Dual ADC Stars Shine at ESMO: Lepu Biopharma Unveils Promising Phase I Data for MRG003 and MRG002
Editor’s Note: This article is republished from Oncology Today of the China Medical Tribune, with authorization granted to VCBeat.
From September 16 to 21, the highly anticipated European Society for Medical Oncology (ESMO) Annual Meeting will be held online in grand style. September, a season of harvest, brings together experts and scholars from the global oncology community in the cloud to discuss cutting-edge advancements, promote academic development, and plan for the future. As one of the research hotspots in recent years, clinical studies on antibody-drug conjugates (ADCs) are being conducted with great enthusiasm. The “magic bullets,” carrying new hope for the field, will once again demonstrate their strength at this year’s ESMO Annual Meeting. The Phase I clinical studies exploring MRG003 and MRG002, led respectively by Professor Xu Ruihua from Sun Yat-sen University Cancer Center and Professor Li Jin from Shanghai East Hospital affiliated with Tongji University, have both been selected as ESMO ePosters. This achievement showcases China’s prowess on the world stage and highlights the remarkable contributions of Lepu Biopharma.
MRG003 is an antibody-drug conjugate (ADC) composed of an EGFR-targeting monoclonal antibody linked to the potent microtubule inhibitor payload MMAE via a vc linker, representing an innovative class of EGFR-targeted ADCs. EGFR, a member of the epidermal growth factor receptor family, plays a critical role in cell growth, development, and differentiation. Studies have shown that EGFR is highly expressed in various solid tumors. EGFR monoclonal antibodies can specifically bind to the EGFR receptor, thereby blocking the interaction between EGFR and its ligands, thus exerting antitumor effects. To further enhance therapeutic efficacy, MRG003 was developed.
This multicenter, open-label, dose-escalation and expansion Phase I clinical study, led by Professor Xu Ruihua from the Sun Yat-sen University Cancer Center, investigated the safety and preliminary efficacy of MRG003 in patients with advanced solid tumors. Part Ia was designed as a “3+3” dose-escalation trial, in which patients with advanced solid tumors received MRG003 once every three weeks for up to eight cycles. The initial starting dose was 0.1 mg/kg, followed by sequential dose escalations to 0.3, 0.6, 1.0, 1.5, 2.0, and 2.5 mg/kg. Part Ib, the expansion cohort, evaluated the safety, dose-limiting toxicities (DLTs), and antitumor activity of MRG003 at a dose of 2.5 mg/kg administered once every three weeks in patients with heavily pretreated, advanced/metastatic squamous cell carcinoma of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). Assessments were conducted every six weeks.
The Phase Ia dose-escalation trial enrolled 22 patients with solid tumors of unknown EGFR status, with a median age of 56.5 years. The Phase Ib expansion trial enrolled 39 patients with solid tumors confirmed as EGFR-positive by immunohistochemistry (IHC) (12 with colorectal cancer [CRC], 13 with squamous cell carcinoma of the head and neck [SCCHN], and 14 with nasopharyngeal carcinoma [NPC]), with a median age of 52 years. The mean number of prior lines of therapy was 3 (range: 1–6). The confirmed recommended Phase 2 dose (RP2D) for Phase Ib was 2.5 mg/kg. Regarding safety, treatment-related adverse events (TRAEs) occurring in ≥20% of patients included rash, elevated aspartate aminotransferase (AST), alopecia, decreased appetite, elevated alanine aminotransferase (ALT), pruritus, myalgia, fatigue, fever, and decreased white blood cell count. Fourteen patients experienced TRAEs of grade ≥3, all of whom were in the 2.5 mg/kg treatment cohort.
In terms of efficacy, 18 patients with stage Ia disease (18/22) underwent efficacy evaluation, yielding an objective response rate (ORR) of 6% and a disease control rate (DCR) of 33%. Among the 27 patients with stage Ib disease who underwent efficacy evaluation (27/39), the best overall response (BOR) included 11 partial responses (PR; 8 confirmed) and 9 cases of stable disease (SD), resulting in an ORR of 30% and a DCR of 63%. Specifically, the ORR was 40% and the DCR was 80% in patients with squamous cell carcinoma of the head and neck (SCCHN), while the ORR was 44% and the DCR was 78% in patients with nasopharyngeal carcinoma (NPC). Patient enrollment for the phase Ib expansion trial has been completed, and patient follow-up is currently ongoing.
