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ASCO 2019 Annual Meeting

ASCO 2019: A Phase II Study of RC48-ADC in HER2-Positive Patients with Locally Advanced or Metastatic Urothelial Carcinoma - Medical Oncologist Perspective

Chicago, IL (UroToday.com) Antibody-drug conjugates (ADCs) have made significant progress in several tumor types over the past few years, including brentuximab vedotin for Hodgkin lymphoma, TDM1 for breast cancer, and inotuzumab ozogamicin for non-Hodgkin lymphoma.1 Linking a targeted monoclonal antibody to a drug allows for increased specificity of drug delivery, potentially sparing normal tissue from toxicity and optimizing drug release strategies by forcing intracellular accumulation of released drug in antigen-positive cells.1   One example of this strategy in metastatic urothelial carcinoma (mUC) is enfortumab vedotin (EV), an ADC that delivers a microtubule-disrupting agent to tumors expressing Nectin-4, a commonly over-expressed protein in UC.2 This abstract describes a new ADC, RC48 in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. Prior data was released at ASCO 2018, where 36 patients with HER2 overexpression as defined by IHC2+ or 3+ were treated in the initial phase I study (mostly gastric cancer). Of the 24 evaluable patients, an objective response rate (ORR) of 33.3% was seen and there were two partial responses in patients with urothelial cancer and biliary cancer.3 Given the partial responses seen in bladder cancer, this study was conducted to further analyze the response of RC48 for HER2+ mUC.
ASCO 2019 RC48 Study design fig 1

This abstract provides data on 43 patients with HER2+ mUC who have been treated with 1 or more prior systemic agents. Key inclusion criteria are shown below:

ASCO 2019 RC48 key inclusion criteria

86% of these patients had visceral metastases and 33% of patients had two prior lines of treatment. 19% of patients had prior immune checkpoint inhibitor therapy. All patients were HER2 positive as defined by IHC 2+ or 3+. A summary of baseline characteristics is shown below.
ASCO 2019 RC48 demographics and baseline characteristics

The objective response rate (ORR) was 60.5% for all patients with a disease control rate of 90.7%. For patients with liver metastases, the objective response rate was 70% (14/20). Confirmed ORR was 51.2%. As you can see from the graph below, there are several patients with ongoing responses past 30 weeks.
ASCO 2019 RC48 best overall response

All patients who were classified as IHC2+ and FISH+ or IHC3+ had shrinkage of the tumor.
ASCO 2019 RC48 fig 1 change of target lesion

There were impressive radiographic examples of response as shown below.
ASCO 2019 RC48 fig 3 CT images

The most common treatment-related adverse events (AEs) were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%). One AE of note was complete and partial small bowel obstruction which occurred in 4.7% of patients.

This abstract provides promising data for a HER2+ ADC which was able to achieve a 60.5% ORR. Overall progression-free survival (PFS) and overall survival (OS) data is not yet mature but the median PFS for the first 9 patients on the study was 7.8 months. The prevalence HER2 overexpression in UC widely varies depending on the study, and interestingly appears to vary depending on geography. In one study, HER2 alterations were seen in 27% of patients from Spain, but only 4% in patients from Greece.4 HER2 is an important biomarker for patients with mUC and the data from this study certainly warrants further evaluation in larger cohorts of HER2+ mUC. A larger study is underway to validate these results and continue to evaluate safety.

Presented by: Xinan Sheng, MD, Peking University Cancer Hospital, Beijing, China

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Current opinion in chemical biology 2010;14:529-37.
  2. Rosenberg JE, Sridhar SS, Zhang J, et al. Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). American Society of Clinical Oncology; 2018.
  3. 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. American Society of Clinical Oncology; 2018.
  4. Bellmunt J, Werner L, Bamias A, et al. HER2 as a target in invasive urothelial carcinoma. Cancer medicine 2015;4:844-52.