Novel ADCs and combination therapy in urothelial carcinoma: latest updates from the 2023 ASCO-GU Cancers Symposium

Enfortumab vedotin (EV) is an ADCs formed by joining a humanized Nectin-4 targeted IgG1 monoclonal antibody, enfortumab, and a microtubule-disrupting agent, monomethyl auristatin E (MMAE), through a cleavable mc-val-cit-PABC linker. The EV-103 cohort K (NCT03288545) evaluated EV or EV + Pembrolizumab (Pembro) as a first-line therapy for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC). Patients were randomized 1:1 to receive EV monotherapy on days 1 and 8, or in combination with Pembro on day 1 of the 3-week cycles. EV monotherapy showed an objective response rate (ORR) of 45.2% (95% CI 33.5–57.3), while the EV + Pembro combination demonstrated an ORR of 64.5% (95% CI 52.7–75.1). Treatment-related adverse events (TRAEs) in the EV + Pembro arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). TRAEs were observed in 68.4% of the patients. This led to the interruption of EV or Pembro, with 48.7% of patients requiring EV dose reduction [1]. This established the foundation for accelerated approval of EV + Pembro by the US Food and Drug Administration (FDA), for cisplatin-ineligible mUC in April 2023.

Another ongoing phase 1 trial (NCT05014139) is studying intravesical EV infusion in high-risk, Bacillus Calmette-Guérin-unresponsive patients with non-muscle-invasive bladder cancer [2].

Sacituzumab govitecan (SG) is an ADC composed of an anti-Trop-2 antibody, sacituzumab, and a topoisomerase I inhibitor, SN-38, bound through the hydrolyzable linker CL2A. The ongoing phase 2 trial TROPHY-U-01, evaluated SG monotherapy and combination therapy in patients with la/mUC (NCT03547973). Cohort 1 demonstrated a 28% ORR (95% CI 20.2–37.6) in 113 patients with la/mUC, who had progressed after platinum-based chemotherapy and checkpoint inhibitor (CPI) treatment. Median overall survival (med-OS) was 10.9 months (95% CI 8.9–13.8), median progression-free survival (med-PFS) was 5.4 months (95% CI 3.5–6.9), and median duration of response (med-DOR) was 6.1 months (95% CI 4.7–9.7, n = 32), leading to accelerated FDA approval for patients in cohort 1 [3]. Cohort 2 assessed SG monotherapy in patients with platinum-ineligible mUC who showed disease progression after CPI treatment [4]. Cohort 3 assessed combined SG and Pembro treatment in 41 patients with mUC, after platinum-based therapy, which supported the need for further evaluation of SG and CPI combination treatment in patients with mUC [5]. The common TRAEs in the cohort included febrile and non-febrile neutropenia, anemia, leukopenia, fatigue, and diarrhea. Anemia and fatigue appeared to be more SG-related, whereas diarrhea was more CPI-related. Cohort 5 evaluated SG + zimberelimab (ZIM) versus ZIM alone versus avelumab for switch maintenance in patients with mUC who received gemcitabine (GEM)/cisplatin without progressive disease [6]. In Cohort 6, we assessed SG monotherapy versus SG + CPI combinations (SG + ZIM, SG + ZIM + domvanalimab) versus carboplatin/GEM, followed by avelumab maintenance, in treatment-naive cisplatin-ineligible patients with la/mUC [7].

Another ongoing trial (NCT04863885) is investigating ipilimumab plus nivolumab combined with SG in cisplatin-ineligible patients with mUC. Phase 1 results: ORR was 66.6% in 6 patients, med-DOR was 9.2 months (95% CI 4.6–12.0), and med-PFS was 8.8 months (95% CI 3.8–NR). The TRAEs included anemia, neutropenia, pruritus, fatigue, diarrhea, lymphopenia, and arthralgia. A phase 2 trial with biomarker analysis is ongoing [8].

Disitamab vedotin (DV; RC48) is an ADC composed of a human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody, hertuzumab, and MMAE via an mc-val-cit-PABC linker. The phase II trial RC48-C005 showed excellent anti-tumor activity and controllable safety of RC48 monotherapy in patients with HER2 + la/mUC after at least one systemic treatment failure [9]. RC48G001 (NCT04879329) is a phase 2 trial assessing RC48's safety, tolerance, and pharmacokinetics in HER2 + patients with la/mUC, with or without Pembro [10].

Overall, the ASCO-GU2023 Cancer Symposium has shown significant progress in the clinical trials of la/mUC. There is promising data on EV, SG and RC48, both as single and combination therapies, as summarized in Tables 1 and 2.