ASCO 2019: A Phase II Study of Investigational Antibody-drug Conjugate RC48 in Human Epidermal Growth Factor Receptor 2 Positive Patients with Locally Advanced or Metastatic Urothelial Carcinoma

Chicago, IL ( Urothelial carcinoma has one of the highest incidences of HER2 overexpression among all cancers.1 RC48-ADC is an antibody-drug conjugate comprised of a HER2 antibody conjugated to the microtubule-disrupting cytotoxic agent monomethyl auristatin E (MMAE). The safety and preliminary efficacy of RC48-ADC were previously established in a small, phase I dose-escalation study including patients with urothelial carcinoma.2 Investigators reported on the results of a single arm phase II study of RC48-ADC in HER2+ locally advanced and metastatic urothelial carcinoma.

A total of 43 patients with unresectable locally advanced or metastatic urothelial cancer who had progressed after at least 1 prior line of systemic therapy were assessed for HER2 status by immunohistochemistry and by FISH. Patients whose tumors exhibited high HER2 expression (IHC2+ or 3+) were treated with RC48-ADC at 2.0 mg/kg q2 weeks until progression or unacceptable toxicity.


Enrolled patients exhibited a number of adverse clinical features, most notably an 86% rate of visceral metastasis with 46.5% rate of liver metastasis. A majority (55.8%) of enrolled patients’ tumors were graded HER2 IHC2+ FISH-.


RC48-ADC demonstrated an impressive 51.2% (22/43) confirmed objective response rate. High response rates were observed even among the most difficult-to-treat populations, with a confirmed objective response rate of 60.0% among patients with liver metastases and a 62.5% response rate in immunotherapy-refractory tumors. Notably, HER2 IHC2+ FISH- patients responded similarly to IHC2+ FISH+ and IHC3+ patients, which was suggested to perhaps represent a “bystander” effect whereby cytotoxic payload is capable of inducing cell death not only in antibody-bound cells but also in neighboring cells, leading to objective responses in FISH- tumors. Discussants speculated that such a “bystander” effect may even be substantial enough to induce responses in ICH1+ tumors.



The investigators concluded that these highly encouraging results support the continued investigation of RC48-ADC in HER2+ advanced urothelial cancer, and a larger phase II trial (NCT03809013) is currently underway.

Presented by: Xinan Sheng, MD, Medical Oncologist, Peking University Cancer Hospital, Bejing, China

Written by: Michael Lattanzi, MD, Internal Medicine Resident, Department of Medicine, NYU School of Medicine, @MikeLattanzi at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer and Metastasis Reviews. 2015 Mar 1;34(1):157-64.
  2. Gong J, Shen L, Wang W, Fang J. Safety, pharmacokinetics and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer.
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