs) were 57.5% for endometrial, 50.0% for cervical, 45.0% for ovarian, 39.0% for bladder, 22.0% for biliary tract, 4.0% for pancreatic cancers, and 30.0% for other tumors.
Among the 75 participants with centrally-confirmed HER2 immunohistochemistry (IHC) 3+ expression, ORRs were 84.6% for endometrial, 75.0% for cervical, 63.6% for ovarian, 56.3% for bladder, 56.3% for biliary tract, 0% for pancreatic cancers, and 44.4% for other tumors.
Responses were observed in patients who received (36.8%) or did not receive (37.4%) prior HER2 therapy. An independent central review demonstrated that 37.5% (n=100) of patients had a confirmed ORR across all tumor types, whereas the proportions by cohort were 57.5% for endometrial, 37.5% for cervical, 42.5% for ovarian, 41.5% for bladder, 26.8% for biliary tract, 12.0% for pancreatic cancers, and 35.0% for other tumors.
Durable Clinical Activity and Significant Survival Benefits
The investigator-assessed median duration of response (DOR) was 11.3 months across all cohorts. The median DOR was not reached in the endometrial cancer cohort. Among HER2 subgroups, patients with IHC 3+ demonstrated the longest median DOR (22.1 months).
The investigator-assessed median progression-free survival (PFS) was 6.9 months, ranging from 3.2 months in pancreatic cancer to 11.1 months in endometrial cancer. Among HER2 subgroups, IHC 3+ patients demonstrated the longest median PFS (11.9 months).
The median overall survival (OS) was 13.4 months across all cohorts, ranging from 5.0 months in pancreatic cancer to 26.0 months in endometrial cancer. Among HER2 subgroups, IHC 3+ patients demonstrated the longest median OS (21.1 months).
Safety Was Consistent With the Established Safety Profile
Grade ≥1 drug-related adverse events (AEs) were observed in 84.6% of patients, with the most common being nausea, anemia, diarrhea, vomiting, and fatigue. Grade ≥3 drug-related AEs were observed in 40.8% of patients, with neutropenia and anemia being the most common. Serious drug-related AEs occurred in 13.5% of patients. Drug-related AEs led to treatment discontinuation in 8.6% of patients and dose reduction in 20.2% of patients. Drug-related AEs resulted in the deaths of four patients. Adjudicated drug-related interstitial lung disease/pneumonitis events occurred in 10.5% of patients, with one grade 3 event and three fatal cases.
Source:
Meric‐Bernstam, F., Makker, V., Oaknin, A., Oh, D., Banerjee, S., González-Martín, A., Jung, K. H., Ługowska, I., Manso, L., Manzano, A., Melichar, B., Siena, S., Stroyakovskiy, D., Fielding, A., Ma, Y., Puvvada, S. D., Shire, N. J., & Lee, J. (2024). Efficacy and safety of trastuzumab deruxtecan in patients with HER2-Expressing solid tumors: Primary results from the DESTINY-PanTumor02 Phase II trial. Journal of Clinical Oncology, 42(1), 47–58. https://doi.org/10.1200/jco.23.02005
