Trastuzumab deruxtecan effectively treats HER2-expressing cancers regardless of tumour location

DESTINY-PanTumor02 is the first tumour-agnostic global study of trastuzumab deruxtecan (T-DXd) in a broad range of HER2-expressing solid tumours. T-DXd showed encouraging objective response rates, particularly in patients with IHC 3+ expression, along with a manageable safety profile in this heavily pre-treated population. These interim results suggest that T-DXd has the potential to become a new treatment option for patients with HER2-expressing solid tumours.

Trastuzumab deruxtecan (T-DXd) has become a standard of care in HER2-expressing unresectable/metastatic breast cancer, HER2-positive locally advanced/metastatic gastric/gastro-oesophageal junction cancer and HER2-mutant unresectable/metastatic NSCLC. Although testing is not routine, HER2 expression (IHC 3+ or IHC 2+) is seen in a wide range of other solid tumours and is associated with a biologically aggressive phenotype. For HER2-expressing tumours without approved HER2-targeted treatments, there is an unmet need for effective therapies, particularly for patients with disease refractory to standard-of-care therapies. In early-phase studies, T-DXd has demonstrated antitumour activity in other HER2-expressing malignancies, including colorectal, salivary gland, biliary tract and endometrial cancers.

Study design

DESTINY-PanTumor02 is an open-label phase II study of T-DXd 5.4 mg/kg once every three weeks in patients with HER2-expressing (immunohistochemistry [IHC] 3+ or IHC 2+ by local or central testing) locally advanced or metastatic disease that progressed after at least one systemic treatment or that has no treatment options. Prior HER2-targeting therapy was allowed. Cohorts with biliary tract (BTC), bladder (URO), cervical (CC), endometrial (EC), ovarian (OC), pancreatic (PC), or other tumours (excluding breast cancer, gastric cancer, colorectal cancer, and non-small cell lung cancer) were enrolled. Efficacy and safety were analysed in all patients who received at least one dose of T-DXd. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free and overall survival (PFS and OS), and safety. Approximately 40 patients per cohort were planned and cohorts with no objective responses in the first 15 patients were to be closed.

Results

At the time of the data cut-off (November 16, 2022), 267 patients had been treated with T-DXd. Of them, 75 patients were IHC 3+ and 125 were IHC 2+ by central testing. The median number of prior treatment lines was two (range 0-13). Overall, the ORR was 37.1% and the median DOR was 11.8 months. Disease control rate at twelve weeks was 68.2%. In patients with IHC 3+, the benefit was more pronounced with an ORR of 61.3% and a median DOR of 22.1 months. Across different disease sites, trastuzumab deruxtecan resulted in the following ORRs:

• Endometrial cancer: 57.5% for all patients, 84.6% for IHC 3+, and 47.1% for IHC 2+
• Cervical cancer: 50.0% for all patients, 75.0% for IHC 3+, 40.0% for IHC 2+
• Ovarian cancer: 45.0% for all patients, 63.6% for IHC 3+, 36.8% for IHC 2+
• Bladder cancer: 39.0% for all patients, 56.3% for IHC 3+, 35.0% for IHC 2+
• Biliary tract cancer: 22.0% for all patients, 56.3% for IHC 3+, 0% for IHC 2+
• Pancreatic cancer: 4.0% for all patients, 0% for IHC 3+, 5.3% for IHC 2+

Almost all patients had a decrease in size of their tumour lesions. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 38.6% of patients and 8.2% of patients discontinued treatment due to TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 20 patients (6.7% [Grade 1, N= 6; Grade 2, N= 12; Grade 3, N= 1; Grade 5, N= 1]).

Conclusion

T-DXd demonstrated clinically meaningful activity across a broad range of HER2-expressing solid tumours, including those that are hard to treat. The trial is still ongoing and OS and PFS will be analysed with additional follow-up. The safety of T-DXd was consistent with its known safety profile. DESTINY-PanTumor02 thus shows T-DXd to be a potential new treatment option for patients with HER2-expressing solid tumours.

Reference

Meric-Bernstam F, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. Presented at ASCO 2023; Abstract LBA3000.