Trastuzumab Deruxtecan Demonstrates Responses Across Advanced Solid Tumors With HER2 Expression

Trastuzumab deruxtecan (Enhertu; AsteraZeneca, Daiichi Sankyo) demonstrated clinically meaningful and durable responses across a range of advanced solid tumors expressing human epidermal growth factor receptor 2 (HER2) in previously treated individuals, according to positive results from an interim analysis of the DESTINY-PanTumor02 (NCT04482309) trial presented at the American Society of Clinical Oncology 2023 Annual Meeting.

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Further, results of the DESTINY-CRC02 (NCT04744831) support 5.4 mg/kg as the optimal dose of trastuzumab deruxtecan in individuals with HER2+ metastatic colorectal cancer.

“The DESTINY-PanTumor02 data showed encouraging and durable response rates across a broad range of HER2-expressing solid tumors where there are currently no approved HER2-targeted treatments. Based on these results, [trastuzumab deruxtecan] has the potential to benefit specific patients with HER2-expressing advanced disease who currently have limited options and may face a poor prognosis,”Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said in a statement.

Trastuzumab deruxtecan is an engineered HER2-directed antibody drug conjugate being jointly developed by AstraZeneca and Daiichi Sankyo. Investigators included previously treated individuals with HER2-expressing advanced solid tumors, which included either biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers, or other tumors treated with trastuzumab deruxtecan.

Data from the DESTINY-PanTumor02 showed a confirmed objective response rate (ORR) of 37.1%, determined at the interim analysis. A higher confirmed ORR of 61.3% was observed in individuals with the highest level HER2 expression, defined as immunohistochemistry (IHC) 3+.

Furthermore, a complete response was observed in 5.6% of patients in the overall trial population and a partial response was observed in 31.5%, with 46.1% of individuals achieving stable disease. The observed disease control rate was 68.2% in the overall trial population of the DESTINY-PanTumor02 study.

Approximately 49.6% of all individuals in the study maintained a response at 1 year. The median duration of response (DoR) was 11.8 months in the overall trial population and 22.1 months in individuals with IHC 3+ expression.

Investigators found that the safety profile was consistent with previous clinical trials with no new safety concerns. The most common treatment-emergent adverse events were neutropenia, anemia, fatigue, and thrombocytopenia. In the DESTINY-PanTumor02 study, 7.5% of patients experienced interstitial lung disease or pneumonitis related to treatment. The majority were low grade, with 1 incident being grade 3 and 1 being grade 5, and there were no grade 4 events.

Additionally, the DESTINY-CRC02 trial evaluated trastuzumab deruxtecan at the 5.4 mg/kg and the 6.4 mg/kg doses in individuals with previously treated, locally advanced, unrespectable, or metastatic HER2+ colorectal cancer, which were BRAF wildtype, RAS wildtype, or RAS mutant tumor types.

Investigators found observed a confirmed ORR of 37.8% and 27.5% for the 5.4 mg/kg and 6.4 mg/kg, respectively. All the responses were partial, and 48.8% of patients in the 5.4 mg/kg arm and 57.5% of those in the 6.4 mg/kg, respectively, achieved stable disease.

In this study, investigators observed greater efficacy in individuals with the highest level of HER2 expression in the 5.4 mg/kg arm. Further, investigators found that anti-tumor efficacy was seen regardless of RAS mutation status, including 29.7% with RAS mutations and 28.6% without RAS mutations, as well as those with prior HER2-directed therapy at 41.2% in the 5.4 mg/kg group.

The median DoR in both strength arms with a median duration of follow-up was 8.9 months and 10.3 months in the 5.4 mg/kg and 6.4 mg/kg, respectively. The median progression-free survival was 5.8 months for 5.4 mg/kg and 5.5 months for 6.4 mg/kg.

Furthermore, the median overall survival was 13.4 months 5.4 mg/kg arm and was not reached in 6.4 mg/kg arm.

The safety profile in the DESTINY-CRC02 was consistent in both strengths across clinical trials of the drug, with no new safety concerns at either dose. There was a more favorable benefit-risk profile observed in individuals treated with the 5.4 mg/kg dosage, which was the investigators’ reasoning as this strength as the recommended dose.

Reference

Enhertu demonstrated clinically meaningful and durable responses in patients across multiple HER2-expressing advanced solid tumors. News release. AstraZeneca. June 5, 2023. Accessed June 5, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-and-durable-responses-in-patients-across-multiple-her2-expressing.html