Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Abstract

Purpose: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.

Methods: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS).

Results: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.

Conclusion: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Trial registration: ClinicalTrials.gov NCT04482309.

FIG 1.

Investigator-assessed responses as per RECIST 1.1. (A) ORR across tumor cohorts, according to HER2 status by central testing. ^aResponses in the other tumors cohort include responses in extramammary Paget disease, oropharyngeal neoplasm, head and neck cancer, and salivary gland cancer. (B) The maximum change in tumor size, according to tumor type. Patients with IHC 3+ status (central testing) are marked with a dot. The other tumors cohort includes responses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer. (C) DOR in patients with an objective response, according to tumor type. DOR was defined as the time from the date of first documented response (complete response or partial response) until the date of documented progression, or death in the absence of disease progression. Response was determined by investigator assessment according to RECIST 1.1 and required confirmation after the first observed response at least 4 weeks later. Censored patients are marked with a rounded dot, patients who stopped responding are marked with a triangular dot, and patients with a complete response are marked with a square dot. BTC, biliary tract cancer; DOR, duration of response; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ORR, objective response rate.

FIG 2.

Kaplan-Meier estimates of PFS, according to tumor type. (A) Endometrial cancer, (B) cervical cancer, (C) ovarian cancer, (D) bladder cancer, (E) other tumors, (F) biliary tract cancer, and (G) pancreatic cancer. IHC, immunohistochemistry; NR, not reached; PFS, progression-free survival.

FIG 3.

Kaplan-Meier estimates of OS, according to tumor type. (A) Endometrial cancer, (B) cervical cancer, (C) ovarian cancer, (D) bladder cancer, (E) other tumors, (F) biliary tract cancer, and (G) pancreatic cancer. IHC, immunohistochemistry; NR, not reached; OS, overall survival.

FIG A1.

Patient disposition. DCO, data cutoff.

FIG A2.

Target lesions size, percentage change from baseline over time (full analysis set). CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.