On November 09, 2015 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) reported clinical and preclinical data related to three of its clinical-stage programs at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, OncoMed, NOV 9, 2015, View Source [SID:1234508139]). Data from three posters covered Phase 1a safety, biomarker and anti-tumor activity of brontictuzumab (anti-Notch1, OMP-52M51), novel biomarker discoveries related to vantictumab (anti-Fzd7, OMP-18R5) in non-small cell lung cancer (NSCLC) and preclinical characterization of safety and efficacy for anti-DLL4/VEGF bispecific (OMP-305B83).
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Brontictuzumab Phase 1a: Single-agent Activity in Biomarker-positive Patients; Manageable Safety Profile
Among the data presented were Phase 1a clinical trial results for brontictuzumab in patients with advanced solid tumors. Brontictuzumab demonstrated single-agent activity in a biomarker-selected refractory patient population. Among 15 patients whose tumors overexpressed the activated form of Notch1, as measured by OncoMed’s proprietary immunohistochemistry (IHC) test, eight patients achieved stable disease or partial response for an overall clinical benefit rate of 53 percent. Anti-tumor activity was observed in adenoid cystic carcinoma, colorectal cancer and HER2 negative breast cancer. Partial responses were observed in two patients with adenoid cystic carcinoma after just one dose of brontictuzumab. Among patients whose tumors measured high in Notch1 activation, five have survived 100 days or longer as of the data cut off. There are five additional Notch1 high patients that are currently ongoing on the study and OncoMed plans to present follow-up data on those patients when the data matures. In biomarker negative subjects, only one of 11 had clinical benefit (9%). Brontictuzumab was generally well tolerated, with the most common adverse event being on-target, manageable diarrhea. Notch pathway and cancer stem cell pathway markers were reduced in serial tumor biopsies and in surrogate patient samples (blood) at doses above 1.5 mg/kg every three weeks. The single agent Phase 2 dose of brontictuzumab was established as 1.5mg/kg every three weeks.
"We are very encouraged by this early evidence of single-agent activity of brontictuzumab in a refractory biomarker-selected patient population. Notch1 has been shown to be elevated in a variety of solid tumor types, including breast, colorectal, esophageal, cholangiocarcinoma, pancreatic, small cell lung and adenoid cystic carcinomas," said Jakob Dupont, M.D., OncoMed’s Senior Vice President, Chief Medical Officer. "Based on these results and the manageable safety profile, Phase 1b combination studies of brontictuzumab in combination with chemotherapy are being contemplated with a particular emphasis on the Notch1 biomarker positive subjects."
These data were presented by Pamela Munster, M.D., Professor of Medicine, Program Leader Development Therapeutics, and Director of Early Phase Clinical Trials’ Program Helen Diller Cancer Center of the University of California, San Francisco in a poster titled: Safety and preliminary efficacy results of a first-in-human Phase I study of the novel cancer stem cell (CSC) targeting antibody brontictuzumab (OMP-52M51, anti-Notch1) administered intravenously to patients with certain advanced solid tumors (Abstract #C42).
"This successful Phase 1 study of brontictuzumab has provided much insight into this drug candidate. We have learned about the safety profile that can be managed; we have evidence of on-target effects against the Notch pathway; and we have observed single-agent activity in biomarker-selected patients," said Dr. Munster. "Taken together, data from this study suggests that brontictuzumab has the potential to benefit patients and should be developed in future studies with standard of care, particularly in biomarker selected patients."
Vantictumab in Non-Small Cell Lung Cancer — Novel Biomarker Identified
In a preclinical patient-derived xenograft non-small cell lung cancer (NSCLC) model, OncoMed researchers confirmed the anti-tumor activity of vantictumab both as a single-agent and in combination with taxane treatment. Sequential dosing (the administration of vantictumab two days prior to treatment with paclitaxel) was more efficacious than same-day dosing. Pharmacodynamic biomarkers showed that vantictumab inhibits genes in cancer stem cell pathways that support its mechanism of action. Importantly, LEF1, a key transcription factor in the Wnt pathway was identified as a potential predictive biomarker for treatment response in patient-derived xenograft models. LEF1 is being retrospectively evaluated as a predictive biomarker in OncoMed’s ongoing Phase 1b clinical trial of vantictumab in combination with docetaxel in patients with previously treated NSCLC. Results of these studies were presented on Friday, November 6 in a poster titled: Predictive and pharmacodynamic biomarkers of vantictumab (OMP-18R5; anti-Frizzled7) in non-small cell lung cancer (Abstract #A30) by Ann Kapoun, Ph.D. of OncoMed.
Anti-DLL4/VEGF Bispecific — Superior Inhibition of Tumor Growth
Preclinical studies of OncoMed’s dual-targeting anti-DLL4/VEGF bispecific antibody in xenograft tumor models demonstrated superior anti-tumor activity compared to either anti-DLL4 and anti-VEGF antibodies alone. The combination of anti-DLL4 and anti-VEGF resulted in broad-spectrum activity in many different tumor types including breast, colon, ovarian and pancreatic tumors. In serial transplantation studies, the anti-DLL4/VEGF bispecific antibody showed a greater effect than anti-DLL4 alone in delaying tumor recurrence following the termination of treatment and reducing the frequency of cancer stem cells in the tumors. Researchers also observed that simultaneous inhibition of DLL4 and VEGF induced a down-regulation of vasculature-related genes and decreased vasculature density. The anti-DLL4/VEGF bispecific antibody showed an improved cardiac profile in cynomolgus monkeys compared to anti-DLL4 which may translate to an improved safety profile in the clinic. OncoMed is currently testing the anti-DLL4/VEGF bispecific in a Phase 1a clinical trial for patients with advanced refractory solid tumors. These data were presented by Wang-Ching Yen, Ph.D., of OncoMed in a poster titled: Dual targeting of the DLL4 and VEGF pathways with a bispecific monoclonal antibody inhibits tumor growth and reduces cancer stem cell frequency (Abstract #C134) on November 8, 2015.
"The results of studies presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting provide valuable information on optimal dosing of vantictumab plus taxane therapy and have identified a promising biomarker in the non-small cell lung cancer indication," said John Lewicki, Ph.D., Executive Vice President, Chief Scientific Officer. "And, in preclinical models, our bispecific is demonstrating robust anti-tumor activity against a number of tumor types and the combination of anti-DLL4 and anti-VEGF appears to have the potential to improve upon the cardiotoxicity profiles of either agent alone. We look forward to evaluating how these data translate into the clinic in our ongoing trials."
Brontictuzumab, vantictumab and the anti-DLL4/VEGF bispecific are novel investigational therapeutics currently being evaluated in ongoing clinical trials. Patients interested in learning more about participating in one of OncoMed’s many clinical trials may learn more by calling 1-866-914-7347 or emailing [email protected].