Esophagogastric Cancer Patients with High DKK1 Levels Respond Better to DKN-01, Keytruda Combo, Phase 1 Trial Shows

A combination of Leap Therapeutics‘ investigational therapy DKN-01 plus Keytruda (pembrolizumab) led to “highly encouraging” responses and survival outcomes in a population of advanced esophagogastric cancer patients with elevated levels of the Dickkopf-1 (DKK1) protein, according to preliminary results of a Phase 1 clinical trial.

These results suggest that DKK1 levels might predict the efficacy of DKN-01, which is being tested in patients with esophagogastric, hepatobiliary, gynecologic, and prostate cancers.

DKN-01 is an immunotherapy that specifically reduces the levels of DKK1, a protein that is often elevated in several types of cancer. Cancer patients with high DKK1 have more aggressive disease and poorer outcomes.

DKK1 controls the Wnt signaling pathway, which is essential during embryonic development but is not active in most adult cells. However, cancer cells can reactivate this pathway, leading to uncontrolled division and suppression of the immune response.

By decreasing DKK1 levels, DKN-01 has the dual effect of causing tumor cell death and boosting the immune response against the tumor. DKN-01 is designed to work alone and in combination with chemotherapies and immunotherapies.

Leap has designed clinical trials to test DKN-01 in several solid tumors, including prostate cancer. An upcoming Phase 1/2 trial (NCT03837353) expects to enroll 97 men with castration-resistant prostate cancer who have high DKK1 levels to test the safety and efficacy of DKN-01 alone or in combination with chemotherapy.

The current preliminary results correspond to a Phase 1 trial (NCT02013154) testing the investigational treatment in combination with Keytruda or chemotherapy in patients with advanced gastroesophageal junction and gastric cancer.

The study showed that patients with high levels of DKK1 benefited more from the combination of DKN-01 and Keytruda than those with low DKK1.

Patients with high DKK1 had a median progression-free survival (the time without disease progression or death) of 22 weeks and an overall survival of 32 weeks, whereas those with low DKK1 survived a median of six weeks without progression and 17 weeks overall.

Half of the patients with elevated DKK1 responded to the combination, and 80% responded or achieved stable disease, whereas 20% of patients with low DKK1 achieved stable disease. The combination was generally well-tolerated.

“The responses and early survival data seen in DKK1-high patients treated with DKN-01 plus [Keytruda] are highly encouraging,” Samuel J. Klempner, MD, an assistant professor at Massachusetts General Hospital Cancer Center and Harvard Medical School, said in a press release.

“This study builds on previously reported positive monotherapy and paclitaxel combination data and importantly suggests that elevated DKK1 expression is a potential predictive biomarker,” he added.