NEW YORK, April 10, 2021 / PRNewswire / – Elevation oncology, a clinical-stage biopharmaceutical company focused on the development of precision drugs for patients with genomically defined cancers, today announced the presentation by its collaborators at the Marc Ladanyi laboratory of Memorial Sloan Kettering (MSK) of new preclinical data on specific inhibition of NRG1 fusion – induced tumorigenesis and signaling by seribantumab, a HER3 monoclonal antibody, at the American Association of Cancer Research 2021 virtual annual meeting. These data (Odintsov et al., 2021) in xenograft models derived from patients (PDX) of NRG1 Pancreas and Fusion Positive Cholangiocarcinoma Build on Previous Studies Generated in Lung and Ovary NRG1 PDX fusion models, recently published in Clinical Cancer Research, and further support the mechanistic rationale for the phase 2 CRESTONE study for patients with solid tumors of any origin harboring a NRG1 gene fusion. The CRESTONE study is currently being recruited at sites across United States.
“Here, we observed that NRG1 fusions activated HER3 and downstream signaling mediators such as AKT in a pancreatic cell line,” said Igor odintsov, MD, MSK researcher and lead author of the poster presentation. “Seribantumab treatment was able to inhibit phosphorylation of activated HER3 and AKT in the same cell line, and subsequent treatment of a APP-NRG1 The positive fusion pancreatic PDX model with seribantumab strongly inhibited tumor growth at clinically feasible doses. “
Regressions were observed in all mice treated with 10 mg / kg of seribantumab BIW, equivalent to a clinical dose of 2.6 g of seribantumab in humans by allometric scaling. As in the previous analysis in the lung and ovary NRG1 PDX fusion, the pan-ERBB inhibitor afatinib was used as an active control in this PDX pancreatic model. No regression was observed in PDX pancreatic tumors treated with afatinib 5 mg / kg once daily.
NRG1 fusions have been identified in a variety of solid tumors, including lung, pancreas, gallbladder, breast, ovarian, colorectal, neuroendocrine, cholangiocarcinomas, and sarcomas. Current data suggests that NRG1 fusions are primarily mutually exclusive with other alterations known to the driver and are therefore considered to be the primary driver of tumor growth and proliferation.
“The scarcity of competing oncogenic factors in tumors caused by a NRG1 fusion presents a strong biological rationale for the use of a targeted anti-HER3 monotherapy approach across tumor types. This approach is reflected in the design of our Phase 2 CRESTONE study as a non-tumor monotherapy study of seribantumab with pre-defined exclusion of patients whose tumors harbor multiple exploitable conductor alterations, ”said Shawn M. Leland, PharmD, RPh, Founder and CEO of Elevation Oncology. “In rare cases where multiple exploitable conductor alterations are identified in the same tumor, we believe there may be a similar biological rationale for treating each conductor alteration by combinations of agents targeting each individual alteration, rather than by traditional combinations with chemotherapy. excited to report the first results of the preclinical exploration of this hypothesis, and we look forward to the pursuit of the search for new treatment paradigms informed by a full genomic profile of tumors. “
“We used a RBPMS-NRG1 PDX model of fusion cholangiocarcinoma which also contained mutations in both ERBB4 and IDH1“, Continued Dr Odintsov.” While treatment with seribantumab or afatinib monotherapy in this model produced mixed results, applying a triple combination of seribantumab with afatinib to target the entire ERBB family and AG-120 to target the mutation IDH1, we were able to perform regressions in the majority of tumors. This suggests that tumors harboring multiple oncogenic factors may benefit from combination therapy that addresses the contribution of each genomic alteration in disease progression. ”
Overall, the data reported support the use of seribantumab as monotherapy to treat gastrointestinal and other cancers due solely to NRG1 merger in the ongoing CRESTONE phase 2 study. Patients and physicians can learn more about the CRESTONE study at www.NRG1fusion.com or at www.ClinicalTrials.gov under NCT number NCT04383210.
About elevation oncology
Elevation oncology is based on the belief that every patient living with cancer deserves to know what is causing their disease to grow and to have access to treatments that can stop it. We aim to make genomic testing actionable by selectively developing drugs to inhibit specific alterations that have been identified as drivers of tumor growth. Together with our peers, we are working for a future in which the result of each tumor’s unique genomic test can be combined with a precision drug specifically designed to enable an individualized treatment plan for each patient. Our lead candidate, seribantumab, is intended to inhibit tumor growth induced by NRG1 fusions and is currently under evaluation in the phase 2 CRESTONE study for patients with solid tumors of any origin having a gene fusion. NRG1. Details on CRESTONE are available at www.NRG1fusion.com. For more information, visit www.ElevationOncology.com.
About seribantumab and NRG1 gene fusions
Seribantumab is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3). HER3 is traditionally activated by binding of its primary ligand, neuregulin-1 (NRG1). NRG1 gene fusion is a rare genomic alteration that combines NRG1 with another partner protein to create chimeric NRG1 “fusion proteins”. The NRG1 fusion protein is often also capable of activating the HER3 pathway, leading to unregulated cell growth and proliferation. It is important to note that NRG1 gene fusions are primarily mutually exclusive with other known genomic mutations and are considered to be a unique oncogenic motor event associated with tumor cell survival.
NRG1 fusions have been identified in a variety of solid tumors, including lung, pancreas, gallbladder, breast, ovaries, colorectals, neuroendocrines, cholangiocarcinomas, and sarcomas. In preclinical experiments, seribantumab prevented activation of HER3 signaling in cells that harbor a NRG1 gene fusion. In addition to extensive characterization and non-clinical testing, seribantumab has been administered to 847 patients in twelve Phase 1 and 2 studies, both as monotherapy and in combination with various cancer therapies. Seribantumab is currently being evaluated in the Phase 2 CRESTONE study for patients with solid tumors of any origin with NRG1 fusion.
About the CRESTONE study
Clinical study of the response to seribantumab in tumors with neuregulin-1 (NRG1) fusions. CRESTONE is a phase 2, tumor-independent “basket trial” of seribantumab in patients with solid tumors who harbor an NRG1 fusion and who have progressed after at least one prior line of standard treatment. The main objective of the study is to describe the antitumor activity and the safety of seribantumab as monotherapy, specifically in patients whose solid tumor is caused only by a fusion of the NRG1 gene. CRESTONE provides a clinical trial opportunity for patients with advanced solid tumors who have not responded or are no longer responding to treatment. Patients are encouraged to talk to their doctor about genomic testing of their tumor. CRESTONE is open and subscribes today to United States. For more information, visit www.NRG1fusion.com.
For more information, please contact:
Last name: David Rosen, Argot Partners
Telephone: +1 (716) 371-1125
E-mail: [email protected]
SOURCE Elevation Oncology