Clinically meaningful topline results for a Phase II clinical trial of RC48-ADC were presented during the annual meeting of the American Society of Clinical Oncology (ASCO), being held May 31 – June 4, 2019 in Chicago, Ill. 
RC48-ADC is a novel, investigational, HER2-targeting antibody-drug conjugate for treatment of patients with HER2-positive solid tumors, including metastatic or unresectable urothelial cancer who have received previous treatment with chemotherapies and had visceral metastasis.
RC48-ADC is comprised of a novel HER2-targeting antibody, a cathepsin cleavable linker and a monomethyl auristatin E (MMAE) payload. The HER2-targeted antibody has a higher affinity for HER2 compared to standard of care, and demonstrated superior anti-tumor activity in pre-clinical development. RC48-ADC was the first antibody-drug conjugate approved for human clinical trials in China and, in clinical trials, has shown excellent safety profile.
In an open-label, multicenter, single-arm, non-randomized phase II study (NCT03507166) 43 eligibility patients (median age of 64 years; with histologically confirmed urothelial cancer, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment) received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) every 2 weeks (Q2W) until investigator assessed loss of clinical benefit, unacceptable toxicity, investigator or participant decision to withdraw from therapy, or death (whichever occurs first).
The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed.
At baseline, the majority of participating patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the Disease Control Rate (DCR), the sum of the complete, partial and stable disease rates, was 90.7% (39/43). The median median PFS was 7.8 months (95% CI: 4.9, 10.7).
Overall, the study results demonstrated a 51% confirmed objective response rate (cORR) per independent central review. The most commonly observed treatment-related adverse events included hypoesthesia (numbness), alopecia and hemotoxicity. The presented results are expected to support a global late stage clinical trial, including an Investigational New Drug Application (IND), with the US Food and Drug Administration (FDA) anticipated in the second half of 2019.
“We are encouraged to see positive data from the RC48 trial now reinforcing what earlier data have shown,” said Jianmin Fang, Ph.D., founder and Chief Executive Office of RemeGen, a biotech company based in Yantai, Shandong Province，China.
“Urothelial carcinoma is a common cancer worldwide and we believe RC48-ADC has the potential to redefine the treatment for these patients, as well as for patients with HER2-expressing cancers who continue to have high unmet medical need.”
Urothelial carcinoma, also known as transitional cell carcinoma, is the most common type of bladder cancer (90%of cases). Worldwide, approximately 549,000 people were diagnosed with bladder cancer in 2018 and there were about 200,000 deaths.
Metastatic or unresectable disease is identified in approximately 20% of patients presenting with invasive urothelial cancer. In addition, up to 50% of patients will develop metastases following radical cystectomy for clinically localized disease.
Unfortunately, no breakthrough treatments for metastatic urothelial carcinoma have emerged in over two decades. The current therapeutic option, which include multiagent, cisplatin-based combination chemotherapy as the standard, first-line treatment, have subpar efficacy. And although urothelial cancer is considered a chemosensitive tumor, metastatic disease is associated with poor prognosis and short-term survival, as is reflected in high rates of recurrence and mortality.
“For HER2-positive urothelial carcinoma patients with previously-treated locally advanced or metastatic urothelial cancer, there’s no targeted treatment available,” said Fang. “These results for RC48-ADC indicate it may be able to help patients whose cancer has progressed following treatment with standard chemotherapy and immuno-oncology agents and we look forward to discussing the data with relevant health authorities.”
A Phase II Study of RC48-ADC in Subjects With HER2 Positive Metastatic or Unresectable Urothelial Cancer – NCT03507166
 Sheng X, Zhou AP, Yao X, Shi Y, Luo H, Shi B, Liu J, Yu G, et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol 37, 2019 (suppl; abstr 4509) [Abstract]
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