Alignment with US Food and Drug Administration
on a Recommended Phase 2 Dose for NVL-655 of 150 mg once
daily
Phase 2 Designed with Registrational Intent
for TKI Pre-Treated Patients with ALK-Positive NSCLC and Enables
Preliminary Evaluation in the TKI-naïve Setting
CAMBRIDGE, Mass., Feb. 12,
2024 /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 ALKOVE-1, its Phase 1/2 clinical trial of
NVL-655 for patients with ALK-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 150 mg once daily (QD).
NVL-655 is a novel brain-penetrant ALK-selective tyrosine kinase
inhibitor (TKI) created with the aim to simultaneously overcome the
clinical challenges of emergent treatment resistance, brain
metastases, and off-target central nervous system (CNS) adverse
events associated with inhibition of the structurally-related
tropomyosin receptor kinase (TRK) family that may limit the use of
currently available ALK TKIs.
In the Phase 1 portion of ALKOVE-1, six dose levels (15 mg to
200 mg QD) of NVL-655 were evaluated in heavily pre-treated
patients with ALK-positive solid tumors, and a maximum tolerated
dose was not reached. The RP2D of 150 mg QD maintained steady state
plasma levels above target efficacy thresholds (ALK wild type
fusions and ALK single and compound mutations in both the periphery
and in the CNS).
"The transition of our NVL-655 program into Phase 2 advances a
second, parallel opportunity towards our goal of bringing potential
best-in-class therapies to patients as efficiently as possible,"
said Darlene Noci, A.L.M., Chief
Development Officer at Nuvalent. "This sense of urgency is
reflected in the thoughtful design of the Phase 2 portion of the
ALKOVE-1 trial which aims to accelerate the clinical investigation
that may support a potential marketing application towards an
initial approval for previously treated patients with ALK-positive
NSCLC. The Phase 2 portion also includes a TKI-naïve cohort which
may provide an opportunity to generate early data, and could be
conducted in parallel with a front-line registration-directed
trial."
Ms. Noci continued, "Support for the design of the
Phase 2 cohorts includes the broad clinical activity and favorable
tolerability observed to date in heavily pre-treated patients in
the Phase 1 portion of ALKOVE-1. Combined with the demonstrated
nonclinical activity of NVL-655 in the periphery and in the CNS,
and its selective inhibition of ALK and ALK single and compound
drug-resistance mutations over the structurally-related TRK
kinases, we believe there is the potential for NVL-655 to provide
durable responses while minimizing adverse events and dose limiting
toxicities for patients with ALK-positive cancers throughout the
treatment paradigm."
"With today's announcement, we've delivered on the first of the
key 2024 milestones laid out in our OnTarget 2026 operating plan,
an achievement made possible by the tireless dedication of our team
to our mission of delivering precisely targeted therapies to
patients with cancer," said James
Porter, Ph.D., Chief Executive Officer at Nuvalent.
"With all of our programs, our goal is to not only address the
existing medical needs for later-line patients but to ultimately
deliver therapies that can move up the treatment paradigm, and
our multi-pronged development strategy for NVL-655 exemplifies this
approach. We look forward to sharing an update from the ALKOVE-1
trial as well as more detail on our broader front-line development
strategy for ALK later this year."
ALKOVE-1 Phase 2 Design
The Phase 2 portion of the ALKOVE-1 trial will be conducted
globally across North America,
Europe, Asia, and Australia. The single arm, open label Phase 2
portion is designed with registrational intent for TKI pre-treated
patients with ALK-positive NSCLC and to enable preliminary
investigation for patients with ALK-positive NSCLC who are TKI
naïve. The Phase 2 cohorts are designed to evaluate NVL-655 in:
- TKI Pre-Treated ALK-Positive NSCLC
- 2 – 3 Prior TKIs: Patients with locally advanced or
metastatic NSCLC harboring an ALK rearrangement, who have received
2-3 prior ALK TKIs. Up to 2 prior lines of chemotherapy and/or
immunotherapy are allowed.
- 1 Prior 2G TKI: Patients with locally advanced or
metastatic NSCLC harboring an ALK rearrangement who have received 1
prior second-generation (2G) ALK TKI (ceritinib, alectinib, or
brigatinib). Up to 2 prior lines of chemotherapy and/or
immunotherapy are allowed.
- 1 Prior 3G TKI: Patients with locally advanced or
metastatic NSCLC harboring an ALK rearrangement, who have received
lorlatinib (third-generation, 3G) as the only prior ALK TKI
therapy. Up to one prior line of chemotherapy and/or immunotherapy
received prior to lorlatinib is allowed.
- TKI-Naïve ALK-Positive NSCLC
- Patients with locally advanced or metastatic NSCLC harboring an
ALK rearrangement, who are naïve to ALK TKI therapy. Up to one
prior line of chemotherapy and/or immunotherapy is allowed.
- Other
- Other ALK-Positive NSCLC: Patients with locally advanced
or metastatic NSCLC harboring an ALK rearrangement, not eligible
for other Phase 2 cohorts.
- Other ALK-Positive Solid Tumors: Patients with other
solid tumors harboring an ALK rearrangement or activating ALK
mutation, who have received ≥1 prior systemic anticancer therapy,
or for whom no satisfactory standard therapy exists.
