Chinese Regulator Conditionally Approves Disitamab Vedotin in Advanced or Metastatic Gastric Cancer

Disitamab vedotin (爱地希^®/Aidixi®; Previously known as RC48; Remegen Biosciences) has been granted conditional marketing approval by the National Medical Products Administration (NMPA; 国家药品监督管理局) of the People’s Republic of China for the treatment of patients with locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least 2 types of systemic chemotherapy.

Disitamab vedotin is an antibody-drug conjugate or ADC which links a humanized monoclonal antibody targeting HER2, to monomethyl auristatin E (MMAE), a small molecule toxin, via a maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker that covalently attaches the MMAE payload to the antibody. The agent’s novel antibody has a higher affinity to HER2 compared to the standard of care. In animal models, the drug demonstrated superior antitumor activity compared to other treatments in animal models.

With this approval, disitamab vedotin, which was independently developed in-house by scientists at Remegen Biosciences, is the second agent approved just three months after the company received its first approval in China for its lupus drug telitacicept (Tai’ai™; previously known as RC18).

Urothelial cancer
Urothelial cancer represents the ninth most common cancer worldwide and the fourth most common cancer in men in the United States

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“An estimated 81,400 new cases of urothelial cancer and 17,980 deaths are predicted in the United States in 2020,” said Jianmin Fang, Ph.D., founder, Chief Executive Officer, and Chief Scientific Officer of RemeGen.

“The high prevalence of metastatic urothelial cancer underscores the need for effective and accessible treatment methods for patients. This Breakthrough Therapy designation will bring RemeGen one step closer to finding a safe and effective treatment for this devastating disease,” Fang added.

Clinical development
The conditional approval is based on the results of RC48-C008 study (NCT03556345), demonstrating 24.4% objective response rate and a median overall survival of 7.9 months.

The multicenter, open label，single arm，phase II study, which enrolled 127 patients, was designed to evaluate the effect and safety of disitamab vedotin in HER2 overexpressing local advanced or metastatic gastric cancer.

To be eligible to participate, patients had histologically confirmed gastric or gastro-esophageal junction cancer, HER2-overexpression (IHC 2+ or 3+), ECOG PS 0-1, post-to ≥2 prior systemic treatment.

In the trial, participating patients receive disitamab vedotin 2.5 mg/kg IV 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 outcome, Objective Response Rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR).  The secondary outcome measures were Progression-Free Survival (PFS) as assessed by the investigators according to RECIST v1.1 and Overall Survival(OS) was defined as the time from the first study treatment to the date of death from any cause.[2]

The median age of the participating patients was 58 years. At baseline, 59 patients (46.5%) had received ≥ 3 lines prior treatments. For the overall 127 patients, the investigator-assessed confirmed ORR was 18.1% (95% CI: 11.8%, 25.9%). Sub-group ORR was 19.4% and 16.9% for the participating patients post to 2 lines and ≥ 3 lines, respectively. For 111 patients who were monitored for ≥ 2 cycles of efficacy assessments (i.e. 12 weeks), the ORR was 20.7% (95% CI: 13.6%, 29.5%). For the 127 patients, the mPFS was 3.8 months (95% CI: 2.7, 4.0, 89 events [70.1%]) and the mOS was 7.6 months (95% CI: 6.6, 9.2, 52 events [40.9%]).[2]

Regulatory approval
In addition to the current conditional approval in China, the U.S, Food and Drug Administration (FDA), in September 2021, granted Breakthrough Therapy designation for disitamab vedotin for the second-line treatment of patients with HER2 positive locally advanced or metastatic urothelial cancer who have also previously received platinum-containing chemotherapy treatment.

The Breakthrough Therapy designation helps drug developers with Fast Track designation features, intensive guidance on an efficient drug development program beginning as early as Phase I. This process is especially designed to help expedite the development and review process of novel therapeutics.

Many firsts
The approval of disitamab vedotin demonstrated RemeGen’s ability to develop biologic drugs and reflects the company’s strong in-house research and development capabilities, especially the ability to develop ADC products.

Disitamab vedotin was the first ADC drug approved for human clinical trials in China. With the current conditional approval, it is also the first domestic antibody-drug conjugate (ADC) to win marketing approval in China.

Scientists at RemeGen are currently studying the drug in multiple late-stage clinical trials across solid tumor types, including breast cancer and lung cancer.

Clinical trials
A Study of RC48-ADC in Subjects With HER2 Overexpressed Metastatic Biliary Tract Cancer – NCT04329429
JS001 in Combination With RC48-ADC in Treatment of HER2-Positive Advanced Malignant Solid Tumors – NCT04280341
A Study of RC48-ADC in Patients With HER2-Expressing Locally Advanced or Metastatic Urothelial Carcinoma – NCT04879329
A Study of RC48-ADC in Subjects With Advanced Non-small Cell Lung Cancer – NCT04311034
A Open-label, Single-arm, Multicenter, Phase II Study of RC48-ADC to Evaluate the Efficacy and Safety of Subjects With HER2 Overexpressing Locally Advanced or Metastatic Urothelial Cancer – NCT03809013
A Study of RC48-ADC in Local Advanced or Metastatic Gastric Cancer With the HER2-Overexpression – NCT04714190
Study of RC48-ADC Administered Intravenously to Subjects With HER2-Positive in Advanced Malignant Solid Tumors – NCT02881190
A Study of RC48-ADC in Subjects With HER2-negative Locally Advanced or Metastatic Urothelial Cancer – NCT04073602
A Study of RC48-ADC(Antibody Drug Conjugate) and JS001 to Evaluate the Safety and Pharmacokinetics of Subjects With Locally Advanced or Metastatic Urothelial Cancer – NCT04264936
A Study of RC48-ADC in Subjects With HER2-Positive Advanced Malignant Solid Tumors – NCT02881138
A Phase II Study of RC48-ADC in Subjects With HER2 Positive Metastatic or Unresectable Urothelial Cancer – NCT03507166
A Study of RC48-ADC in Local Advanced or Metastatic Gastric Cancer Subjects With the Overexpression of HER2 – NCT03556345
A Study of RC48-ADC Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer – NCT03500380
A Study of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2 – NCT04400695
A Study of RC48-ADC in Subjects With Advanced Breast Cancer – NCT03052634

Reference
[1] Jiang J, Li S, Shan X, Wang L, Ma J, Huang M, Dong L, Chen F. Preclinical safety profile of disitamab vedotin：a novel anti-HER2 antibody conjugated with MMAE. Toxicol Lett. 2020 May 15;324:30-37. doi: 10.1016/j.toxlet.2019.12.027. Epub 2019 Dec 23. PMID: 31877330.
[2] Peng Z, Liu T, Wei J, Wang A, He Y, Yang L, Zhang X, et al A phase II study of efficacy and safety of RC48-ADC in patients with locally advanced or metastatic HER2-overexpressing gastric or gastroesophageal junction cancers. Abstract 4560. Journal of Clinical Oncology. 38, no. 15_suppl (May 20, 2020) 4560-4560. DOI: 10.1200/JCO.2020.38.15_suppl.4560
[3] Sheng X, Zhou A-P, Yao X, et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2019;37(15_suppl):4509-4509.