Editor's Note: The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting will take place in Chicago from May 31 to June 4. Led by Professor Nanlin Li from Xijing Hospital of the Air Force Medical University, a single-center, single-arm phase II clinical study focused on the efficacy and safety of the HER2-targeting antibody-drug conjugate (ADC) RC48 in the neoadjuvant treatment of HER2-positive breast cancer has disclosed its data. The study shows that although RC48 achieved lower pathological complete response rates (pCR) compared to traditional chemotherapy combined with targeted therapy, it effectively reduced tumor size rapidly, achieved moderate to significant remission, and had high safety with minimal toxicity. These findings provide a new option for neoadjuvant treatment of HER2-positive breast cancer and may expand the indications for domestically developed ADC drugs. This article reports the relevant data.

Study Overview

Background: Patients who achieve pCR during neoadjuvant therapy for breast cancer generally have better prognoses. Whether ADC drugs can replace traditional chemotherapy combined with dual anti-HER2 therapy in the neoadjuvant setting remains to be explored. RC48 is a newly developed HER2-targeting ADC drug with a payload of the small molecule toxin MMAE. It features a cleavable linker and a bystander effect, which allows it to kill both HER2-positive tumor cells and HER2-low or heterogeneously expressing tumor cells. This study aims to explore the efficacy and safety of RC48 in the neoadjuvant treatment of HER2-positive breast cancer.

Methods: The study aimed to enroll 30 patients aged ≥18 years with HER2-positive breast cancer, tumor size >20 mm, or confirmed axillary lymph node metastasis. Patients received RC48 (2.5 mg/kg, q14d, 6 cycles) before surgery, followed by EC (q21d, 4 cycles) post-surgery, and then maintenance therapy with trastuzumab and pertuzumab for 1 year. The primary endpoints were the objective response rate (ORR) and pathological complete response rate (pCR).

Results: By the time of the abstract submission, 23 patients had been successfully enrolled, all of whom completed surgical treatment by February 4, 2024. The median age of the enrolled patients was 45 years (range, 38-70 years). Thirteen percent (3 patients) achieved pCR, 78.3% (18 patients) achieved partial response (PR), and 8.7% (2 patients) experienced disease progression (PD). The ORR was 91.3%. Of the 12 patients with initial axillary lymph node positivity, 42% (5 patients) were node-negative post-surgery. Among the 17 HR-negative HER2-positive patients, 11.8% (2 patients) achieved pCR. Tumor shrinkage was categorized as 0-50% (mild response), 51%-75% (moderate response), and 76%-100% (significant response). In the HR-negative HER2-positive subgroup, 23% (4 patients) had a mild response, and 77% (13 patients) had a moderate to significant response. Among the six HR-positive patients, 16.7% (1 patient) achieved pCR, and 100% (6 patients) had tumor shrinkage >50%, indicating moderate to significant response. No severe (grade 3/4) toxicities were reported among all patients.

Conclusion: Our current data show that RC48 for neoadjuvant treatment of HER2-positive breast cancer achieves rapid tumor shrinkage with moderate to significant responses in 82.6% of cases, although the pCR rate is lower than traditional chemotherapy combined with targeted therapy. Additionally, the ORR for HR-positive HER2-positive breast cancer in this study reached 100%, suggesting that the new ADC significantly inhibits the crosstalk between ER and HER2. We anticipate similar results from the Destiny Breast 11 study. This regimen also shows a high probability of converting axillary lymph node-positive patients to node-negative status.

In summary, RC48 is a potential effective neoadjuvant treatment option for HER2-positive breast cancer, with high safety, minimal toxicity, and good patient compliance. This clinical trial has been registered on clinicaltrials.gov (NCT05134519).

Researcher’s Perspective

ADC drugs consist of an antibody, a cytotoxic drug, and a linker. ADC drugs combine the targeting capability of antibodies with the killing power of small molecule drugs, achieving therapeutic effects beyond ordinary antibodies and providing more treatment opportunities for cancer patients. In recent years, ADC drugs targeting HER2 have been explored and have achieved success in multiple tumor types. T-DM1 was the first HER2-targeting ADC drug approved in the US in 2013 and in China in January 2020. Vidicizumab (RC48-ADC) is the first domestically developed ADC drug to submit an application for market approval in China.

RC48 is a novel HER2 ADC, a humanized anti-HER2 monoclonal antibody conjugated with the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable linker. Compared to T-DM1, the vc-MMAE linker in RC48 is cleavable, allowing the rapid release of the small molecule toxin through a single enzymatic hydrolysis reaction. T-DM1’s linker is non-cleavable and requires lysosomal degradation to release the LyS-MCC-DM1 molecule slowly. Additionally, RC48 has a bystander killing effect, where the released small molecule toxin can kill surrounding (tumor) cells.

Preclinical studies have shown that RC48-ADC exerts antitumor effects through two main pathways: inhibiting HER2-activated downstream signaling pathways (e.g., PI3K/AKT), interfering with cell transcription, growth, and proliferation; and disrupting microtubule formation through the small molecule MMAE, inducing cell cycle arrest in the G2 phase. In vitro studies have demonstrated that RC48-ADC exerts tumor inhibitory effects through antibody-dependent cell-mediated cytotoxicity (ADCC) on HER2-overexpressing cancer cells.

This single-center, single-arm phase II clinical study aims to evaluate the efficacy and safety of RC48 in the neoadjuvant treatment of HER2-positive breast cancer (NCT05134519). It is the first to explore the efficacy of the domestically developed ADC drug RC48 in this setting, potentially expanding its indications and providing more treatment options for HER2-positive breast cancer.