Additional details can be found on www.clinicaltrials.gov
(NCT05384626).
Selection of NVL-655 RP2D
The selection of 150 mg QD as the RP2D for NVL-655 was supported
by the FDA based on clinical data from the Phase 1 dose escalation
portion of the ALKOVE-1 trial. The company believes that the
preliminary Phase 1 data support the opportunity for NVL-655 as a
potential best-in-class therapy that may be able to move up the
treatment paradigm for patients with ALK-positive NSCLC.
The selection was based on the following considerations:
- The dose level of 150 mg QD maintained steady state plasma
levels above target efficacy thresholds (ALK wild type fusions and
ALK single and compound mutations in both the periphery and in the
CNS).
- Favorable tolerability of NVL-655 was observed at the 150 mg QD
dose level, continuing to suggest the potential for a highly
ALK-selective, TRK sparing safety profile.
- Early anti-tumor activity was observed in ALK-positive NSCLC
patients across a broad range of doses, including 150 mg QD.
Objective responses (RECIST 1.1) were observed in heavily
pre-treated patients including patients who had received one or
more second-generation TKIs (alectinib, brigatinib, or ceritinib)
plus lorlatinib, patients who were lorlatinib-naïve, patients with
ALK single and compound resistance mutations, and patients with CNS
metastases.
Preliminary Phase 1 data were presented in October 2023, and the company expects to share an
update from the ALKOVE-1 trial at a medical meeting in 2024.
About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor
created with the aim to overcome limitations observed with
currently available ALK inhibitors. NVL-655 is designed to remain
active in tumors that have developed resistance to first-, second-,
and third-generation ALK inhibitors, including tumors with both
single or compound treatment-emergent ALK mutations such as G1202R.
In addition, NVL-655 is designed for central nervous system (CNS)
penetrance to improve treatment options for patients with brain
metastases, and to avoid inhibition of the structurally related
tropomyosin receptor kinase (TRK) family. Together, these
characteristics have the potential to avoid TRK-related CNS adverse
events seen with dual TRK/ALK inhibitors and to drive deep, durable
responses for patients across all lines of therapy. NVL-655 has
received orphan drug designation for ALK-positive non-small cell
lung cancer (NSCLC) and is currently being investigated in the
ALKOVE-1 clinical trial (NCT05384626), a first-in-human Phase 1/2
clinical trial for patients with advanced ALK-positive NSCLC and
other solid tumors.
About OnTarget 2026
OnTarget 2026 delineates Nuvalent's 3-year operating plan
towards bringing new, potential best-in-class medicines to patients
with cancer. As part of this plan announced in January 2024, Nuvalent outlined the following
anticipated milestones throughout 2024, leading to the company's
first potential pivotal data in 2025 and first potential approved
product in 2026:
- 2024: Execute on Global Registrational Strategies
- Progress the Phase 2 portion of the ARROS-1 trial of NVL-520 in
patients with advanced ROS1-positive NSCLC with registrational
intent;
- Initiate the Phase 2 portion of the ALKOVE-1 trial of NVL-655
in patients with advanced ALK-positive NSCLC, including cohorts in
pretreated patients with registrational intent;
- Launch the front-line development strategy for its ALK
program;
- Present interim data from the ongoing ARROS-1 and ALKOVE-1
clinical trials at medical meetings; and,
- Initiate the Phase 1 trial for its HER2 program.
- 2025: First Pivotal Data
- 2026: First Approved Product
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 investigational
candidates for ROS1-positive, ALK-positive, and HER2-positive
non-small cell lung cancer, and multiple discovery-stage research
programs.
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, clinical
trial initiations, and FDA product approvals; the preclinical and
clinical development programs for NVL-520, NVL-655 and NVL-330; the
potential clinical effect of NVL-655; the design and enrollment of
the ARROS-1 and ALKOVE-1 trials, including their intended pivotal
registration-directed design; the potential of Nuvalent's pipeline
programs, including NVL-520, NVL-655 and NVL-330; the implications
of data readouts and presentations; timing and content of potential
discussions with regulators and investigators; the design and
timing of the planned Phase 2 portion of the ARROS-1 and ALKOVE-1
trials; Nuvalent's research and development programs for the
treatment of cancer; and risks and uncertainties associated with
drug development. The words "may," "might," "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 or ALKOVE-1 trials 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; the risk that
results of earlier clinical trials may not be predictive of the
results of later-stage clinical trials; the risk that data from our
clinical trials 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 our product
candidates; the occurrence of adverse safety events; risks that the
FDA may not approve our potential products on the timelines we
expect, or at all; 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 and ALKOVE-1 trials; the timing and outcome
of Nuvalent's planned interactions with regulatory authorities;
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 Nuvalent's Quarterly Report on Form 10-Q for the quarterly
period ended September 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.
View original content to download
multimedia:https://www.prnewswire.com/news-releases/nuvalent-initiates-the-phase-2-portion-of-alkove-1-clinical-trial-for-patients-with-alk-positive-nsclc-and-other-solid-tumors-302059149.html
SOURCE Nuvalent, Inc.