OncoMed’s demcizumab fails to meet primary endpoint in pancreatic cancer trial

OncoMed Pharmaceuticals’ demcizumab (anti-DLL4, OMP-21M18) has failed to meet its primary endpoint in the Phase 2 YOSEMITE clinical trial in combination with Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in previously untreated metastatic pancreatic cancer patients.

The randomized Phase 2 “YOSEMITE” trial was designed to assess the efficacy and safety of demcizumab plus standard-of-care chemotherapy in first-line metastatic pancreatic cancer with the primary endpoint of progression-free survival and a secondary endpoint of overall survival.

The trial did not meet the primary endpoint of progression-free survival.  Additionally, the interim median overall survival analysis did not show a benefit for demcizumab in combination with Abraxane plus gemcitabine compared to the Abraxane, gemcitabine plus placebo arm in patients with first-line metastatic pancreatic cancer.

Paul J. Hastings, Chairman and CEO of OncoMed Pharmaceuticals said: “Patients in all three arms of the Phase 2 YOSEMITE trial surpassed the published median overall survival rates for Abraxane plus gemcitabine in first-line metastatic pancreatic patients.

“While the interim median overall survival was 13.2 months in the pooled demcizumab arms, the interim median overall survival of Abraxane plus gemcitabine was not reached at the time of these analyses.  Based on the lack of benefit over standard-of-care, which performed remarkably well, we will be discontinuing this trial.

“We will conduct additional analyses, together with our partner, Celgene, to understand these outcomes.  We will also discontinue any additional enrollment in our other ongoing demcizumab trials and conduct analyses of the data from those trials as planned.

“OncoMed remains focused on completing and analyzing the results of the two randomized Phase 2 clinical trials, PINNACLE and DENALI, that are anticipated in the first half of this year and in continuing the advancement of our portfolio of biotherapeutic candidates.”

Summary of Key Findings

Progression-Free Survival:  The median progression-free survival (mPFS) was essentially the same across all arms of the study.  For patients receiving demcizumab (either one or two truncated courses) in combination with Abraxane plus gemcitabine the mPFS was 5.5 months compared to a mPFS of 5.5 months for those in the Abraxane, gemcitabine plus placebo group (HR=0.93).

In addition, no significant differences were observed when the individual treatment arms were compared to the Abraxane, gemcitabine plus placebo arm: in patients receiving a single truncated course of demcizumab the mPFS was 5.4 months (HR=1.03), and the mPFS was 5.5 months (HR=0.83) in patients receiving two truncated courses of demcizumab.

Interim Overall Survival:  The interim median overall survival (mOS) for patients receiving either one or two truncated courses of demcizumab in combination with Abraxane plus gemcitabine (n =136) was 13.2 months, while a mOS was not reached for the Abraxane, gemcitabine plus placebo arm (HR=1.02).

No significant differences were observed when the individual treatment arms were compared:  an interim mOS of 10.6 months was observed with a single course of demcizumab (n=71) (HR=1.2) and an interim mOS of 13.3 months was seen among patients receiving two courses of demcizumab (n=65) (HR=0.87).

These results are based on an analysis that occurred at the 125th PFS event at which time there were 75 deaths.

Response and Clinical Benefit Rates:  Overall response rate (defined as complete responses and partial responses) was 33.1% (45 of 136 patients) in the combined demcizumab, Abraxane plus gemcitabine groups and 41.2% (28 of 68 patients) in the Abraxane, gemcitabine plus placebo group.

The overall clinical benefit rate (defined as complete responses, partial responses and stable disease) was slightly higher in the pooled demcizumab arms at 74.3% (101 of 136 patients) compared to 70.6% (48 of 68 patients) in the Abraxane, gemcitabine plus placebo group.  Response was measured using the RECIST 1.1 criteria and is based on unconfirmed investigator assessment.

Safety and tolerability:  Demcizumab, Abraxane plus gemcitabine were generally well tolerated with nausea, diarrhea, anemia and fatigue being the most common reported toxicities.

The incidence of Grade 3 or greater heart failure, pulmonary hypertension and bleeding were (3.7% vs. 0%), (0.7% vs 0%) and (8.1% vs. 1.5%) in the pooled demcizumab, Abraxane plus gemcitabine arms and the Abraxane, gemcitabine plus placebo arm, respectively.

Robert Stagg, PharmD, Senior Vice President of Clinical Research and Development said: “Pancreatic cancer has proven to be a uniquely challenging disease, and these data appear to reflect some of those disease and treatment complexities.

“The safety data seen in the YOSEMITE trial were generally consistent and in line with our expectations.  We continue to analyze these data, and look forward to presenting the full study findings at a future scientific congress.

“We would like to sincerely thank the patients and their families, investigators and staff for their support and participation in this study.”

About the Phase 2 YOSEMITE Trial

The randomized Phase 2 “YOSEMITE” trial was designed to assess the efficacy and safety of demcizumab in combination with Abraxane plus gemcitabine, compared to Abraxane, gemcitabine plus placebo in first-line pancreatic cancer patients with metastatic disease.

Two-hundred and seven patients were randomized and 204 patients were treated in one of three study arms: 1) Abraxane,  gemcitabine plus placebo, 2) Abraxane, gemcitabine plus one 70-day truncated course of demcizumab (given once every 2 weeks with the last dose given on Day 70) or 3) Abraxane, gemcitabine plus two 70-day truncated courses of demcizumab (separated by a 98 day period without demcizumab) with the last demcizumab dose given on day 238.

The primary endpoint of YOSEMITE was progression-free survival.  Secondary and exploratory endpoints were overall survival, response rate, pharmacokinetics, immunogenicity, safety and biomarker analyses.

The YOSEMITE Phase 2 trial was conducted at 49 clinical sites in the U.S., Canada, Europe and Australia.  OncoMed initiated YOSEMITE in April 2015 and completed enrollment of patients in September 2016.