Encouraging preliminary signs of activity
observed in heavily pre-treated patients with ALK-positive NSCLC,
including in subgroups of patients who have previously received a
2nd generation ALK TKI and lorlatinib, have brain
metastases, or have single or compound ALK resistance
mutations
Favorable preliminary safety profile is
consistent with an ALK-selective, TRK sparing design
Company to host a conference call today,
October 13, at 8:00am EDT
CAMBRIDGE, Mass., Oct. 13,
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 updated
preliminary data from the Phase 1 dose-escalation portion of its
ongoing ALKOVE-1 Phase 1/2 clinical trial of NVL-655 for patients
with advanced ALK-positive non-small cell lung cancer (NSCLC) and
other solid tumors. These data will be presented today at the
35th AACR-NCI-EORTC (ANE) Symposium in Boston, Massachusetts.
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 tropomyosin receptor kinase (TRK) inhibition
that may limit the use of currently available ALK TKIs.
"Significant advancements have been made with the development of
three generations of ALK TKIs, and the five ALK inhibitors that are
currently FDA-approved provide important treatment options for
patients with advanced ALK fusion-positive cancers. However, some
limitations remain with the available therapies, ranging from
association with TRK-related neurologic adverse events that can
limit adequate coverage of ALK single resistance mutations to the
emergence of refractory compound mutations following sequential
treatment with ALK TKIs," said presenting investigator
Jessica J. Lin, M.D., Assistant
Professor of Medicine, Harvard Medical
School and Attending Physician, Mass General Cancer
Center. "These preliminary data support the potential for
NVL-655 as an ALK-selective inhibitor that may combine, for the
first time, potent and selective targeting of diverse ALK fusions
and secondary ALK resistance mutations, including single and
compound mutations involving G1202R and I1171N, brain penetrance,
and the avoidance of TRK inhibition that can be dose limiting."
As of the enrollment and data cut-off date of August 8, 2023 for the preliminary data, 93
patients have been enrolled in the Phase 1 portion of the ALKOVE-1
trial across six evaluated dose levels of NVL-655 ranging from 15
mg once daily (QD) to 200 mg QD. Enrollment in the Phase 1 portion
of the trial is ongoing.
Preliminary activity data as of the cut-off date were available
from 51 heavily pre-treated response-evaluable NSCLC patients. The
objective response rate (ORR) by RECIST 1.1 was 39% (20/51) of
patients treated at all doses, of which all were partial responses
(4 pending confirmation). In the subset of 41 patients treated at
dose levels of 50 mg QD or higher, the ORR was 44% (18/41).
To evaluate key target characteristics of NVL-655, activity was
examined in subgroups of the 51 response-evaluable patients treated
at all doses, including:
- Patients with any history of CNS metastases (ORR 52%,
15/29);
- Patients with any ALK resistance mutation (ORR 54%,
15/28), including those with compound ALK mutations (ORR 56%, 9/16)
and those with ALK G1202R single or compound mutations (ORR 71%,
12/17);
- The most heavily pre-treated of patients, after receiving ≥3
prior ALK TKIs including at least one 2nd
generation (2G) ALK TKI (alectinib, brigatinib, or ceritinib) plus
lorlatinib, and prior chemotherapy (ORR 42%, 8/19); and,
- Lorlatinib-naïve patients who had received at least one 2G +/-
1G ALK TKI (ORR 71%, 5/7).
Preliminary pharmacokinetic (PK) analyses were available for
dose levels 15 mg QD to 150 mg QD. Treatment with NVL-655 resulted
in exposure above target efficacy thresholds in both the periphery
and in the CNS. These preliminary PK data suggest that dose levels
of 50 mg QD and above may provide increased coverage of single and
compound mutations in the CNS. Preliminary pharmacodynamic analysis
showed that NVL-655 induced clearance of diverse ALK resistance
mutation alleles across a wide dose range.
As of the cut-off date for the preliminary data, 67% (34/51) of
response-evaluable patients remained on treatment with NVL-655 with
duration of treatment up to 12 months (median duration of treatment
of 3.4 months). All patients with tumor response continued on
treatment without disease progression. NVL-655 was well-tolerated
with a preliminary safety profile that was favorable and consistent
with its ALK-selective, TRK sparing design.
"We are excited to present the first look at the safety and
clinical activity of NVL-655 from our ALKOVE-1 clinical trial,
which we believe supports the potential for NVL-655 to address each
key area of its desired target product profile," said
Christopher Turner, M.D., Chief
Medical Officer of Nuvalent. "Across a wide dose range, NVL-655
demonstrated activity in a heavily pre-treated patient population
that uniquely includes patients in the post-lorlatinib setting,
with a favorable preliminary safety profile consistent with its
ALK-selective, TRK sparing design. Importantly, all patients with
tumor response remained on treatment without disease progression as
of the data cut-off date, suggesting the potential for durable
responses even in this late line population."
Dr. Turner continued, "Ultimately, we view the ability to
keep patients on therapeutically relevant dose levels as a key
indicator of the potential for NVL-655 to drive clinically
meaningful durable responses when used earlier in the treatment
paradigm. In earlier lines of therapy, potent activity against ALK
as well as single or compound ALK resistance mutations in both the
periphery and the brain has the potential to delay or prevent the
emergence of both treatment resistance and CNS progression.
Furthermore, selective inhibition of wild-type ALK and its
resistance variants may minimize TRK-related CNS adverse events and
other off-target toxicities that can be dose limiting. We believe
that the preliminary characteristics of NVL-655 observed in this
heavily pre-treated patient population support its opportunity as a
potential best-in-class therapy that can move up the treatment
paradigm to deliver deep and durable responses for patients with
ALK-positive cancers."
