Novel Antibody-Drug Conjugate Shows Potential in Solid Tumor Treatment
MRG004A, a novel antibody-drug conjugate, elicited antitumor activity and had manageable toxicities when used in heavily pretreated patients with multiple tumor types with high tissue factor.
Pancreatic cancer anatomy concept , malignant tumor of pancreas: © Лилия Захарчук - stock.adobe.com
Antitumor activity was seen with MRG004A when used in heavily pretreated patients with multiple tumor types with high tissue factor (TF), including those with pancreatic cancer, according to findings from a phase 1/2 first-in-human trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.1,2
Nineteen patients enrolled in the trial had pancreatic cancer, 13 of which (68%) had TF ≥50%. Five of these patients received dose <2 mg/kg once every 3 weeks.
Of the 12 evaluable patients with pancreatic cancer included in the 2.0mg/kg cohort and who were treated with a median of 3 lines of prior therapy, 4 patients had partial responses (PR) and 6 had stable disease (SD). The overall response rate (ORR) observed for these patients was 33.3% (n = 4) and the disease control rate (DCR) was 83.3% (n = 10). Further, 5 patients with pancreatic cancer of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2 mg/kg. Four of these patients had a PR, and 1 had SD.
"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 [chemotherapy] 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," said Wungki Park, MD, MS, professor at Memorial Sloan Kettering Cancer Center, in a press release.
MRG004A is a novel antibody-drug conjugate being developed for the treatment of advanced solid tumors with high TF expression. Significantly elevated levels of TF, particularly in pancreatic cancer, are strongly linked to poor prognosis and metastasis. Because of this, TF is now seen as a pivotal target for new treatments which work in bettering treatment outcomes for those with solid tumors.
This first-in-human, phase 1/2 study is ongoing in the US and China and included patients with an unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy and had an ECOG status of 0 or 1. A total of 63 patients were enrolled, including 43 in dose-escalation phase which evaluated 8 dose levels of MRG004A ranging from 0.3 to 2.6mg/kg, and 20 patients in the dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). MRG004A was given as a monotherapy once every 3 weeks via intravenous infusion.
Investigators assessed the primary end points of safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose. Further, baseline tissue was evaluated for the association of TF expression with ORR and DCR.
The median age of patients was 58 (range, 38-75), 8 patients (13%) had an ECOG performance score of 0, and 37 (59%) patients were female. Patients were given a median of 3 prior lines of therapy (range, 1-10). The MTD was not reached.
Additional findings from the study showed that treatment-related adverse events (TRAEs) of any grade commonly seen among patients consisted of conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%). A total of 7.9% (5/63) of patients had serious AEs. Only 1 dose-limiting toxicity was seen, which occurred in a patient with triple-negative breast cancer (TNBC) treated at 1.8mg/kg. While this patient had grade 3 Stevens-Johnson syndrome, it resolved, and no other dose-limiting toxicity was reported.
MRG004A also demonstrated efficacy in other cancer types. Among 4 patients with heavily treated TNBC, the ORR was 25%, and the DCR was 50%. Of 2 patients with cervical cancer treated with 4 prior lines of therapy, 1 had a PR and 1 had SD.
These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors. The dose-expansion phase and mature outcome evaluation are ongoing.
“TF high level probably matters for [pancreatic cancer]. 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 [adverse] effects, a marked reduction in bleeding events, and significant improvement in other [adverse] effect profiles. Its safety record surpasses previous drugs. Given its proven efficacy, safety, orphan drug destination and fast track designation, 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," added Park.
