NEW YORK, April 10, 2021 /PRNewswire/ -- Elevation
Oncology, a clinical stage biopharmaceutical company focused on the
development of precision medicines for patients with genomically
defined cancers, announced today the presentation by its
collaborators in the Marc Ladanyi lab at Memorial Sloan Kettering
(MSK) of further preclinical data on the specific inhibition of
NRG1 fusion-induced tumorigenesis and signaling by seribantumab, a
HER3 monoclonal antibody, at the American Association of Cancer
Research Virtual Annual Meeting 2021. These data (Odintsov et al.,
2021) in patient-derived xenograft (PDX) models of NRG1
fusion-positive pancreatic and cholangiocarcinoma build on earlier
studies generated in lung and ovarian NRG1 fusion PDX
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 an
NRG1 gene fusion. The CRESTONE study is currently enrolling
at sites across the 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,
Research Fellow at MSK and lead author of the poster presentation.
"Treatment with seribantumab was able to inhibit phosphorylation of
the activated HER3 and AKT in the same cell line, and subsequent
treatment of an APP-NRG1 fusion-positive pancreatic PDX
model with seribantumab robustly inhibited tumor growth at
clinically achievable doses."
Regressions were observed in all mice treated with 10 mg/kg BIW
seribantumab, equivalent to a clinical dose of 2.6 g seribantumab
in humans by allometric scaling. As in prior analysis in lung and
ovarian NRG1 fusion PDX models, the pan-ERBB inhibitor
afatinib was used as an active control in this pancreatic PDX
model. No regression was observed in pancreatic PDX tumors treated
with afatinib at 5 mg/kg QD.
NRG1 fusions have been identified in a variety of
solid tumors, including lung, pancreatic, gallbladder, breast,
ovarian, colorectal, neuroendocrine, cholangiocarcinomas, and
sarcomas. Current data suggest that NRG1 fusions are
predominantly mutually exclusive with other known driver
alterations and are therefore considered to be the primary driver
of the tumor's growth and proliferation.
"The rarity of competing oncogenic drivers in tumors driven by
an NRG1 fusion presents a strong biological rationale for
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 tumor-agnostic study of monotherapy
seribantumab with pre-defined exclusion of patients whose tumors
harbor multiple actionable driver alterations," said Shawn M. Leland, PharmD, RPh, Founder and Chief
Executive Officer of Elevation Oncology. "In rare instances when
multiple actionable driver alterations are identified in the same
tumor, we believe there may be a similar biological rationale for
addressing each driver alteration through combinations of agents
targeted to each individual alteration, rather than the traditional
combinations with chemotherapy. We are excited to report early
results from preclinical exploration of this hypothesis, and look
forward to continued investigation of new treatment paradigms
informed by comprehensive genomic profiling of tumors."
"We utilized an RBPMS-NRG1 fusion cholangiocarcinoma PDX
model that also contained mutations in both ERBB4 and
IDH1," continued Dr. Odintsov. "While treatment with
monotherapy seribantumab or afatinib in this model produced mixed
results, by applying a triple combination of seribantumab with
afatinib to target the entire ERBB family, and AG-120 to target the
IDH1 mutation, we were able to achieve regressions in the majority
of tumors. This suggests that tumors harboring multiple oncogenic
drivers may benefit from combination therapy that addresses the
contribution of each genomic alteration in disease
progression."
In totality, the data reported support the use of monotherapy
seribantumab to treat GI and other cancers that are uniquely driven
by an NRG1 fusion in the ongoing Phase 2 CRESTONE study.
Patients and physicians can learn more about the CRESTONE study at
www.NRG1fusion.com or on www.ClinicalTrials.gov under the NCT
number NCT04383210.
About Elevation Oncology
Elevation Oncology is
founded on the belief that every patient living with cancer
deserves to know what is driving the growth of their disease and
have access to therapeutics that can stop it. We aim to make
genomic tests actionable by selectively developing drugs to inhibit
the specific alterations that have been identified as drivers of
tumor growth. Together with our peers, we work towards a future in
which each tumor's unique genomic test result can be matched with a
purpose-built precision medicine to enable an individualized
treatment plan for each patient. Our lead candidate, seribantumab,
is intended to inhibit tumor growth driven by NRG1 fusions and is
currently being evaluated in the Phase 2 CRESTONE study for
patients with solid tumors of any origin that have an NRG1 gene
fusion. 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 through binding of its primary ligand, neuregulin-1
(NRG1). The 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 able to
activate the HER3 pathway, leading to unregulated cell growth and
proliferation. Importantly, NRG1 gene fusions are predominantly
mutually exclusive with other known genomic driver mutations and
are considered a unique oncogenic driver event associated with
tumor cell survival.
NRG1 fusions have been identified in a variety of solid
tumors, including lung, pancreatic, gallbladder, breast, ovarian,
colorectal, neuroendocrine, cholangiocarcinomas, and sarcomas. In
preclinical experiments, seribantumab prevented the activation of
HER3 signaling in cells that harbor an NRG1 gene fusion. In
addition to extensive nonclinical characterization and testing,
seribantumab has been administered to 847 patients across twelve
Phase 1 and 2 studies, both as a monotherapy and in combination
with various anti-cancer therapies. Seribantumab is currently being
evaluated in the Phase 2 CRESTONE study for patients with solid
tumors of any origin that have an NRG1 fusion.
About the CRESTONE Study
Clinical Study of
Response to Seribantumab in Tumors with Neuregulin-1 (NRG1)
Fusions. CRESTONE is a Phase 2 tumor-agnostic "basket trial" of
seribantumab in patients with solid tumors that harbor an NRG1
fusion and have progressed after at least one prior line of
standard therapy. The primary objective of the study is to describe
the anti-tumor activity and safety of seribantumab as a monotherapy
specifically in patients whose solid tumor is uniquely driven by an
NRG1 gene fusion. CRESTONE offers 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 enrolling today in the United
States. For more information visit www.NRG1fusion.com.
For further information, please contact:
Elevation
Oncology
Name: David Rosen,
Argot Partners
Phone: +1 (716) 371-1125
Email: media@ElevationOncology.com
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