Leap Announces Positive Results for DKN-01, Keytruda Combination

Leap Therapeutics announced its anti-Dickkopf-1 (DKK1) antibody, DKN-01, in combination with Merck's anti-PD-1 antibody, Keytruda® (pembrolizumab), demonstrated higher survival and objective response outcomes in patients with advanced gastroesophageal junction and gastric cancer (GEJ/GC) whose tumors expressed high levels of DKK1 (DKK1-high).

DKN-01 plus Keytruda therapy achieved over 22 weeks median progression-free survival (PFS) and nearly 32 weeks median overall survival (OS) with a 50% overall response rate (ORR) and 80% disease control rate (DCR) in patients with DKK1-high GEJ/GC who had not received prior anti-PD-1/PD-L1 therapy.

"Gastric and gastroesophageal junction cancers represent a major global cancer burden with significant unmet needs, particularly in patients with advanced disease. Outside of rare microsatellite instable tumors and EBV-associated cancers the response rates to immune checkpoint inhibitors are low and median progression free survival remains short, in the range of 6-8 weeks. Oncologists and patients are eager for new therapeutic combinations and biomarkers to help predict patients most likely to benefit from a given treatment," Samuel J. Klempner, MD, Assistant Professor, Massachusetts General Hospital Cancer Center and Harvard Medical School said.

"The responses and early survival data seen in DKK1-high patients treated with DKN-01 plus pembrolizumab are highly encouraging," said Dr. Klempner. "This study builds on previously reported positive monotherapy and paclitaxel combination data and importantly suggests that elevated DKK-1 expression is a potential predictive biomarker. DKN-01 warrants further study in gastroesophageal cancers in combination with immune checkpoint inhibitors and with chemotherapy."

The esophagogastric cancer clinical trial is a multipart study of DKN-01 as a monotherapy and in combination with paclitaxel or pembrolizumab. Sixty-three patients were treated with DKN-01 plus Keytruda combination therapy across all arms and dose groups of the study. Fifty-three patients had not received prior PD-1/PD-L1 therapy, and ten patients were refractory to PD-1/PD-L1 therapy. All of the patients enrolled had tumors that were microsatellite stable or unknown. Patients in the study were heavily pretreated having had received one to five prior lines of therapy, with nearly 64% having received a prior taxane regimen, 37% having received prior ramucirumab, and 24% having received prior trastuzumab. The combination therapy was well tolerated with no new safety signals.

The combination of DKN-01 and Keytruda in GEJ/GC patients demonstrated improved outcomes in patients whose tumors are DKK1-high and who were PD-1/PD-L1 naïve. DKK1-high patients experienced over 22 weeks median PFS and nearly 32 weeks OS, with a 50% ORR and 80% DCR in ten evaluable patients. DKK1-low patients experienced nearly 6 weeks median PFS and over 17 weeks OS, with a 20% DCR in fifteen evaluable patients.

PD-L1 Combined Positive Scores (CPS) did not predict efficacy on the combination of DKN-01 plus Keytruda. In multi-variate analysis, DKK1-high status correlated with longer PFS independent of PD-L1 CPS scores. One-third of patients in the study were DKK1-high.

Among the six GEJ/GC patients who were refractory to PD-1/PD-L1 therapy, three DKK1-high patients had a best response of stable disease, whereas the three patients with DKK1-low tumors had progressive disease.

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