Twice as nice

OncoMed’s preclinical comparison study shows improved antitumore, immune responses for bispecific antibody

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REDWOOD CITY, Calif.—OncoMed Pharmaceuticals Inc. presented new preclinical data for anti-DLL4 combined with anti-VEGF and anti-PD1, a combination targeted toward blocking potent tumor growth while enhancing immune-oncology activity, during the 2015 Society for Immunotherapy of Cancer Conference.
A series of preclinical experiments at the Nov. 9 event compared the impact of an anti-DLL4/VEGF bispecific and a triple blockade of DLL4-VEGF-PD1 on antitumor immune responses.  The combination of anti-DLL4/VEGF and anti-PD1 was found to have more potent antitumor and enhanced immuno-oncology activity than either agent alone, across a number of measures, according to the poster. The triple blockade of DLL4-VEGF-PD1 significantly inhibited tumor growth with more pronounced tumor regression, while the addition of anti-DLL4/VEGF also improved antitumor activity of anti-PD1 alone in both PD1-responsive and nonresponsive cancers in murine models.
“These data highlight the ability of the anti-DLL4/VEGF bispecific to combine with anti-PD1 and to modulate antitumor immune responses,” remarked Austin Gurney, senior vice president of molecular and cellular biology at OncoMed. “In addition to increased antitumor efficacy, we note an enhanced generation of memory T cell responses and reduced tumor-associated macrophages, showing that co-targeting of DLL4 and VEGF with PD1 might be an effective and durable anticancer therapy in part by promoting antitumor immune responses and inhibiting pro-tumor immune responses.”
DLL4 is a ligand within the Notch pathway and plays important roles in regulating cancer stem cells, tumor angiogenesis and pro-tumor immune responses. 
On Dec. 11, OncoMed presented new data on the development of a novel predictive biomarker for vantictumab at the San Antonio Breast Cancer Symposium, detailing the identification and validation of a novel six-gene signature assay being evaluated as a predictive biomarker of response to vantictumab plus paclitaxel in the treatment of breast cancer. Vantictumab is being studied in three Phase 1b combination clinical trials, including one with paclitaxel in patients with HER2-negative breast cancer.
“The research presented today is one example of OncoMed’s efforts to identify biomarkers early and aggressively that can be evaluated alongside our therapeutic candidates in order to optimize treatment regimens and patient outcomes,” commented John Lewicki, executive vice president and chief scientific officer of OncoMed. “In preclinical testing, the six-gene biomarker assay has been strongly predictive of antitumor responses to treatment with vantictumab in HER2-negative breast cancers.”
“If these results are corroborated in our ongoing clinical study of vantictumab in breast cancer, it will provide an excellent opportunity to develop a companion diagnostic and tailor vantictumab use to patients with the highest likelihood of benefit,” he added.
OncoMed has two clinical agents targeting DLL4: demcizumab, currently in Phase 2 trials for the treatment of pancreatic cancer and non-small cell lung cancer (NSCLC), and anti-DLL4/VEGF bispecific, currently in a Phase 1a trial in advanced solid tumors, Gurney tells DDNews. The combination of anti-DLL4/VEGF bispecific with anti-PD1 demonstrated a distinct mechanistic profile versus prior observations of the synergistic combination of anti-DLL4 and anti-PD1 presented at the American Association for Cancer Research 2015 Annual Meeting, suggesting potential for increased T cell activation, maintenance and memory T cell function.
“We are currently studying our anti-DLL4/VEGF bispecific in a Phase 1a dose-escalating clinical trial,” Gurney continued. “Depending on results from that study, we may consider future combination Phase 1b’s in collaboration with our partner, Celgene.”
The data presented at SITC “highlighted that the anti-DLL4/VEGF combination is highly active in preclinical antitumor efficacy studies, including against tumors that do not respond to anti-PD1,” Gurney said. “Additionally, the data highlighted that the anti-DLL4/VEGF combination can be combined with anti-PD1 to achieve increased anti-tumor activity.”
“It is notable that we observe activity of the anti-DLL4/VEGF combination against tumors that do not respond to anti-PD1,” he added.
OncoMed researchers also have “observed antitumor activity with the DLL4/VEGF bispecific across a broad range of tumor types in our preclinical studies,” according to Gurney. “These results help shape our understanding of how the DLL4/VEGF bispecific might be able to be paired with anti-PD1 agents,”
The pharmaceutical also presented clinical and preclinical data related to three of its clinical-stage programs at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Data from three posters covered Phase 1a safety, biomarker and antitumor activity of brontictuzumab, novel biomarker discoveries related to vantictumab in NSCLC and preclinical characterization of safety and efficacy for anti-DLL4/VEGF bispecific.
In the Phase 1a clinical trial 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, eight patients achieved stable disease or partial response, an overall clinical benefit rate of 53 percent. Anti-tumor activity was observed in adenoid cystic carcinoma, colorectal cancer and HER2 negative breast cancer.
A poster presented on Nov. 6 confirmed the antitumor activity of vantictumab, both as a single-agent and in combination with taxane treatment, in a preclinical patient-derived xenograft NSCLC model. Pharmacodynamic biomarkers showed that vantictumab inhibits genes in cancer stem cell pathways that support its mechanism of action.
A third poster reported on preclinical studies of OncoMed’s dual-targeting anti-DLL4/VEGF bispecific antibody in xenograft tumor models, which demonstrated superior antitumor activity compared to either anti-DLL4 and anti-VEGF antibodies alone. This combination also 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, decreased vascular density and demonstrated an improved cardiac profile in cynomolgus monkeys compared to anti-DLL4.

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