Trastuzumab deruxtecan (T-DXd) in pretreated patients (pts) with HER2-expressing bladder cancer: Final results from the bladder cancer cohort in Part 1 of DESTINY-PanTumor02 (DP-02).

734 Background: In the DP-02 Part 1 primary analysis, T-DXd showed clinically meaningful antitumor activity in HER2-expressing tumors, with an investigator-assessed (INV) objective response rate (ORR) of 37.1%. In the bladder cancer cohort, ORR was 39.0% (56.3% and 35.0% in HER2 IHC 3+ and IHC 2+ tumors, respectively). Findings from the final analysis, including an overall ORR of 37.5%, were consistent with the primary results. Here, we report subgroup analyses in the bladder cancer cohort (urothelial carcinoma, including transitional cell carcinoma of the renal pelvis, ureter, urinary bladder, or urethra). Methods: DP-02 is a two-part, open-label, Phase 2 study (NCT04482309). Part 1 evaluated T-DXd (5.4 mg/kg Q3W) in HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced/metastatic solid tumors after ≥1 systemic treatment (Tx), or without Tx options. The primary endpoint was INV confirmed ORR. Secondary endpoints included INV duration of response (DOR) and progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included subgroup analyses of efficacy outcomes. Results: At data cutoff (Oct 2024), 41 pts with bladder cancer received T-DXd (median follow up: 12.65 range 0.4–42.9 months mo; median Tx exposure: 6.2 range 0.4–40.8 mo; median Tx cycles: 8.0 range 1.0–56.0). INV ORR was 41.5% (17/41; 95% CI 26.3, 57.9). Of the 17 pts with an objective response (OR), 7 had received > 2 prior Tx regimens, 14 had received prior anti-PD-L1 Tx, and 7 had a prior cystectomy. The Table shows efficacy outcomes in all pts and by IHC 3+/2+ expression by central testing; results were generally consistent by the local or central HER2 IHC test result used for enrollment. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4 (9.8%) pts (n = 1 Grade 1; n = 3 Grade 2). Conclusions: T-DXd continued to show durable and clinically meaningful activity in HER2-expressing bladder cancer; responses were seen in pts with varied Tx backgrounds. Safety was consistent with the known profile, with no new signals. Data further support T-DXd as a Tx option for pts with pretreated HER2-expressing advanced bladder cancer. Clinical trial information: NCT04482309 . All pts IHC 3+ IHC 2+ n* 41 16 20 Pts with an OR, n (%) 95%CI 17 (41.5) 26.3, 57.9 9 (56.3) 29.9, 80.2 8 (40.0) 19.1, 63.9 Complete response 1 (2.4) 1 (6.3) 0 Partial response 16 (39.0) 8 (50.0) 8 (40.0) Stable disease ≥5 weeks 17 (41.5) 5 (31.3) 8 (40.0) Progressive disease † 7 (17.1) 2 (12.5) 4 (20.0) Median DOR, mo (95% CI) 9.5 (4.3, 11.8) 8.7 (2.8, 10.6) 10.3 (4.3, 17.8) Median PFS, mo (95% CI) 7.0 (4.2, 9.7) 7.4 (3.0, 11.9) 7.8 (2.6, 11.6) Median OS, mo (95% CI) 12.8 (11.2, 15.1) 13.4 (6.7, 19.8) 13.1 (11.0, 19.9) *5 pts were enrolled, per protocol, as IHC 3+/2+ by local testing with IHC 1+/0/unknown tumors by central testing; † includes RECIST-defined disease progression and death.