2024ASCO｜Memorial Sloan Kettering Cancer Center (MSK)'s Prof. Wungki Park Unveils Precision Targeting of TF in Pancreatic Cancer, Signaling ADC Drug Innovations

Wed, 12 Jun 2024 19:31:00 +0800

Introduction: ADC Drug Breakthrough Targets TF in Pancreatic Cancer

CHICAGO, June 12, 2024 /PRNewswire/ -- The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago from May 31 to June 4, shone a spotlight on MRG004A, a novel antibody-drug conjugate (ADC) designed to treat advanced solid tumors with high tissue factor (TF) expression. TF, whose levels are significantly elevated in various cancers, particularly in pancreatic cancer, is strongly linked to poor prognosis and metastasis. As a result, TF has emerged as a pivotal target for new therapeutic strategies aimed at enhancing the treatment outcomes of patients with solid tumors. At the conference, a highly anticipated oral presentation focused on the "Phase I/II First-in-Human Study to Evaluate the Efficacy and Safety of TF-ADC MRG004A in Patients with Solid Tumors." The study was featured in a 15-minute keynote session, standing out as one of only two ADC studies presented in the ASCO Main Session. This recognition underscores the significance of the research and ASCO's high regard for the clinical study. To provide further insights, YIXUEJIE invited the study's lead investigator, Prof. Wungki Park from Memorial Sloan Kettering Cancer Center (MSK), to offer a detailed explanation of this groundbreaking research.

Background

TF overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, this research presents the preliminary safety and efficacy data from phase I/II MRG004A-001.

Methods

This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR).

Results

Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose <2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing.

Conclusions

MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors.

Expert Commentary
MRG004A: Pioneering TF-Targeted Therapy for Pancreatic Cancer

Highlighting the significance of TF as an emerging treatment target in pancreatic cancer, and the success stories of ADC drugs targeting this marker, Prof. Park remarked, "TF's high expression in pancreatic cancer presents a precise target for ADC drugs. MRG004A, a novel ADC targeting TF, precisely recognizes and acts on TF-expressing cancer cells, effectively suppressing their growth and spread. The FDA-approved Tivdak (tisotumab vedotin-eftv), the first TF-targeted ADC, has achieved notable efficacy in cervical cancer treatment, offering robust evidence for TF targeting in pancreatic cancer therapies."

Prof. Park shed light on MRG004A's promising potential, "Phase I and II clinical trials for TF high-expressing tumors are progressing in China and the US, evaluating MRG004A's safety, efficacy, and other attributes. In pancreatic cancer patients, MRG004A displayed remarkable results, with four of 12 patients treated with 2.0 mg/kg achieving remission. Notably, one patient resistant to both FOLFIRINOX and PD-1 therapy responded well to MRG004A. A 100% disease control rate (DCR) was achieved in patients with baseline TF expression ≥50% and limited prior therapies. This underscores MRG004A's significant therapeutic potential and broad applicability. We eagerly await the study's completion, paving the way for new treatment options for patients."

MRG004A: High Efficacy, Low Toxicity, and Broad Prospects

Commenting on the current state of pancreatic cancer treatment and the potential of MRG004A, Prof. Park stated, "Researchers in pancreatic cancer treatment must persist in developing innovative therapies and identifying more effective targets to forge new drugs and refine strategies. The need is dire for more efficacious options for patients, often diagnosed at later stages with limited survival rates. Standard chemo combinations, though widely used, have modest results. MRG004A, however, shows remarkable promise for those resistant to second-line therapies, offering fresh hope for extended survival and enhanced quality of life."

Highlighting MRG004A's unique advantages, Prof. Park stated, "TF high level probably matters for PDAC. MRG004A's efficacy transcends target expression levels, even exhibiting efficacy in low expression states, owing to its exceptional specificity and stability. Clinical trials reveal no serious toxic side effects, a marked reduction in bleeding events, and significant improvement in other side effect profiles. Its safety record surpasses previous drugs. Given its proven efficacy, safety, Orphan Drug Destination (ODD) and Fast Track Designation (FTD), MRG004A promises to be a key treatment option for pancreatic cancer. The research team aims to further explore its application in a broader range of diseases."

MRG004A Pioneers New Pancreatic Cancer Treatment Frontiers, Highlighting Potential in Combination Therapy and TF Research

Commenting on the pancreatic cancer treatment approach, Prof. Park highlighted, "Despite being in early development, MRG004A holds promise in combination therapies. Experts are exploring synergies with existing chemotherapeutics, targeted therapies, and immunotherapeutics to boost efficacy and patient survival. This multi-pronged approach will broaden treatment options for pancreatic cancer patients and inspire new approaches for other challenging diseases. To expedite patient access, industry experts are committed to securing timely approvals at critical trial stages."

Envisioning the future of pancreatic cancer research, Prof. Park emphasized TF's role as a key therapeutic target. Its high expression in pancreatic cancer presents precision therapy opportunities, leading to the development of MRG004A, an ADC drug targeting TF. Preliminary studies have validated its high specificity and stability. The research team will continue to investigate TF's mechanism in pancreatic cancer and explore effective combinations with therapies like immune checkpoint inhibitors, aiming to design tailored regimens based on tumor microenvironments. Additionally, they will focus on other therapeutic targets to broaden patient treatment options and improve prognosis.