Disitamab Vedotin Shows Efficacy in HER2-Negative Metastatic Urothelial Carcinoma

Disitamab vedotin demonstrated promising efficacy with a tolerable safety profile in patients with HER2-negative metastatic urothelial carcinoma.

Disitamab vedotin (RC48-ADC) demonstrated promising efficacy with a tolerable safety profile in patients with HER2-negative metastatic urothelial carcinoma, according to results from the phase 2 RC48-C011 trial (NCT04073602) presented during the 2022 ASCO Annual Meeting.1

As of the data cutoff of May 5, 2022, the confirmed objective response rate (ORR) with the agent was 26.3% (95% CI, 9.1%-51.2%), with all 5 responders experiencing partial responses. Moreover, 68.4% of patients achieved stable disease, and 5.3% experienced disease progression.

The median duration of response was 4.3 months (95% CI, 2.7–not evaluable). The disease control rate achieved with the agent was 94.7% (95% CI, 74.0%-99.9%). Additionally, the median progression-free survival with disitamab vedotin was 5.5 months (95% CI, 3.9-6.8), and the median overall survival was 16.4 months (95% CI, 7.1-21.7).

“This phase 2 trial indicated the efficacy of [disitamab vedotin] in HER2-negative metastatic urothelial cancer patients, especially immunohistochemistry [IHC score of] 1+, by confirmed objective response,” Huayan Xu, of Key Laboratory of Carcinogenesis and Translational Research, Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, and colleagues, wrote in a poster. “Most treatment-related adverse effects [TRAEs] were grade 1 [or] 2…and similar to previous [disitamab vedotin] monotherapy studies. The [safety profile] of [disitamab vedotin] was tolerable and manageable.”

Disitamab vedotin is an antibody-drug conjugate (ADC) that selectively delivers anticancer agent monomethyl auristatin E (MMAE) into HER2-positive tumor cells; its novel antibody has a higher affinity to the HER2 oncogene compared with the standard of care. Additionally, the agent has demonstrated superior antitumor activity vs other treatments when examined in animal models.

According to the National Cancer Institute, the estimated number of new cases of urothelial cancer in 2022 is 81,180, which translates to 4.2% of all new cancer cases reported in the United States. An estimated 17,100 patients will die of the disease this year.2

China added disitamab vedotin to its National Reimbursement Drug List in December 2021 for the treatment of locally advanced or metastatic HER2-positive gastric cancer. The agent is China's first domestically-produced ADC accepted for this indication.3

Gastric cancer is the second most common cancer and the second leading cause of cancer‐related deaths in China;4 it is associated with a high disease burden, accounting for 9,824,990 disability‐adjusted life‐years in 2019.5

Investigators recruited 19 patients with locally advanced or unresectable metastatic HER2-negative urothelial cancer into the open-label, single-arm study. Patients were required to have progressed on at least 1 line of systemic chemotherapy and to have an ECOG performance status of 0 or 1.

Study participants received 2.0 mg/kg of intravenous disitamab vedotin once every 2 weeks until disease progression, intolerable toxicity, patient decision, or death. The primary end point of the trial was ORR, and secondary end points included PFS, DOR, DCR, OS, and safety.

The median patient age was 64 years (range 36-77). The population included 13 men (68.4%) and 6 women (31.6%). Six patients had an IHC score of 0 and 13 had a score of 1+. ECOG performance status was 0 for 11 (57.9%) patients and 1 for 8 patients (42.1%). The ureter was the site of primary lesion for 7 (36.8%) patients. Bladder and renal pelvis were the primary sites for 6 patients each. Thirteen patients had visceral metastases; 12 (63.2%) had them in the lung and 6 (31.6%) had them in the liver.

Twelve (63.2%) patients had received 2 prior lines of treatment, 4 (21.1%) received 1 prior line, and 3 (15.8%) received 3 or more. Thirteen patients previously received PD-1/PD-L1–directed therapy. Bellmunt risk score was 0 for 9 (47.3%) patients, 1 for 4 (21.1%) patients, 2 for 4 (21.1%) patients, and 3 for 2 (10.5%) patients.

Patients with an IHC score of 0 (n = 6) had no response to therapy. The overall response rate for those with an IHC score of 1+ (n = 13) was 38.5% (95% CI, 13.9%-68.4%). The confirmed ORR in those who received 1 prior line of chemotherapy (n = 4) was 25.0% (95% CI, 0.6%-80.6%) with the ADC; this rate was 33.3% (95% CI, 9.9%-65.1%) in those who received 2 prior lines of chemotherapy (n = 12). All 3 patients who received 3 or more prior lines of chemotherapy did not respond to treatment.

The any-grade rate of TRAEs was 100%. Common TRAEs experienced with the ADC included leukopenia, hypoesthesia (all-grade, 47.4%), alopecia (all-grade, 47.4%), aspartate aminotransferase increase (all-grade, 42.1%), alanine aminotransferase increase (all-grade, 42.1%), neutropenia (all-grade, 42.1%; grade 3 or higher, 10.5%), and fatigue (all-grade, 42.1%).

The most common grade 3/4 TRAEs were neutropenia and decreased white blood cell count (5.3%).

In September 2020, the FDA granted a breakthrough therapy designation for disitamab vedotin for the second-line treatment of patients with HER2-positive locally advanced or metastatic urothelial carcinoma who have also previously received platinum-containing chemotherapy treatment.6


  1. Xu H, Sheng X, Zhou L, et al. A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2022;40(suppl 16):4519. doi:10.1200/JCO.2022.40.16_suppl.4519
  2. National Cancer Institute. Cancer stat facts: bladder cancer. Accessed June 30, 2022. https://bit.ly/2DW5tA1
  3. RemeGen's telitacicept and disitamab vedotin enter China's National Reimbursement Drug List for SLE and gastric cancer treatment. News release. December 3, 2021. Accessed June 30, 2022. https://prn.to/3uac1b2
  4. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394‐424. doi:10.3322/caac.21492
  5. He Y, Wang Y, Luan F, et al. Chinese and global burdens of gastric cancer from 1990 to 2019. Cancer Med. 2021;10(10):3461-3473. doi:10.1002/cam4.3892
  6. RemeGen announces US FDA has granted Breakthrough Therapy designation for Disitamab Vedotin (RC48) in urothelial cancer. News release. September 25, 2020. Accessed June 30, 2022. https://prn.to/3y3fFos