Leap Therapeutics Inc. said its anti-Dickkopf-1 (DKK1) antibody, DKN-01, in combination with the anti-PD-1 antibody Keytruda (pembrolizumab, Merck & Co. Inc.), turned up 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).

"We're very encouraged that our biomarker strategy is bearing fruit," Cyndi Sirard, vice president of clinical development, told BioWorld. Chief Operating Officer Gus Lawlor said the Cambridge, Mass.-based firm is "still evaluating the next steps, but our objective is to move into controlled clinical studies."

A multipart phase Ib experiment, the study tests DKN-01 as a monotherapy and with paclitaxel or Keytruda. Sixty-three patients were treated with DKN-01 plus Keytruda combo therapy across all arms and dose groups. Fifty-three patients had not received prior PD-1/PD-L1 therapy, and 10 patients were refractory to it. All of the patients enrolled had tumors that were microsatellite stable or unknown. Patients in the study were heavily pretreated, having received one to five prior lines of therapy, with nearly 64% having received a prior taxane regimen, 37% having been given Cyramza (ramucirumab, Eli Lilly and Co.), and 24% having received Herceptin (trastuzumab, Roche Holding AG).

The pairing demonstrated improved outcomes in patients whose tumors are DKK1-high as well as PD-1/PD-L1-naïve. DKK1-high patients experienced over 22 weeks median progression-free survival (PFS) and nearly 32 weeks overall survival (OS), with a 50% overall response rate and 80% disease control rate (DCR) in 10 evaluable patients. DKK1-low patients experienced nearly six weeks median PFS and more than 17 weeks OS, with a 20% DCR in 15 evaluable patients.

PD-L1 Combined Positive Scores (CPS) did not predict efficacy regarding the duo, but in a multivariate analysis, DKK1-high status correlated with longer PFS independent of PD-L1 CPS scores, the company said. 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 subjects had a best response of stable disease, whereas the three with DKK1-low tumors had progressive disease.

The combo therapy was well-tolerated with no new safety signals, and investigators have remarked positively on the profile. "We've been able to dose up to 600 mg in the past," Sirard said. "Given the activity we've seen at 300 mg, we're satisfied but curious" and will explore dosing further.

At the end of last month, Keytruda was cleared by the FDA as a monotherapy for patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. First approved by U.S. regulators in September 2014 for advanced melanoma, the compound has steadily added indications to the label.

ISTs prove 'growing interest'

Cancers targeted by the latest-to-report Leap study represent a major global burden, especially with advanced patients. Outside of rare microsatellite-instable tumors and Epstein-Barr virus-associated cancers, the response rates to immune checkpoint inhibitors are low and median PFS remains short, in the range of six to eight weeks, so doctors and patients need new combinations as well as biomarkers to predict who is most likely to benefit.

Leap is also conducting a phase I study to evaluate DKN-01 as a monotherapy or with paclitaxel in advanced gynecological cancers. The company plans to provide a clinical update from that study, which would include biomarker analysis of Wnt pathway mutations and expression of DKK1, in the third quarter of this year. Leap's anti-GITR product, TRX-518, is undergoing a phase I/II study with either gemcitabine, Keytruda or Opdivo (nivolumab, Bristol-Myers Squibb Co.) in patients with advanced solid tumors. Data are due in the fourth quarter.

A number of investigator-sponsored studies, disclosed and undisclosed, are ongoing in indications that include prostate cancer, which "reflects the growing interest in the target and more particularly growing interest in this antibody," Lawlor said. He acknowledged that Wall Street often has difficulty valuing early stage cancer combo studies, and shares (NASDAQ:LPTX) seemed to reflect as much, closing Tuesday at $1.77, down 31 cents or 15%. His firm is the leader in DKK1 research, he said.

But there's scientific probing in other quarters. This week, the nonprofit Cholangiocarcinoma Foundation awarded grants in the fifth cycle of its research fellowship program. Supported are seven projects, including one to the University of Edinburgh to deepen the understanding of DKK1/GRP78 interactions and the implications for the tumor microenvironment.

Findings in gastric cancer continue to roll out. In late June, the Journal of the American Medical Association Oncology published the results of a study showing the lifetime risk of gastric cancer for individuals with pathogenic variants in CDH1 is significantly lower than previously described. Overall, the lifetime risk of gastric cancer associated with pathogenic CDH1 variants was found to be 42% in males and 33% in females, compared to previously published estimates of 40% to 70% for males and 56% to 83% for females.

At the end of the first quarter, Leap had cash, cash equivalents and marketable securities totaling $21.7 million. Last month, the company entered stock purchase agreements for up to $21 million with Lincoln Park Capital Fund LLC (LPC), a Chicago-based institutional investor and current shareholder. LPC agreed to buy $1 million of Leap's registered common stock at a price of $1.75 per share, for net proceeds to the company of about $950,000.