Antibody-drug conjugates (ADCs) targeting HER2 are rapidly becoming standard therapies across various solid tumors, including breast, gynecologic, gastrointestinal (GI), lung, and genitourinary (GU) cancers. This paradigm shift includes distinct categorizations such as HER2-positive, -mutated, and -amplified diseases. Experts at a recent OncLive Peer Exchange® discussed the current standing of HER2-directed ADCs in solid tumors, highlighting findings from clinical trials presented at the 2024 ASCO Annual Meeting.
HER2-Directed ADCs in Breast Cancer
Two FDA-approved HER2-targeted ADCs for breast cancer are ado-trastuzumab emtansine (T-DM1; Kadcyla) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). T-DM1 was initially approved in 2013 for HER2-positive metastatic breast cancer patients previously treated with trastuzumab and taxane-based chemotherapy. T-DXd later gained approval for unresectable or metastatic HER2-positive breast cancer after prior anti-HER2 therapy or recurrence during/within 6 months of completing therapy, based on the phase 3 DESTINY-Breast03 trial. T-DXd also earned an indication for HER2-low disease and adjuvant treatment of HER2-positive early breast cancer with residual invasive disease following neoadjuvant treatment, supported by the phase 3 KATHERINE trial.
Updated findings from the phase 3 DESTINY-Breast03 study, comparing T-DXd to T-DM1 in HER2-positive metastatic breast cancer, showed a median investigator-assessed PFS of 29.0 months for T-DXd vs 7.2 months for T-DM1 (HR, 0.30; 95% CI, 0.24-0.38). Confirmed ORRs were 78.9% vs 36.9%, respectively. The median OS was 52.6 months vs 42.7 months, respectively.
Advancements in Gynecologic Cancers
T-DXd is under investigation in gynecologic malignancies via the phase 2 DESTINY-PanTumor02 trial. Updated findings showed ORRs of 57.5% in endometrial cancer, 50.0% in cervical cancer, and 45.0% in ovarian cancer. Notably, patients with confirmed HER2 expression of IHC3+ achieved even higher ORRs: 84.6% for endometrial, 75.0% for cervical, and 63.6% for ovarian cancer. The median PFS was also promising, particularly in the IHC3+ groups.
T-DXd is also being evaluated in the phase 2 STATICE trial for HER2-expressing advanced or recurrent uterine carcinosarcoma. Results showed ORRs of 54.5% in the HER2-high group and 70.0% in the HER2-low group. The median PFS was 6.2 months and 6.7 months, respectively, and the median OS was 13.3 months and NR, respectively.
Expanding Use in GI Cancers
In GI cancer, T-DXd received FDA approval in January 2021 for HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma after prior trastuzumab-based treatment, based on the phase 2 DESTINY-Gastric01 study. Final survival data showed an ORR of 51.3% with T-DXd vs 14.3% with physician’s choice of chemotherapy (P < .0001). The median OS was 12.5 months vs 8.9 months (HR, 0.60; 95% CI, 0.42-0.86), and the median PFS was 5.6 months vs 3.5 months (HR, 0.47; 95% CI, 0.31-0.71).
The phase 1b/2 DESTINY-Gastric03 trial is evaluating T-DXd as monotherapy and in combination with fluorouracil or capecitabine plus pembrolizumab in treatment-naive, HER2-positive or HER2-low gastric cancer.
Targeting Lung Cancer
T-DXd is approved by the FDA for HER2-mutant metastatic non–small cell lung cancer (NSCLC). This accelerated approval was supported by the phase 2 DESTINY-Lung02 trial and marked the first agent approved for HER2-mutated NSCLC. Final analysis of DESTINY-Lung02 showed confirmed ORRs of 50.0% and 56.0% in the 5.4-mg/kg and 6.4-mg/kg arms, respectively. The median DOR was 12.6 months and 12.2 months, respectively, the median PFS was 10.0 months and 12.9 months, respectively, and the median OS was 19.0 months and 17.3 months, respectively.
Urothelial Cancer Advancements
DESTINY-PanTumor02 included a cohort of patients with bladder cancer. Results from 41 patients with urothelial cancer showed an ORR of 39.0%, a median DOR of 8.7 months, and a median PFS of 7.0 months. In patients with an HER2 IHC score of 3+, the ORR was 56.3%, the median DOR was 8.7 months, and the median PFS was 7.4 months.
On April 5, 2024, the FDA granted accelerated approval to T-DXd for previously treated unresectable or metastatic HER2-positive solid tumors with an IHC score of 3+ who have no satisfactory treatment options.
