PracticeUpdate Oncology May 2019

CONFERENCE COVERAGE 30

DKN-01 Antibody Appears Promising inWnt-Activated Recurrent GynecologicMalignancies DKN-01 promotes antitumor immune activity by inhibiting DKK1.

A n anti-Dickkopf-1 (DKK) antibody known as DKN-01 has demonstrated partial responses and tumor reduc- tions as monotherapy and in combination with chemotherapy. DKN-01 has been well tolerated with no new safety signals and appears to exert enhanced activity in patients with Wnt-ac- tivated advanced recurrent gynecologic malignancies, finds an ongoing, multi- center, phase II basket study. Rebecca C. Arend, MD, PhD, of the Univer- sity of Alabama at Birmingham, told Elsevier’s PracticeUpdate , “We are impressed with the clinical activity of DKN-01 and its safety profile as seen so far. Tumors with Wnt path- way alterations and elevated DKK1 have responded to DKN-01 in other cancers, and our hypothesis is that they may respond to DKN-01 in gynecological cancers as well.” Dr. Arend and colleagues are studying patients with recurrent endometrial can- cer or platinum-resistant/refractory ovarian cancer. Approximately 50% of patients har- bor tumors with Wnt signaling alterations, including stabilizing β-catenin mutations. Patients with advanced endometrial or ovarian cancer are assigned to one of the following: • DKN-01 300 mg on days 1 and 15 as monotherapy • DKN-01 300 mg on days 1 and 15 + weekly paclitaxel (80 mg/m 2 on days 1, 8, and 15 of a 28-day cycle) The primary endpoint is the number of patients whose tumors have decreased >30% from baseline, (objective response rate). Secondary endpoints include the rate of objective disease control, which includes response and stable disease outcomes, overall and progression-free survival, safety, and pharmacokinetics/ pharmacodynamics. The study also includes genetic analysis of Wnt signaling alterations and DKK1 expres- sion levels as predictive biomarkers. A total of 62 patients have been enrolled and are receiving one of the following:

" Tumors withWnt pathway alterations and elevated DKK1 have responded to DKN-01 in other cancers, and our hypothesis is that they may respond to DKN-01 in gynecological cancers as well. "

chemotherapy (n=1) and unrelated vasova- gal syncope (n=1). Dr. Arend explained, “Wnt/β-catenin signal- ing is frequently dysregulated in the tumors of patients with gynecologic malignancies and is associated with poor prognosis. Mutations that result in constitutive Wnt/β- catenin pathway activation can also lead to elevated levels of DKK1.” She continued, “DKN-01 is a humanized monoclonal antibody that targets this pro- tein. DKN-01 is a Wnt pathway modulator that can suppress the immune system’s ability to target cancer.” Stabilizing mutations in CTNNB1, the gene that encodes for β-catenin, result in con- stitutive pathway activation and elevated DKK1. DKN-01 is a humanized monoclonal antibody targeting DKK1. Dr. Arend concluded that preliminary genetic tumor analysis of enrolled patients has demonstrated that approximately 52% harbor stabilizing β-catenin mutations and/ or Wnt signaling alterations. “Results we’ve seen thus far,” Dr. Arend concluded, “are very encouraging. The study has enrolled very rapidly over the past few months, and we look forward to seeing the data mature throughout the year in this cohort of patients with recurrent endometrial or platinum-resistant/refractory ovarian cancer.” www.practiceupdate.com/c/81357

One patient with Wnt-altered endometrial cancer achieved a 37.5% reduction in tumor burden after 8 months of therapy. In all, 6 patients (n=2 with Wnt-altered endometrial cancer, n=2 with Wnt-altered ovarian can- cer, n=2 with nonaltered ovarian cancer) achieved stable disease for >6 weeks. Of 41 patients who have received DKN-01 + paclitaxel, 26 patients were evaluable with post-baseline imaging. A 46-year-old patient with recurrent uter- ine carcinosarcoma was treated previously with neoadjuvant carboplatin and adjuvant paclitaxel, debulking surgery, and cispla- tin + radiotherapy for advanced recurrent disease. After receiving DKN-01 + paclitaxel, her first scans revealed 61% reduction in tumor bur- den with resolution of lung nodules known to be Wnt driven. In addition, 15 patients who received com- bination therapy have experienced stable disease of >6 weeks duration. No treatment-related serious adverse events have been reported. Most treatment-emergent adverse events have been grade 1/2. Those reported in more than one patient have been arthral- gia, constipation, fatigue, hypokalemia, and lymphopenia (n=2 each). Grade ≥3 treatment-emergent adverse events have included lymphocytope- nia related to DKN-01 + platinum-based

• DKN-01 monotherapy (n=21) • DKN-01 + paclitaxel (n=41)

Overall, 12 of the 21 patients who have received DKN-01 monotherapy ae evalu- able with post-baseline imaging.

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