Novel Monoclonal Antibody Demonstrates Clinical Activity in Gynecologic Malignancies

DKN-01, a novel monoclonal antibody that targets the DKK1 gene, demonstrated clinically meaningful activity as a monotherapy and in combination with paclitaxel chemotherapy in treating patients with advanced gynecologic malignancies, according to findings from the phase II P204 clinical trial (NCT03395080), Leap Therapeutics announced in a press release.¹

"We are seeing clinically meaningful monotherapy activity of DKN-01 in heavily pre-treated endometrial cancer and carcinosarcoma populations, including a complete response, a partial response, and durable tumor reductions in many patients. In combination with paclitaxel, DKN-01 is generating durable responses and disease control in paclitaxel-experienced patients," said Rebecca Arend, MD, assistant professor and associate scientist, Gynecologic Oncology Clinic, The University of Alabama at Birmingham School of Medicine Comprehensive Cancer Center Experimental Therapeutics Program, in a statement.

Activity with DKN-01 monotherapy was shown in terms of progression-free survival (PFS) and overall survival (OS). Patients with Wnt mutations had a longer median PFS of 168 days compared with patients who did not have Wnt mutations, for whom the median PFS was only 56 days. The median OS was not reached in the Wnt-mutated group and was 328 days in the non-Wnt activating mutation group.

A difference in PFS and OS was also realized in patients with high DKK1 tumor expression versus those with DKK1-low tumors. The median PFS was 168 days in the DKK1-high group versus 56-day in the DKK1-low group. For OS, the median was 450 days in the DKK1-high group versus 276 days in the DKK1-low group.

"This study also demonstrates the importance of the mechanism of action-based biomarkers for DKN-01 therapy, as patients with high tumor DKK1 expression or Wnt activating mutations had enhanced progression-free survival and overall survival. These biomarkers should be the foundation for additional DKN-01 studies in [patients with] endometrial and carcinosarcoma, as monotherapy and in combination with other active agents," added Arend.

P204 is a basket study, which is evaluating the efficacy and safety of DKN-01 in patients with recurrent epithelial endometrial cancer (EEC), epithelial ovarian cancer (EOC), or carcinosarcoma. One of the primary end points of the study was ORR, and secondarily, the study is investigating mutations in the Wnt signaling pathway as well as DKK1 expression and predictive biomarkers of response to DKN-01 in gynecologic malignancies.

In a webcast held on April 23, Arend presented background information on DKN-01 as well as the study design and findings from P204.

Thus far, 51 patients have received DKN-01 monotherapy and 54 patients have received DKN-01 plus paclitaxel. In terms of tumor type, 29 patients in the monotherapy group had EEC, 14 had EOC, and 8 had carcinosarcoma. In the combination group, 25 patients had EEC, 19 had EOC, and 10 had carcinosarcoma.²

Patients in the 6-arm study were randomized to receive DKN-01 300 mg alone or in combination with paclitaxel. The fifth and sixth arms received DKN-01 600 mg or DKN-01 plus paclitaxel.

Overall, the agent was well tolerated as monotherapy or in combination with paclitaxel. The most common treatment-emergent adverse events (TEAEs) with monotherapy were nausea (43.8%) and fatigue (43.8%). The most common TEAEs for combination therapy were anemia (35.0%), fatigue (32.5%), diarrhea (30.0%), and nausea (25.0%). Serious adverse events occurred in 4.5% of patients who received monotherapy and 6.4% of patients who received combination therapy. Serious TEAEs determined to be DKN-01 related were nausea (2.3%) and active kidney injury (2.3%) in the monotherapy group and hypokalemia (2.1%), anemia (2.1%), paresthesia (2.1%), and colitis (2.1%) in the combination group. No TEAEs lead to death in the study.

According to Arend, there is good scientific rationale behind using DKN-01 for treatment of patients with gynecologic malignancies. Wnt/beta-catenin mutations, which have a high prevalence in gynecologic cancers, activate signaling pathways. Activation of these pathways triggers expression and multiple target genes, including DKK1, ultimately causing metastasis. DKK1 is an important target for cancer because it inhibits canonical Wnt signaling, activates nonconical signaling, and activates PI3K/AKT signaling. DKK1 also creates an immunosuppressive tumor microenvironment by decreasing activated natural killer (NK) cells and increasing myeloid-derived suppressor cell accumulation.

The mechanisms of action of DKN-01 include a direct anti-tumor effect, activation of the innate immune response, and acting as an anti-angiogenic agent. Because of these actions, DKN-01 is likely to incite responses from Wnt activating tumors.

Aside from gynecologic malignancies, DKN-01 is also being studied in combination with tislelizumab (Tisle) and xelox (Capox) in patients with esophagogastric cancer, with docetaxel in patients with prostate cancer, with nivolumab (Opdivo) in patients with biliary tract cancer, with atezolizumab (Tecentriq) in patients with esophagogastric cancer, and in combination with sorafenib (Nexavar) in patients with hepatocellular carcinoma.

_References

_{1. Leap Therapeutics to present updated data for dkn-01 monotherapy and paclitaxel combination in gynecologic cancers [new release]. Cambridge, Massachusetts: Leap Therapeutics; April 23, 2020. https://bit.ly/2S2Ry4R. Accessed April 23, 2020.}

_{2. Arend, R and Sirard C. DKN-01 Gynecologic Cancers Program Update Call & Webcast. Leap Therapuetics website. https://bit.ly/2xU7Tlt. Accessed April 23, 2020.}