On April 6, 2021 Elevation Oncology, a clinical stage biopharmaceutical company focused on the development of precision medicines for patients with genomically defined cancers, reported the publication in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), of peer-reviewed data in support of the scientific rationale for the Phase 2 CRESTONE study for patients with solid tumors of any origin that have an NRG1 fusion (Press release, Elevation Oncology, APR 6, 2021, View Source [SID1234577611]). The CRESTONE study is currently enrolling at sites across the United States.
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The manuscript titled "The anti-HER3 monoclonal antibody seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic NRG1 fusions," can be accessed online here: Odintsov et al., Clinical Cancer Research 2021
"With this work, we aimed to expand the biological understanding of NRG1 fusions as an oncogenic driver and the importance of broad inhibition of downstream signaling activated through ERBB family complexes involving HER3 (ERBB3) in tumors driven by NRG1 rearrangements," said Igor Odintsov, MD, Research Fellow, Memorial Sloan Kettering Cancer Center (MSK), lead author, who performed these studies with Romel Somwar, PhD, Senior Research Scientist in the Ladanyi Lab at MSK. "Given that HER3 is required for NRG1 fusion-driven tumor growth but does not have an active kinase domain to directly target with small molecule antagonists, targeting HER3 with an antibody is an attractive therapeutic strategy."
The study results reported in the manuscript suggest that targeted inhibition of HER3 with the anti-HER3 mAb seribantumab is not only able to inhibit ligand-dependent activation by the NRG1 fusion protein but also to de-stabilize the entire subsequent ERBB and downstream signaling pathways that drive tumor growth and proliferation, leading to significant tumor regression of 50 – 100% in NRG1 fusion models. Notably, the entire biologically effective dose range observed in these models of 1 mg BIW – 10 mg BIW seribantumab falls below the equivalent human dosage of seribantumab currently being used in clinical trials. In contrast, similar tumor regression in response to afatinib, a pan-ERBB inhibitor, was only observed at 15 mg/kg QD, above the recommended dose of afatinib for patients based upon allometric scaling.
Seribantumab is currently being clinically evaluated in the tumor-agnostic Phase 2 CRESTONE trial for patients with solid tumors harboring an NRG1 fusion. CRESTONE is currently open and enrolling patients across the United States. The primary objective of the study is to describe the Objective Response Rate (ORR) of seribantumab by independent central radiographic review, and key secondary endpoints are Duration of Response (DoR) and safety.
"We thank our collaborators at MSK for their rigorous evaluation of therapeutic approaches for this rare, genomically defined patient population, and their commitment to developing the novel NRG1 fusion models that enable targeted preclinical investigation of seribantumab," said Shawn Leland, PharmD, RPh, Founder and CEO of Elevation Oncology. "This publication represents the first peer-reviewed data in support of the specific development of seribantumab for patients whose solid tumors are driven by an NRG1 fusion, showing that across these preclinical models of aggressive disease in various tumor types and fusion partners, direct inhibition of HER3 by seribantumab shows potential to generate significant and durable anti-cancer effects at clinically achievable doses."