Results from a robust oncology pipeline, including the latest phase II data of an investigational antibody-drug conjugates (ADC) called RC48 being developed by RemeGen (Yantai, Shangdong; China), will be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO), being held in Chicago, Illinois, from May 31- June 4, 2019.

RC48 is a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE) via a cleavable linker which has showed high specificity and potency in vivo and in vitro models of gastric cancer and other HER2+ solid tumors.

The trial drug has a novel antibody with a higher affinity to HER2 compared to standard of care and demonstrated superior anti-tumor activity compared to other treatments in animal models. The novel agent which, in a Phase I clinical trial demonstrated excellent safety profile, was the first antibody-drug conjugate approved for human clinical trials in China. It is currently being studied in multiple late-stage clinical trials across solid tumor types.[1][2]

Phase II data
“The poster discussion session at ASCO 2019 will feature new data from [an open-label, multicenter, single-arm, non-randomized] Phase II study of RC48, a novel humanized anti-HER2 antibody-drug conjugate (ADC), for patients with metastatic urothelial cancer,” said Jianmin Fang, Ph.D., founder and Chief Executive Officer of RemeGen, Ltd.

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The phase II study (NCT03507166) was designed to evaluate the activity of RC48 in HER2-positive patients with locally advanced or metastatic urothelial carcinoma, the most common type of bladder cancer and cancer of the ureter, urethra, and urachus.

Study design
Patients were eligibility when the showed a histologically confirmed urothelial carcinoma, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, and were treated with ≥1 prior systemic treatment.

As part of the trial, patients received RC48 alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed.

The trial enrolled 43 patients with a median age of 64 years of age. At baseline, most of the enrolled patients (37/43) had visceral metastasis. A total of fourteen patients (32.6%) had received ≥ 2 lines prior treatment and 8 patients (18.6%) had prior immune checkpoint inhibitor (CPI) therapy in second line treatment.[3]

Trial results
The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the disease control rate (DCR) or clinical benefit rate (CBR), the sum of the complete, partial and stable disease rates and percentage of patients whose disease shrank or remained stable, was 90.7% (39/43).[3]

As of January 23, 2019, the median progress-free survival or PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started treatment with RC48 prior to June 30, 2018.[3]

The objective response rate or ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in patients with liver metastasis. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy.[3]

Common adverse events (AE) related to the treatment RC48 included leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%). Most of the adverse events were Grade 1 or 2.[3]

Based on the results, the researchers noted that RC48 demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive metastatic urothelial carcinoma patients, including those who underwent failure to the immunotherapy.

“These data support the scientific view that this pathway may play a key role in the treatment of many cancers with tumors that express HER2 antigen such as gastric, breast, lung, ovarian and bladder cancers,” Fang observed.

Amplification of the HER2 gene and overexpression of its product were first discovered in breast cancer and are significantly associated with worse outcomes.[4] Many studies have demonstrated that HER2 is also present in several other cancers, including colorectal, ovarian, prostate lung and particularly, gastric and gastroesophageal cancers.[5]

[1] Study of RC48-ADC Administered Intravenously to Subjects With HER2-Positive in Advanced Malignant Solid Tumors – NCT02881190
[2] A Phase II Study of RC48-ADC in Subjects With HER2 Positive Metastatic or Unresectable Urothelial Cancer – NCT03507166
[3] Sheng X, Zhou AP, Yao X, Shi Y, Luo H, Shi B, Liu J, Yu G, He Z, et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. Abstract No. 4509 (June 3, 2019, 4:30 – 6:00 p.m. CST). J Clin Oncol 37, 2019 (suppl; abstract 4509).
[4] Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182.
[5] 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 Metastasis Rev. 2015;34:157–164.

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