Conclusion: This Phase I clinical study demonstrated the manageable safety profile and encouraging antitumor activity of MRG003 in patients with advanced solid tumors, including nasopharyngeal carcinoma (NPC) and squamous cell carcinoma of the head and neck (SCCHN), who had received multiple prior lines of therapy. Based on a comprehensive analysis, the investigators concluded that 2.0 mg/kg may be a safer and more tolerable dose of MRG003 compared to 2.5 mg/kg. The efficacy and safety of MRG003 at 2.0 mg/kg will be further explored in future Phase II clinical trials.
MRG002 is an antibody-drug conjugate composed of glycoengineered trastuzumab linked to MMAE via an enzyme-cleavable valine-citrulline (vc) linker. Trastuzumab specifically binds to HER2 antigens on the surface of tumor cells, facilitating internalization and subsequent release of the cytotoxic payload MMAE. MMAE effectively inhibits tubulin polymerization, thereby disrupting microtubule-related functions such as mitosis, ultimately leading to tumor cell death.
This multicenter, open-label, dose-escalation and expansion Phase I clinical study, led by Professor Li Jin from Shanghai East Hospital affiliated with Tongji University, aims to evaluate the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of MRG002 in patients with HER2-positive advanced/metastatic solid tumors. The Ia phase is designed as a “3+3” dose-escalation trial, starting at a dose of 0.3 mg/kg, followed by incremental doses of 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. The Ib expansion cohort explores the safety, dose-limiting toxicities (DLTs), and antitumor activity of MRG002 administered at 2.6 mg/kg every three weeks in patients with heavily pretreated, HER2-positive advanced/metastatic solid tumors, such as breast cancer and gastric cancer. Assessments are conducted every two cycles.
In Stage Ia, a total of 25 patients with HER2-positive advanced/metastatic solid tumors (19 with breast cancer, 3 with salivary gland cancer, 2 with gastric cancer, and 1 with colorectal cancer) were enrolled to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of MRG002. The median age of the patients was 53 years (range: 30–66), and the median number of prior lines of therapy was 5 (range: 1–11). Patients received MRG002 once every three weeks for up to eight cycles. Regarding safety, treatment-related adverse events (TRAEs) occurring in ≥20% of patients included neutrophil count decreased, aspartate aminotransferase (AST) increased, white blood cell count decreased, lactate dehydrogenase increased, alopecia, creatine phosphokinase (CPK) increased, alanine aminotransferase (ALT) increased, triglycerides increased, cholesterol increased, gamma-glutamyl transferase (GGT) increased, decreased appetite, and hypoesthesia. Most adverse events were mild to moderate in severity. The most common Grade ≥3 TRAEs were neutrophil count decreased and triglycerides increased, each occurring in 3 patients. Six patients experienced treatment-related serious adverse events (SAEs), including GGT increased, AST/ALT increased, neutrophil count decreased, left ventricular ejection fraction (LVEF) decreased, fatigue, and peripheral neuropathy.
In terms of efficacy, among the 21 patients who underwent at least one tumor assessment, 9 were assessed as having a partial response (PR; 43%), 8 as having stable disease (SD; 38%), and 4 as having progressive disease (PD; 19%). The investigator-assessed objective response rate (ORR) was 43%, and the disease control rate (DCR) was 81%. Among the 16 patients with HER2-positive breast cancer, the efficacy assessment showed 8 PRs and 5 SDs, yielding an ORR of 50% (8/16) and a DCR of 81% (13/16). Two dose-limiting toxicities (DLTs) occurred at the 3.0 mg/kg dose level, including decreased left ventricular ejection fraction (LVEF) and elevated creatine phosphokinase (CPK). Consequently, the final confirmed recommended phase 2 dose (RP2D) was determined to be 2.6 mg/kg. An Ib expansion trial evaluating the efficacy and safety of MRG002 at this dose is currently actively underway.
Conclusion: The dose-escalation trial of MRG002 demonstrated manageable safety and encouraging antitumor activity in patients with HER2-positive solid tumors (such as breast cancer and gastric cancer), paving the way for further exploration in Phase II clinical studies.
Good news keeps coming! At the 24th National Clinical Oncology Conference and the 2021 Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), to be held from September 25 to 29, Professor Li Jin will provide a detailed account of the research progress in the plenary session. Meanwhile, Professor Jiang Zefei from the Department of Oncology, Chinese PLA General Hospital, will deliver a themed report in the Innovation Session on the multicenter Phase II study of the novel antibody-drug conjugate (MRG002-ADC) for the treatment of HER2-low advanced breast cancer. Stay tuned!
At this year’s ESMO Congress, Phase I clinical studies of two antibody–drug conjugate (ADC) therapies demonstrated manageable safety profiles and robust antitumor activity. These encouraging findings further underscore the clinical potential of ADCs. We look forward to the release of additional clinical data that may provide new treatment options for patients with EGFR-positive or HER2-positive solid tumors.