1990P - MRG002-HER2 ADC combined with pucotenlimab (a PD-1 inhibitor), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase I/II study

Background

Recent studies showed that the combination of antibody-drug conjugate (ADC) and immune checkpoint inhibitors can bring survival benefit to advanced UC patients. MRG002 (an ADC directed against HER2) and pucotenlimab (HX008, a programmed death 1 inhibitor) showed enhanced antitumor activity in preclinical studies. This phase I/II study was to evaluate the safety and activity of combination therapy in mUC patients who failed 1st line chemotherapy or not suitable for cisplatin as 1L therapy.

Methods

IIn dose-escalation stage (Phase I), Eligible patients were assigned to MRG002 at cohort of 1.8mg/kg or 2.2mg/kg Q3W, combined with HX008 3mg/kg (cap with 200mg) Q3W. The primary endpoint was safety/tolerability and recommended MRG002 dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS.

Results

As the data cut-off (Apr 19 2024), 33 HER2-expressing mUC patients, (19 males, median age 67y [43-77]) were enrolled. The majority (26/33, 78.8%) were systemic treatment naïve. HER2 expression was positive (defined as IHC 2+ or 3+) in 89.4% pts (28/33). The recommended dose for MRG002 was 1.8mg/kg. For all the evaluated patients, the ORR and DCR were 67.9% (19/28) and 89.0% (25/28). For MRG002 at 1.8 mg/kg cohort, the ORR and DCR of evaluable pts were 75.0% (15/20) and 90.0% (18/20). For HER2+ pts, the ORR and DCR of evaluable pts were 76.5% (13/17) and 94.1% (16/17). The longest patient treated has had a PFS for more than 26.5 months and still ongoing.With a median follow-up visit of 7.9 months, the 12-month PFS-rate was 84% (95%CI, 0.63, 0.94), 12-months DOR rate was 100%. The median PFS and DOR was not reached. Most common treatment related adverse events (TRAEs) were asthenia (42.4%), neuropathy (39.4%), weight loss (27.3%), diarrhea (27.3%), constipation (27.3%), rash (24.2%), alopecia (21.2%), and fever (21.2%). Only 3 pts experienced grade 3-4 TRAEs (9.1%), and only 1 patient discontinued treatment due to TRAE (3.0%).

Conclusions

Compared with other combination of IO+ADCs, MRG002+HX008 results less incidence of grade 3/4 toxicities, and can bring durable progression-free survival benefit. Further evaluation of safety and efficacy is ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Lepu Biopharma Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.