OncoMed Pharmaceuticals is reassessing its portfolio strategy following its second set of setbacks in as many weeks. OncoMed today acknowledged that its cancer candidate tarextumab—part of a collaboration with GlaxoSmithKline (GSK)—failed a Phase II combination treatment trial, while halting a Phase Ib study for a second cancer candidate, brontictuzumab, recently passed on by GSK.

The new setbacks come a week after OncoMed disclosed two negative events: Bayer opted not to license two OncoMed Wnt pathway inhibitor biologics designed to fight cancer, while OncoMed halted a failed Phase II trial assessing demcizumab (anti-Delta-like ligand 4 [anti-DLL4], OMP-21M18) in a combination cancer therapy.

“Based on the events of today and last week, we will be undertaking a comprehensive portfolio prioritization review immediately,” OncoMed chairman and CEO Paul J. Hastings said in a statement.

Tarextumab missed its primary endpoint of progression-free survival (PFS) in the Phase II PINNACLE trial assessing the candidate in combination with etoposide plus either cisplatin or carboplatin chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer.

Results for the combination of tarextumab plus chemotherapy showed no differentiation from those of chemotherapy plus placebo, OncoMed said.

PINNACLE enrolled 145 patients who received either 15 mg/kg of tarextumab every 3 weeks in combination with six cycles of etoposide and either cisplatin or carboplatin chemotherapy, followed by tarextumab maintenance to progression or six cycles of chemotherapy and a placebo.

Median PFS (mPFS) for tarextumab plus chemotherapy was 5.6 months versus 5.5 months for chemotherapy plus placebo. The median overall survival (mOS) analysis did not show a benefit for tarextumab in combination with chemotherapy compared to the chemotherapy plus placebo arm (10.3 months). 

In addition, five individual Notch biomarkers (Hes1, Hes6, Hey1, Hey2, and Notch3) failed to identify a definitive subset of patients with a treatment effect on either mPFS or mOS.  Overall response rates were 68.5% and 70.8% in the tarextumab and placebo arms, respectively.

“Small-cell lung cancer is a very difficult-to-treat disease, and unfortunately tarextumab did not show benefit over placebo in this Phase II trial,” Hastings said.

Tarextumab, also called OMP-59R5, is a novel anticancer stem cell antibody designed to work by preventing signaling through both the Notch2 and Notch3 receptors. In preclinical models, tarextumab inhibited cancer stem cell growth, promoted cell differentiation, and disrupted tumor angiogenesis by inhibiting vascular pericytes.

Up to $344.5M GSK Collaboration

Tarextumab is being developed through a collaboration launched in 2007 with GSK that gives the pharma giant an option to obtain an exclusive license to the candidate during certain time periods through completion of proof-of-concept Phase II trials.

OncoMed has been eligible for up to $344.5 million in milestone and contingent payments related to tarextumab, including a $25 million opt-in payment and research, development, regulatory, and commercialization payments, in addition to royalties in the low double digits to high teens on net product sales.

As of December 31, 2016, OncoMed earned $25 million in milestone payments from GSK related to tarextumab, according to OncoMed’s Form 10-K Annual report for 2016.

OncoMed would regain rights to tarextumab if GSK elects not to exercise its options, or if it terminates the program. “We expect to submit a data package designed to inform GSK’s option decision regarding tarextumab in the first half of 2017,” OncoMed stated in the Form 10-K.

The GSK collaboration was originally announced in 2007 as a four-candidate, up to $1.4 billion partnership, but was narrowed in 2011 to two compounds, tarextumab and brontictuzumab. On October 31, 2016, GSK told OncoMed it was terminating its option for an exclusive license to develop and commercialize brontictuzumab effective January 29, returning its rights to OncoMed.

OncoMed also said today it was halting enrollment of patients in a Phase Ib clinical trial assessing brontictuzumab in combination with trifluridine/tipiracil (Lonsurf®) in third-line colorectal cancer patients.

“The combination of brontictuzumab plus chemotherapy was not tolerable in this patient population,” OncoMed stated, without offering details.

Brontictuzumab, also called OMP-52M51, is a novel anticancer stem cell antibody designed to work by binding the Notch1 receptor. Blocking Notch1 has been shown in preclinical models to inhibit cancer stem cell growth and promote cell differentiation, as well as to disrupt tumor angiogenesis, according to OncoMed.

Notch1 signaling is prevalent in several solid tumor types, including certain breast, esophageal, colorectal, gastric, pancreatic, and small-cell lung cancers, as well as adenoid cystic carcinoma and cholangiocarcinoma.

“The immediate task ahead is to thoroughly examine the available data, our resources, and the opportunities to refocus our efforts,” Hastings added. “We ended the first quarter of 2017 with $156.9 million in cash and short-term investments.”

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