medwireNews: Trastuzumab deruxtecan (T-DXd) could offer a tumor-agnostic treatment option for patients with HER2-expressing malignancies, the DESTINY-PanTumor02 investigators reported at the 2023 ASCO Annual Meeting in Chicago, Illinois, USA.
Funda Meric-Bernstam (University of Texas MD Anderson Cancer Center, Houston, USA) reported that the antibody–drug conjugate achieved “clinically meaningful activity across a broad range of HER2-expressing solid tumors, including those that are hard to treat.”
The study included 227 participants with advanced cervical, endometrial, ovarian, biliary tract, pancreatic, or bladder cancer, as well as a mixed cohort of 40 patients with other tumor types for which T-DXd had not been approved. All patients had an initial local or central immunohistochemistry (IHC) tumor assessment of 3+ or 2+ HER2 expression.
The primary endpoint of investigator-assessed objective response rate (ORR) to T-DXd 5.4 mg/kg every 3 weeks was 37.1% for the group as a whole, with a complete response reported in 5.6% and a partial response in 31.5%. A further 46.1% had stable disease and this gave a disease control rate at 12 weeks of 68.2%.
Patients with endometrial, cervical, or ovarian cancer had the highest ORRs, at 57.5%, 50.0%, and 45.0%, respectively. This was followed by those with bladder cancer (39.0%), biliary tract cancer (22.0%), other malignancies (30.0%), such as head and neck cancer, and pancreatic cancer (4.0%).
Central analysis of HER2 status classified tumors as IHC 3+ (28.1%), IHC 2+ (46.8%), IHC 1+ (9.4%), IHC 0 (11.2%), or unknown (4.5%).
Using these classifications, the researchers found that patients with IHC 3+ tumors generally had better ORRs than those with IHC 2+ disease. For example, 84.6% of patients with IHC 3+ endometrial cancer had an ORR versus 47.1% of those with IHC 2+ disease and the corresponding rates for biliary cancer were 56.3% and 0.0%.
The median duration of response in the overall study was 11.8 months and this was longer for patients with IHC 3+ versus IHC 2+ tumors (22.1 vs 9.8 months), and Meric-Bernstam remarked that almost all patients who achieved an ORR in the study continued to respond at 12 months of follow-up.
The T-DXd safety summary was “consistent with the known profile,” the presenter said. Drug-related treatment-emergent adverse events (TEAEs) at grade 3 or higher occurred in 38.6% of patients, most commonly neutropenia (19.1%), anemia (8.6%), and fatigue (6.0%).
Such TEAEs led to dose interruptions, reductions, or discontinuation in 18.4%, 18.7%, and 8.2% of patients, respectively, and to death in 0.7%.
AEs of special interest included interstitial lung disease or pneumonitis in 7.5% of patients including grade 3 and more severe events in 0.8%. Ejection fraction decreases were reported for 2.6% including one case (0.4%) at grade 3 and there was one case (0.4%) of cardiac failure at grade 3.
“DESTINY-PanTumor02 shows T-DXd to be a potential new treatment option for patients with HER2-expressing solid tumors,” summarized Meric-Bernstam. She added that the study is ongoing and will report progression-free and overall survival findings in the future.
Session discussant Kohei Shitara (National Cancer Center Hospital East, Kashiwa, Japan) said the ORR for T-DXd in the study was similar to that used to gain agnostic approval for pembrolizumab and other agents.
Given the cost and difficulty of running clinical trials for such a wide range of tumor types, he suggested that an agnostic approach to HER2-targeted therapy “warrants a discussion with regulatory authorities.”
However, Shitara also observed that central review of IHC in the study did not agree with the initial local assessment in 19% of cases, prompting the need for further research on the optimal HER2 classification technique.
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