Mipsagargin Demonstrates Clinical Benefit in Patients With Advanced HCC

Devalingam Mahalingam, MD

The first-in-class prodrug, mipsagargin (G-202), showed promising antitumor activity and enabled patients with advanced sorafenib (Nexavar)-refractory hepatocellular carcinoma (HCC) to achieve disease stabilization, investigators reported at the 2017 International Liver Congress in Amsterdam.

Posttreatment objective disease assessment was done on the efficacy evaluable population in this study, which comprised 19 patients completing at least 2 cycles of treatment of the 25 patients initially enrolled. Although objective responses, according to RECIST criteria, were not observed, the disease control rate was 63%, with 12 patients achieving stable disease. Median time to progression (TTP) in this population was 4.5 months (range, 50-421 days), which was significantly greater statistically when compared with the historic median TTP of 2.1 months (P <.001).

The median overall survival (OS) was 6.8 months (range, 74-211 days) and median progression-free survival (PFS) was 4.3 months (range, 50-421 days).

Nearly half of the cohort (41%) experienced tumor volume reduction by RECIST criteria.

Mipsagargin is a derivative of the SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) pump inhibitor, thapsigargin, which has been linked to a masking peptide that targets the prostate-specific membrane antigen (PSMA). Cytotoxic activity is directed to PSMA-expressing cells by PSMA-mediated cleavage of the masking peptide, according to Devalingam Mahalingam, MD, Department of Hematology/Oncology, University of Texas Health in San Antonio.

“HCC is a highly-vascularized tumor and tumor angiogenesis is essential to its growth. This high degree of vascularization may make HCC particularly sensitive to therapies targeting it. PSMA is expressed on epithelial cells within the tumor vasculature, but is not expressed in the vasculature of the normal liver. Therefore, PSMA-targeting agents may be particularly relevant in HCC,” he explained.

Within 2 cycles of mipsagargin exposure, blood flow in HCC lesions and at metastatic sites was nearly halved. An assessment of blood flow metrics done in 11 lesions from 5 patients determined that all lesions showed a reduction in blood flow, demonstrating an average 52% (range, 13%-90%) reduction in Ktrans.

“Mipsagargin is a PSMA-activated, thapsigargin-based pro-drug that disrupts blood flow in HCC tumors that may provide clinical benefit in patients with advanced, sorafenib-refractory HCC,” said Mahalingam.

He emphasized the rationale behind developing mipsagargin: “HCC is frequently diagnosed at an advanced stage, when surgical resection is only suitable for approximately 5% of patients. The kinase inhibitor sorafenib is the only accepted treatment for unresectable HCC; unfortunately, efficacy with sorafenib is modest with median survival times of less than 11 months.”

This multicenter, single-arm, phase II study was conducted in patients with advanced sorafenib-refractory HCC who received mipsagargin intravenously on days 1, 2 and 3 of a 28-day cycle until disease progression or unacceptable toxicity.

The primary study objective was to evaluate the effect of second-line mipsagargin on TTP. Secondary objectives included tumor response rate, PFS, and OS. Tumor blood flow was measured in consenting patients via dynamic contrast enhanced MRI before and after cycle 2 of treatment. Blood flow metrics were described by quantitation of Ktrans and evidence of decreased arterial phase hyper-enhancement.

The median patient age was 64 years (range, 51-73 years) and ECOG PS was 0 in 32% of patients and PS 1 in 68% of patients. Child-Pugh scores of 5, 6, 7, and 8 were recorded for 10 (40%), 8 (32%), 6 (24%), and 1 (4%) patients, respectively.

All 25 patients in the safety cohort reported at least 1 drug-related adverse event (AE). Serious AEs were reported for 14 patients; of these, 5 (20%) were considered treatment-related.

The most frequently reported AEs included increased blood creatinine, which occurred in 68% of patients, and fatigue was reported by 56% of patients. Nausea and increased alanine aminotransferase were each reported by 44% of patients. Increased aspartate aminotransferase, increased bilirubin, decreased appetite, and pruritus were each reported in 40% of patients.

“Despite the advanced stage of disease of the enrolled patient population, the majority of patients experienced disease stabilization,” Mahalingam summarized. “Taken together, the observation of disease stabilization, decreased tumor blood flow, and prolonged TTP demonstrate that mipsagargin may have clinical activity in patients with advanced, refractory HCC.”

“These results provide rationale for future studies combining mipsagargin with VEGF inhibitors,” he commented.

Mahalingam D, Peguero J, Cen P, et al. Mipsagargin, a PSMA-directed prodrug, provides clinical benefit in patients with advanced sorafenib-refractory hepatocellular carcinoma. Presented at: 2017 International Liver Congress; April 19-23, 2017; Amsterdam, Netherlands. Abstract THU-073.

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