Pan-tumor application of trastuzumab deruxtecan (T-DXd) monotherapy in HER2 3+ advanced solid tumors: A pilot study challenging existing treatment restrictions.

e15012 Background: T-DXd, a novel HER2-targeting antibody–drug conjugate, has demonstrated potent antitumor activity in HER2+ malignancies. Although FDA has approved T-DXd for HER2+ advanced solid tumors with IHC 3+ expression, its use remains largely restricted to patients who have received prior therapies or lack satisfactory alternatives. However, emerging pharmacologic and clinical data suggest that T-DXd may outperform existing treatments and need not be limited to later-line settings. We hypothesized that relaxing current restrictions for HER2 3+ advanced malignancies could substantially improve clinical outcomes. To evaluate this, we conducted a pilot study of T-DXd monotherapy in patients with HER2 3+ advanced solid tumors, without limitations on tumor type or prior treatment status. Methods: Adults with unresectable or metastatic HER2 3+ (IHC 3+) tumors were enrolled, regardless of prior treatment. Enrolled patients received T-DXd 5.4 mg/kg IV q3w until disease progression or unacceptable toxicity. Results: Between October 2022 and October 2024, 10 patients (8 male, 2 female) were enrolled: 5 with gastric cancer, 3 with colorectal cancer, 1 with lung cancer, and 1 with biliary tract cancer. Seven patients were treatment-naïve, while 3 had undergone prior therapy. As of December 2024, 8 achieved PR and 2 had SD, yielding an ORR of 80% and a DCR of 100%. Median PFS was 5.5 months (range 2–24), and median OS was 10.0 months (range 2–24). Four patients remain on study; among the 6 who discontinued treatment, 1 died from severe infection without PD, 1 died from gastrointestinal hemorrhage without PD, 1 died from cancer progression, and 2 experienced PD but remain alive. One treatment-naïve gastric cancer patient achieved a deep response after 4 cycles, subsequently underwent surgery and liver radiofrequency ablation, and has maintained no evidence of disease for over 24 months. NGS was performed in 9 patients, revealing ERBB2 amplification (median 10.7-fold, range 2.5–41.5) in all cases, with no clear correlation to ORR or PFS. The most common adverse events were nausea (7/10), fatigue (6/10), and hematologic toxicity (4/10), all of which were grade 1–2; no grade ≥3 events were observed. Conclusions: This pilot study indicates that T-DXd monotherapy confers substantial clinical benefit with manageable toxicity in patients with HER2 3+ advanced solid tumors, regardless of tumor histology or prior treatment. Achieving an ORR of 80% in advanced malignancies is particularly notable, underscoring the potential of T-DXd as a more immediate therapeutic option upon identification of HER2 3+ status, rather than reserving it as a last-line treatment. Larger, multicenter trials are warranted to validate these findings, refine patient selection, and further assess T-DXd in the frontline setting for HER2 3+ cancers.