Belapectin/Pembrolizumab Shows Early Activity, Tolerability in Metastatic Melanoma & Head and Neck Cancer

The combination of the galactin-3 inhibitor belapectin (GR-MD-02) plus pembrolizumab (Keytruda) has demonstrated early potential for disease control with acceptable tolerability in patients with metastatic melanoma and head and neck cancer, according to topine data from an extension cohort of an investigator-initiated phase 1b trial (NCT02575404).¹

Results showed that among 9 patients with melanoma, 1 patient had a partial response to the doublet, 4 achieved disease stability, and 4 experienced disease progression. The disease control rate (DCR) achieved with belapectin plus pembrolizumab was 56% (n = 5/9). In 5 patients with head and neck cancer, 2 patients achieved stable disease with the doublet and 3 experienced disease progression; this translated to a DCR of 40% (n = 2/5).

“A very significant volume of data has recently accumulated demonstrating the nefarious role that galectin-3 plays in the tumor microenvironment to stimulate tumor progression,” Ben Carson, MD, Emeritus Professor of Oncology at the Johns Hopkins School of Medicine, and senior advisor to Galectin Therapeutics, stated in a press release. “More recently, we have been able to understand how the inhibition of galectin-3 helps to modify this microenvironment to possibly enhance the action of cancer immunotherapeutic endeavors while perhaps decreasing the adverse effects.”

Belapectin is a complex carbohydrate drug that targets galectin-3, which is a protein that plays an important role in the pathogenesis of NASH and fibrosis. Moreover, galectin-3 is involved in diseases like fibrotic disorders of the liver, lung, kidney, heart, and vascular system. The agent binds to galectin-3 and interrupts its function.

The patients enrolled to the extension trial were heavily pretreated, having received prior systemic therapy that included chemotherapy, immunotherapy, BRAF inhibitors or MEK inhibitors, as well as surgery and radiation. These patients also had a high burden of metastasis, with the most involved organs including the lungs, soft tissues, and the liver. Additionally, 4 of the 9 patients with melanoma had an ocular tumor as a primary site of their cancer and developed liver metastasis.

Patients were administered pembrolizumab per its label, followed by belapectin at 4 mg/kg of lean body mass, given every 3 weeks via infusion. Investigators assessed responses at day 85 per RECIST criteria. Patients with melanoma received a median of 4 treatment cycles (range, 3-15); those with head and neck cancer had a median of 5 treatment cycles (range, 4-8).

Regarding safety, the doublet was well tolerated. The most common pembrolizumab-related adverse effects (AEs) included grade 1 pruritus (n = 6) and grade 2 fatigue (n = 3). All other toxicities were reported to be just grade 1 in severity. No grade 3 or higher AEs occurred. Notably, no AE was noted to be associated with belapectin.

Earlier results from the study showed that the combination elicited an objective response rate of 50% in the patients with melanoma (n = 7/14) and 33% in those with head and neck squamous cell carcinoma (n = 2/6).² These data were found to compare favorably with what has been reported with single-agent pembrolizumab.

An analysis of tumor tissue collected from patients showed a reduction in monocytic myeloid-derived suppressor cells and an increase in effector memory T-cell activation in patients who responded to the doublet vs those who did not. Moreover, an increase in baseline expression of galectin-3–positive tumor cells was linked with clinical response to treatment.

“Patients in this extension cohort had a significantly higher tumor burden when enrolled as compared to the initial study, and I view these results as encouraging,” Brendan Curti, MD, principal investigator of the study, added in the press release. “These results of the extension cohort support the rationale to conduct a phase 2 randomized controlled study to further evaluate the combination of belapectin with [pembrolizumab] compared with [pembrolizumab] alone and fully establish the benefit and immunological effects of this combination.”

References

1. Galectin Therapeutics announces positive top-line results from a phase 1b clinical trial extension of belapectin in combination with KEYTRUDA in advanced melanoma and head and neck cancer. News release. Galectin Therapeutics, Inc. July 9, 2021. Accessed July 10, 2021. https://bit.ly/2Uxogzv
2. Curti BD, Koguchi Y, Leidner RS, et al. Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor. Journal ImmunoTher Cancer. 2021;9:e002371. doi:10.1136/jitc-2021-002371