Editor's Note: The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting was held from May 31 to June 4 in Chicago, USA, showcasing numerous cutting-edge research findings that will further advance the diagnosis and treatment practices in the field of urological tumors. Among them, a multicenter Phase II clinical study conducted in China, led by Peking University Cancer Hospital, on disitamab vedotin (RC48) combined with toripalimab for neoadjuvant treatment of muscle-invasive bladder cancer (MIBC) with HER2 expression has been included (Abstract No. 4568). "Oncology Frontier" invites Professor Xinan Sheng from Peking University Cancer Hospital to share the latest findings. 

Study Overview

Title: Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle-invasive bladder cancer (MIBC) with HER2 expression.

Background:

Disitamab vedotin (RC48) is a humanized anti-HER2 antibody-drug conjugate (ADC). Previous studies have shown that disitamab vedotin combined with toripalimab, a recombinant humanized anti-PD-1 inhibitor, has antitumor activity in metastatic urothelial carcinoma. This study evaluates the safety and efficacy of disitamab vedotin combined with toripalimab as a neoadjuvant treatment strategy for patients with HER2-expressing MIBC.

Methods:

This is a prospective, multicenter, Phase II trial planning to enroll 40 patients. The primary endpoint is the pathologic complete response (pCR) rate; secondary endpoints include pathologic response rate, safety, and tolerability. The study enrolled previously untreated MIBC (cT2-T4aN0-1M0) patients who were medically fit and consented to radical cystectomy plus pelvic lymph node dissection (RC+PLND) and had HER2 expression of immunohistochemistry (IHC) ≥1+. Patients received disitamab vedotin 2 mg/kg combined with toripalimab 3 mg/kg every two weeks for a total of six cycles, followed by RC+PLND within four weeks. Preliminary efficacy and safety results were analyzed.

Results:

A total of 47 patients were enrolled with clinical staging at diagnosis: cT2N0 (40.4%), cT3N0 (29.8%), cT4aN0 (12.8%), and cT2-4aN1 (17.0%). HER2 expression IHC 1+, 2+, or 3+ was observed in 10.6%, 57.4%, and 31.9% of patients, respectively. Forty-five patients completed neoadjuvant therapy, with two still undergoing treatment. As of the data cutoff (April 2024), 31 patients had completed RC. The pCR rate was 61.3% (19/31). Common treatment-related adverse events (TRAEs) were mostly grade 1 or 2, including alopecia (38.3%), elevated alanine aminotransferase (29.8%), elevated aspartate aminotransferase (29.8%), rash (21.3%), and peripheral sensory neuropathy (21.3%). The incidence of grade 3-4 TRAEs was 15.9%. No deaths occurred, and no surgeries were canceled due to TRAEs. Survival data is still immature.

Conclusion:

For surgically resectable MIBC patients with HER2 expression, disitamab vedotin combined with toripalimab neoadjuvant therapy showed good efficacy and tolerability. These results support further exploration of this combination in this patient population.

Researcher Insights

At this year’s ASCO Annual Meeting, our team presented preliminary results from a Phase II clinical study (RC48-C017) on the neoadjuvant use of disitamab vedotin combined with toripalimab for muscle-invasive bladder cancer (MIBC). Our team has long been committed to studying antibody-drug conjugates (ADCs) in the treatment of advanced urothelial carcinoma. In the previous RC48-C014 study, we found that the objective response rate for HER2 IHC 1+ and above patients with advanced urothelial carcinoma exceeded 70%.

Since May 2022, under the guidance of Professor Guo Jun and Professor He Zhiyong from Peking University First Hospital’s Department of Urology, in collaboration with other medical centers nationwide, including The First Affiliated Hospital of Wenzhou Medical University, Shandong Cancer Hospital, and The Affiliated Hospital of Qingdao University, we completed the Phase II clinical study on the neoadjuvant use of disitamab vedotin combined with toripalimab for MIBC. A total of 47 patients participated in this study, with 31 completing all clinical trials and undergoing radical surgery.

At this ASCO meeting, we reported the primary endpoint of pathologic complete response rate (pCR). Overall, the pCR rate reached 61.3%. Notably, with higher HER2 expression levels, the pCR rate showed a significant upward trend, exceeding 80% in the HER2 IHC 3+ patient group.

This RC48-C017 study is the first report of immunotherapy combined with an ADC drug in neoadjuvant therapy and the world’s first of its kind. While this year’s ASCO meeting will also present results on sacituzumab govitecan as neoadjuvant therapy for MIBC, it is only for single-agent ADC neoadjuvant clinical research. The combination of enfortumab vedotin (EV) and pembrolizumab as neoadjuvant therapy has directly entered Phase III clinical research, but no clinical data on EV combined with PD-1 inhibitors has been released yet. Our team is the first to release clinical research results on the use of HER2-targeted MMAE ADC drugs in neoadjuvant therapy, currently leading in pCR among all neoadjuvant clinical studies. This rate significantly exceeds those of previous chemotherapy and immunotherapy combined with chemotherapy in neoadjuvant settings, laying a solid foundation for further exploration of ADC combined with immunotherapy in neoadjuvant applications. Based on current research results, we plan to further expand relevant clinical research and explore new strategies for bladder preservation treatment in muscle-invasive urothelial carcinoma.