Alignment with US Food and Drug Administration
on a Recommended Phase 2 Dose for NVL-520 of 100 mg daily
CAMBRIDGE, Mass., Sept. 5,
2023 /PRNewswire/ -- Nuvalent,
Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical
company focused on creating precisely targeted therapies for
clinically proven kinase targets in cancer, today announced the
initiation of the Phase 2 portion of ARROS-1, its Phase 1/2
clinical trial of NVL-520 for patients with ROS1-positive non-small
cell lung cancer (NSCLC) and other solid tumors, following
alignment with the US Food and Drug Administration (FDA) on a
recommended Phase 2 dose (RP2D) of 100 mg daily.
NVL-520 is a novel brain-penetrant ROS1-selective tyrosine
kinase inhibitor (TKI) created with the aim to simultaneously
overcome the clinical challenges of emergent treatment resistance,
off-target central nervous system (CNS) adverse events associated
with TRK inhibition, and brain metastases that may limit the use of
currently available ROS1 TKIs.
"The ARROS-1 trial was designed to support a seamless transition
from first-in-human dose-exploration in a heavily pre-treated
population to a Phase 2 portion designed with the potential to
support registration. We are thrilled to achieve this milestone
towards our goal of bringing a potential best-in-class therapy to
patients with ROS1-positive NSCLC as efficiently as possible," said
Darlene Noci, A.L.M., Chief
Development Officer at Nuvalent.
"The Phase 2 portion of the ARROS-1 trial includes multiple
cohorts which enable the parallel investigation of NVL-520 for
patients with ROS1-positive NSCLC who are either TKI naïve or
pre-treated with a ROS1 TKI," Ms. Noci continued. "Support for the
Phase 2 cohort design includes the demonstrated nonclinical
activity of NVL-520 in the periphery and in the CNS, and its
selective inhibition of ROS1 and ROS1 drug-resistance mutant G2032R
over the structurally-related TRK kinases. Combined with the broad
clinical activity and favorable tolerability observed to date in
heavily pre-treated patients in the Phase 1 portion of ARROS-1, we
believe there is the potential for NVL-520 to provide durable
responses while minimizing adverse events and dose limiting
toxicities for patients with ROS1-positive cancers throughout the
treatment paradigm."
In the Phase 1 portion of ARROS-1, six dose levels (25 mg to 150
mg daily) of NVL-520 were evaluated in heavily pre-treated patients
with ROS1-positive solid tumors. A maximum tolerated dose (MTD) was
not reached, and no clinically significant exposure-response
relationships for safety and efficacy were observed across the dose
levels evaluated. The RP2D of 100 mg daily maintained steady state
plasma levels above all target efficacy thresholds (ROS1 wild type
and ROS1 G2032R in both the periphery and in the CNS).
"With the advancement of the first of our parallel lead programs
into a Phase 2 trial with registrational intent, the Nuvalent team
demonstrates its continued ability to scale while maintaining
ambitious timelines towards our goal of delivering precisely
targeted therapies to patients with cancer," said James Porter, Ph.D., Chief Executive Officer at
Nuvalent. "We look forward to providing an update from the ARROS-1
trial at a medical meeting in 2024."
ARROS-1 Phase 2 Design
The Phase 2 portion of the ARROS-1 trial will be conducted
globally across North America,
Europe, Asia and Australia with planned enrollment of
approximately 225 TKI naïve and TKI pre-treated patients with
ROS1-positive NSCLC and other solid tumors. The single arm, open
label Phase 2 cohorts are designed to evaluate NVL-520 across the
treatment paradigm for patients with ROS1-positive NSCLC, and
include both potentially registration-directed pivotal cohorts and
an additional exploratory cohort:
- Potential Pivotal Cohorts
-
- Cohort 2a: Patients with advanced/metastatic
ROS1-positive NSCLC naïve to TKI therapy. Up to one prior line of
chemotherapy and/or immunotherapy is allowed.
- Cohort 2b: Patients with
advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1
TKI (either crizotinib or entrectinib) and no prior chemotherapy or
immunotherapy allowed.
- Cohort 2c: Patients with advanced/metastatic
ROS1-positive NSCLC treated with 1 prior ROS1 TKI (either
crizotinib or entrectinib) and 1 prior line of platinum-based
chemotherapy with or without immunotherapy.
- Cohort 2d: Patients with advanced/metastatic
ROS1-positive NSCLC treated with at least 2 prior ROS1
TKIs (with crizotinib or entrectinib as the initial ROS1 TKI) and
up to 1 line of chemotherapy and/or immunotherapy.
- Exploratory Cohort
-
- Cohort 2e: Patients with any advanced/metastatic
ROS1-positive solid tumor (including patients with ROS1-positive
NSCLC not otherwise eligible for any other cohorts) and progressed
on any prior therapy (includes, but is not limited to, patients who
have progressed on prior ROS1 TKIs).
Additional details can be found on www.clinicaltrials.gov
(NCT05118789).
Selection of NVL-520 RP2D
The selection of 100 mg daily as the RP2D for NVL-520 was
discussed and supported by FDA based on clinical data from the
Phase 1 dose escalation portion of the ARROS-1 trial with a data
cut-off of May 17, 2023. These data
included a safety database of 87 ROS1-positive patients enrolled
across six dose levels from 25 mg to 150 mg daily, including 37
patients at dose levels of ≥100 mg daily. The selection was based
on the following considerations:
- The dose level of 100 mg daily maintained steady state plasma
levels above all target efficacy thresholds (ROS1 wild type and
ROS1 G2032R in both the periphery and in the CNS).
