Disitamab vedotin/pembrolizumab shows promise in HER2-expressing urothelial carcinoma

The combination of disitamab vedotin and pembrolizumab (Keytruda) demonstrated encouraging preliminary activity with a manageable safety profile in treatment-naïve patients with HER2-expressing, locally advanced or metastatic urothelial carcinoma, according to data from cohort C of the phase 2 RC48G001 trial (NCT04879329).

Matthew D. Galsky, MD

The findings were presented at the 2024 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain.¹

“Vedotin-based [antibody drug conjugates] have changed the treatment landscape for metastatic urothelial cancer. However, biomarker-based approaches may further improve outcomes,” explained Matthew D. Galsky, MD, who presented the results on behalf of the RC48G001 trial investigators. Galsky is a professor of medicine (Hematology and Medical Oncology), director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and the associate director for Translational Research at The Tisch Cancer Institute at Mount Sinai in New York, New York.

In total, the intent-to-treat population for cohort C of the trial will include 170 patients with previously untreated HER2-expressing locally advanced or metastatic urothelial carcinoma. The findings presented at ESMO reported data from part 1 of cohort C, the safety run-in, which included 20 patients who were stratified based on HER2 status.

HER2-positive was defined as tumors with IHC 3+ or IHC 2+ and ISH-positive. HER2-low was defined as tumors that were IHC 2+ and ISH-negative or IHC 1+. The majority of patients (70%; 14/20) had HER2-low tumors.

All patients received disitamab vedotin every 2 weeks and pembrolizumab every 6 weeks.

At a median follow-up of 9 months (range, 4-16), the confirmed objective response rate (ORR) was 75% (95% CI, 50.9-91.3) in the overall population. This consisted of a complete response in 35% (7) of patients and a partial response in 40% (8) of patients. Stable disease was reported in 20% (4) of patients and progressive disease was reported in 5% (1) of patients. The median duration of response was not reached (95% CI, 3.9-NR).

Specifically, in the HER2-positive cohort, the confirmed ORR was 66.7% (95% CI, 22.3-95.7). In the HER2-low cohort, the confirmed ORR was 78.6% (95% CI, 49.2-95.3).

Regarding safety, treatment-related adverse events (TRAEs) of any grade were experienced by all patients (n = 20). The most common TRAEs included diarrhea (55%), fatigue (55%), alopecia (50%), and peripheral sensory neuropathy (40%). Grade 3 or higher TRAEs occurred in 45% (9) of patients. The most common TRAEs of grade 3 or higher included fatigue (15%), malaise (10%), and anemia (5%).

There were no grade 5 TRAEs nor any treatment-emergent AEs of special interest. Additionally, no patients experienced pneumonitis or interstitial lung disease in this cohort.

In total, 95% of patients required a dose modification for disitamab vedotin and 80% required a dose modification for pembrolizumab. For disitamab vedotin, dose modifications included dose delays in 75% (n = 15) of patients, dose reductions in 15% (n = 3) of patients, and discontinuation of treatment in 5.0% (n = 1) of patients. For pembrolizumab, dose modifications included dose delays in 50% (n = 10) of patients and discontinuation of treatment in 30% (n = 6) of patients. The median time to first dose modification was 2.0 months (range, 1-6) in the disitamab vedotin arm and 4.6 months (range, 2-6) in the pembrolizumab arm.

According to the authors, these findings are consistent with results from a phase 1b/2 study of disitamab vedotin plus toripalimab, which was completed in China. Results from this trial were also presented at ESMO.²

Part 2 of the current study is currently enrolling participants. Patients enrolled will be randomly assigned 1:1 to receive either disitamab vedotin every 2 weeks plus pembrolizumab every 6 weeks or to disitamab vedotin alone every 6 weeks.

The efficacy and safety of first-line disitamab vedotin plus pembrolizumab vs chemotherapy is also being assessed in a phase 3 trial (SGNDV-001; NCT05911295) in patients with previously untreated urothelial carcinoma that expresses HER2. The trial is currently enrolling or planning to enroll patients across North America, Latin America, Europe, Australia, and Asia.

Reference

1. Galsky MD, Koshkin VS, Campbell MT, et al. Preliminary efficacy and safety of disitamab vedotin (DV) with pembrolizumab (P) in treatment (Tx)-naive HER2-expressing, locally advanced or metastatic urothelial carcinoma (la/mUC): RC48G001 cohort C. Presented at: 2024 European Society for Medical Oncology Congress. Barcelona, Spain. September 13-17, 2024. Abstract 1967MO.https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1967MO.html.pdf

2. Zhou L, Yang K, Zhang S, et al. Disitamab vedotin (DV) plus toripalimab (T) in unresectable locally advanced or metastatic urothelial carcinoma (la/mUC): Long-term outcomes from a phase Ib/II study Presented at: 2024 European Society for Medical Oncology Congress. Barcelona, Spain. September 13-17, 2024. Abstract 1979P. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1979P.html.pdf