Monotherapy Demonstrates Promising Clinical Activity in Endometrial Cancer

New clinical trial results presented at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer has found clinical activity of DKN-01 monotherapy in patients with endometrial cancer, according to Leap Therapeutics.

DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein, which activates the innate immune system in the tumor microenvironment and anti-tumor activity, according to the company. The trial results found clinical activity with DKN-01 both as a monotherapy and in combination with paclitaxel (Abraxane; Bristol Myers Squibb) in patients with advanced gynecological malignancies.

“DKN-01 demonstrated objective responses, including a monotherapy complete response continuing now for over 2 and a half years, and durable tumor reductions as a single agent and in combination with paclitaxel in the advanced gynecologic cancer patients treated in the study,” said Rebecca Arend, MD, MSPH, an associate professor at the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, in a prepared statement. “The disease control rate and progression-free survival were strongest in patients whose tumors express high levels of DKK1 (DKK1-high), which is a group that real world evidence has shown to have poorer outcomes on other therapies.”

The P204 study (NCT03395080) was a phase 2 basket study evaluating DKN-01 in groups composed of epithelial endometrial cancer (EEC), epithelial ovarian cancer (EOC), or carcinosarcoma (MMMT) patients. The primary endpoint was overall response rate (ORR), and secondary endpoints include disease control rate (DCR) and progression-free survival (PFS). In each group, at least 50% of patients were required to have specified Wnt signaling pathway alterations, a subgroup of which are known to drive high tumoral DKK1 expression.

According to Leap Therapeutics, 111 patients were enrolled in the study, including 29 patients with EEC in a DKN-01 monotherapy group, 24 patients with EEC in a DKN-01 plus paclitaxel group, 14 patients with EOC in a DKN-01 monotherapy group, 19 patients with EOC in a DKN-01 plus paclitaxel group, 9 patients with MMMT in a DKN-01 monotherapy group, and 16 patients with MMMT in a DKN-01 plus paclitaxel group.

The investigators found that patients with EEC and patients with Wnt activating mutations express higher levels of DKK1 than patients with EOC. Among patients with EEC, patients with endometrioid histology had higher DKK1 expression than those with non-endometrioid histology, and patients whose tumors had Wnt activating mutations expressed 14.4 times higher levels of DKK1.

Furthermore, the found that DKN-01 has enhanced activity in patients whose tumors express high levels of DKK1. In the group of 22 patients with EEC treated with DKN-01 monotherapy for whom DKK1 expression data was available, patients with DKK1-high tumors had greater ORR, DCR, and median PFS compared to patients with DKK1-low tumors. In addition, 7 patients did not have DKK1 expression results available, of whom 1 had a complete response and 5 had a best response of stable disease, including 3 patients with Wnt activating mutations.

Within the EEC study population, DKN-01 activity was strongest in those with endometrioid histology, according to Leap Therapeutics. In the pooled group of 27 patients with endometrioid histology for whom DKK1 expression data was available, patients with DKK1-high tumors had greater DCR and median PFS than patients with DKK1-low tumors. Furthermore, 7 patients with endometrioid histology did not have DKK1 expression results available, of whom 1 had a complete response and 5 had a best response of stable disease, including 2 patients with Wnt activating mutations.

“The activity of DKN-01 in this study was comparable to the monotherapy data from other widely-used immuno-oncology or targeted therapies,” Arend said. “As DKN-01 was extremely well tolerated, additional studies of DKN-01 as a monotherapy and in combination with anti-PD-1 antibody therapy are warranted in endometrial cancer patients with DKK1-high tumors.”

REFERENCE

Leap Therapeutics Presents DKN-01 Clinical Data at the Society of Gynecologic Oncology 2021 Annual Meeting on Women’s Cancer [news release]. Leap Therapeutics; March 22, 2021. Accessed March 22, 2021. https://investors.leaptx.com/news-releases/news-release-details/leap-therapeutics-presents-dkn-01-clinical-data-society