- Favorable tolerability of NVL-520 was observed across all dose
levels to date.
- No clinically significant exposure-response relationships for
safety and efficacy were observed across the dose levels evaluated
(25 mg – 150 mg daily).
Based on these data, early anti-tumor activity continued to be
observed in ROS1-positive NSCLC patients, including objective
responses (RECIST 1.1) in heavily pre-treated patients, patients
previously treated with lorlatinib or repotrectinib, patients with
ROS1 G2032R resistance mutations, and patients with CNS metastases.
A favorable preliminary safety profile continued to suggest the
potential for a highly ROS1-selective, TRK sparing design. Overall,
the company believes these findings to be consistent with the
conclusions from a preliminary data disclosure in October 2022 with data cut-off date of
September 13, 2022, and believes that
these data continue to support the opportunity for NVL-520 as a
potential best-in-class therapy that may be able to move up the
treatment paradigm for patients with ROS1-positive NSCLC.
The company expects to share an update from the ARROS-1 trial at
a medical meeting in 2024.
About NVL-520
NVL-520 is a brain-penetrant
ROS1-selective inhibitor designed to remain active in tumors that
have developed resistance to currently available ROS1 inhibitors,
including tumors with the prevalent G2032R resistance mutation and
those with the S1986Y/F, L2026M, or D2033N resistance mutations.
NVL-520 has been designed for brain penetrance to potentially
improve treatment options for patients with brain metastases.
NVL-520 has been observed in preclinical studies to selectively
inhibit wild-type ROS1 and its resistance variants over the
structurally related tropomyosin receptor kinase (TRK) family to
potentially avoid TRK-related CNS adverse events seen with dual
TRK/ROS1 inhibitors and drive more durable responses for patients.
NVL-520 is currently being investigated in the ARROS-1 trial
(NCT05118789), a first-in-human Phase 1/2 clinical trial for
patients with advanced non-small cell lung cancer (NSCLC) and other
solid tumors.
About Nuvalent
Nuvalent, Inc. (Nasdaq: NUVL) is a
clinical-stage biopharmaceutical company focused on
creating precisely targeted therapies for patients
with cancer, designed to overcome the limitations of existing
therapies for clinically proven kinase targets. Leveraging deep
expertise in chemistry and structure-based drug design, we develop
innovative small molecules that have the potential to overcome
resistance, minimize adverse events, address brain metastases, and
drive more durable responses. Nuvalent is advancing a robust
pipeline with parallel lead programs in ROS1-positive and
ALK-positive non-small cell lung cancer (NSCLC), a program in
HER2 Exon 20 insertion-positive cancers, and multiple
discovery-stage research programs. We routinely post information
that may be important to investors on our website
at www.nuvalent.com. Follow us on Twitter (@nuvalent)
and LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, implied and
express statements regarding Nuvalent's strategy, business plans,
and focus; the expected timing of data announcements; the
preclinical and clinical development programs for NVL-520 and other
product candidates; the potential clinical effect of NVL-520; the
design and enrollment of the ARROS-1 trial, including its intended
pivotal registration-directed design; the potential of NVL-520;
Nuvalent's research and development programs for the treatment of
cancer; and risks and uncertainties associated with drug
development. The words "may," "might," "will," "could," "would,"
"should," "expect," "plan," "anticipate," "aim," "goal," "intend,"
"believe," "expect," "estimate," "seek," "predict," "future,"
"project," "potential," "continue," "target" or the negative of
these terms and similar words or expressions are intended to
identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Drug
development and commercialization involve a high degree of risk,
and only a small number of research and development programs result
in commercialization of a product. You should not place undue
reliance on these statements or the scientific data presented.
Any forward-looking statements in this press release are based
on management's current expectations and beliefs and are subject to
a number of risks, uncertainties, and important factors that may
cause actual events or results to differ materially from those
expressed or implied by any forward-looking statements contained in
this press release, including, without limitation: risks that
Nuvalent may not fully enroll the ARROS-1 trial or that enrollment
will take longer than expected; unexpected concerns that may arise
from additional data, analysis, or results obtained during
preclinical studies or clinical trials, including ARROS-1; the risk
that results of earlier ARROS-1 clinical trials may not be
predictive of the results of later-stage clinical trials; the risk
that the data from the ARROS-1 Phase 2 trial may not be sufficient
to support registration and that Nuvalent may be required to
conduct one or more additional studies or trials prior to seeking
registration of NVL-520; the occurrence of adverse safety events;
risks of unexpected costs, delays, or other unexpected hurdles;
risks that Nuvalent may not be able to nominate drug candidates
from its discovery programs; the direct or indirect impact of
public health emergencies or global geopolitical circumstances on
the timing and anticipated timing and results of Nuvalent's
clinical trials, strategy, and future operations, including the
ARROS-1 trial; the timing and outcome of Nuvalent's planned
interactions with regulatory authorities; and risks related to
obtaining, maintaining, and protecting Nuvalent's intellectual
property. These and other risks and uncertainties are described in
greater detail in the section entitled "Risk Factors" in the
Company's Quarterly Report on Form 10-Q for the quarterly period
ended June 30, 2023, as well as any prior and subsequent
filings with the Securities and Exchange Commission. In addition,
any forward-looking statements represent Nuvalent's views only as
of today and should not be relied upon as representing its views as
of any subsequent date. Nuvalent explicitly disclaims any
obligation to update any forward-looking statements.
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SOURCE Nuvalent, Inc.