Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC).

Abstract

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—Focus on proactive monitoring, diagnosis, and management

“…Due to the potential for patients to experience ILD/pneumonitis with T-DXd or immunotherapy agents individually, research is needed to assess any risks with the combination of these therapies. In a trial assessing T-DXd combined with nivolumab in patients with HER2-expressing advanced/ metastatic urothelial carcinoma (n = 34), adjudicated drug-related ILD/ pneumonitis was reported in 23.5% (grade 1, n = 2; grade 2, n = 4; grade 3, n = 1; grade 5, n = 1) [58]. Additional trials of T-DXd combined with immunotherapy agents are ongoing, and results from these studies will allow for further understanding of ILD/pneumonitis with T-DXd combination therapy [21,[59][60][61][62][63][64].…”

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates

“…Galsky et al [ 37 ] have communicated a primary analysis from a phase Ib/II trial combining T-DXd and nivolumab in 34 patients with Her-2-expressing mUC, achieving an ORR of 36.7% (4 CR and 7 PR among 30 patients with IHC 2+/3+, and 2 PR among 4 patients with IHC 1+). The median PFS was 6.9 months, and the median duration of response was 13.1 months.…”

Bladder cancer organoids as a functional system to model different disease stages and therapy response

“…However, its clinical effectiveness was less evident in different studies, probably due to the insufficient patient stratification or to a limited predictive role of the EGFR/ERBB2 status (79). Interestingly, in an ongoing trial, trastuzumab, another ERBB2-target drug, is showing positive results in BLCa patients with ERBB2-expressing tumor (80). Samples enriching for mutations in FGFR1 pathway were also more sensitive to lapatinib activity.…”