"With today's data, Nuvalent has presented preliminary
proof-of-concept data for both of its novel parallel lead programs
in ROS1 and ALK-positive cancers in just over 5 years since the
company's inception," said James
Porter, Ph.D., Chief Executive Officer at Nuvalent. "We
believe this achievement is a testament to the dedication of the
Nuvalent team, and to our approach of collaboration with leading
physician-scientists, identification of medical needs stemming from
the limitations of existing therapies, and focused application of
our innovative chemistry and deep expertise in structure-based drug
design to develop precisely targeted therapies according to
well-defined target product profiles."
Dr. Porter continued, "Most importantly, we
recognize that this achievement is made possible by the patients,
caregivers, and investigators who are participating in the ALKOVE-1
trial and offer our sincere gratitude. We look forward to
discussions with investigators and regulators on the selection
of a recommended Phase 2 dose (RP2D) and the transition to the
planned Phase 2 portion of ALKOVE-1 for patients with
lorlatinib-naïve and lorlatinib-treated ALK-positive NSCLC. We also
look forward to using the preliminary data to guide discussions
with physicians regarding potential development strategies for
patients with TKI-naïve ALK-positive NSCLC as we work towards our
goal of bringing new treatment options to all patients with
ALK-positive cancers."
NVL-655 First-in-Human Preliminary Phase 1 Data
NVL-655 is currently being evaluated in the ALKOVE-1 Phase 1/2
clinical trial, a first-in-human study of NVL-655 in patients with
advanced ALK-positive NSCLC and other solid tumors (NCT05384626).
The Phase 1 dose escalation portion is enrolling ALK-positive NSCLC
patients who have previously received at least one ALK TKI and
patients with other ALK-positive solid tumors who have been
previously treated with at least one prior systemic anticancer
therapy. The primary objectives are to determine the RP2D and if
applicable, the maximum tolerated dose (MTD) of NVL-655 in patients
with ALK-positive solid tumors. Additional objectives include
characterization of the overall safety, tolerability, and
pharmacokinetic profile, and evaluation of the preliminary
anti-tumor activity and intracranial activity of NVL-655.
As of the enrollment and data cut-off date of August 8, 2023 for the preliminary data, 93
patients were enrolled in the Phase 1 portion of the ALKOVE-1
trial, of which 91 patients had ALK-positive NSCLC and 58% (54/93)
had a history of CNS metastases.
The patient population was heavily pre-treated:
- 100% (93/93) had received a 2G ALK TKI or lorlatinib;
- 77% (72/93) had received two or more ALK TKIs, including a
2G ALK TKI and lorlatinib;
- 44% (41/93) had received three or more ALK TKIs, including
a 2G ALK TKI and lorlatinib; and,
- 46% (43/93) had an identified secondary ALK mutation,
including 26% (24/93) with any compound ALK mutation.
Preliminary Activity Analysis
As of the cut-off date for the preliminary data, patients were
treated in six NVL-655 dose cohorts of 15 mg, 25 mg, 50 mg, 100 mg,
150 mg, and 200 mg QD. Fifty-one patients with NSCLC were
response-evaluable by investigator assessment with duration of
treatment up to 12 months (median duration of treatment of 3.4
months).
Key findings include early anti-tumor activity in ALK-positive
NSCLC patients, including partial responses (RECIST 1.1) in:
- Heavily pre-treated patients: An ORR of 39% (20/51) was
observed in response-evaluable patients, and all patients with
tumor response continued on treatment without disease progression
as of the data cut-off date.
- For dose levels of 50 mg or greater, which may provide
increased coverage of single and compound mutations in
the CNS, an ORR of 44% (18/41) was observed.
- In patients who have likely exhausted all available treatment
options (≥3 prior ALK TKIs including a 2G ALK TKI and
lorlatinib), the observed ORR was 40% (10/25) regardless of prior
chemotherapy and 42% (8/19) with prior chemotherapy.
- Patients with ALK single or compound resistance
mutations: An ORR of 54% (15/28) was observed in patients
with any ALK resistance mutation, including an ORR of 56% (9/16) in
patients with compound ALK mutations, and an ORR of 71% (12/17) in
patients with ALK G1202R single or compound mutations.
- Patients with CNS metastases: An ORR of 52% (15/29)
was observed in patients with any history of CNS metastases. All
patients with tumor response who had a history of CNS disease
continued on treatment without CNS progression.
- Lorlatinib-naïve patients: Of patients who received at
least one 2G +/- 1G ALK TKI and had not previously received
lorlatinib, 5 of 7 (71%) responded.
Preliminary Safety, Pharmacokinetic, and Pharmacodynamic
Analysis
A favorable preliminary safety profile was observed with NVL-655
treatment in the 93 patients enrolled across the dose-escalation
portion of ALKOVE-1, consistent with an ALK-selective, TRK-sparing
design. Most treatment-related adverse events (TRAEs) were
low-grade and manageable, with the highest incidence of TRAEs being
ALT increase (19%, 18/93 any grade; 6%, 6/93 ≥ Grade 3), AST
increase (18%, 17/93 any grade; 4%, 4/93 ≥ Grade 3), and nausea
(10%, 9/93 of which all were Grade 1 or 2). TRAEs requiring dose
modification were infrequent, with 2% (2/93) discontinuations and
5% (5/93) dose reductions. There was one dose-limiting toxicity of
transient asymptomatic Grade 4 CPK increase at the 200 mg QD dose
level. An MTD was not reached, and the preliminary overall safety
profile was consistent with avoidance of TRK-related
neurotoxicities.
The observed favorable preliminary safety profile allowed for
achievement of NVL-655 exposure levels above target CNS efficacy
thresholds for ALK, ALK single and compound G1202R mutations, and
other recalcitrant ALK single mutations such as I1171N. Favorable
PK and low intra-cohort patient PK variability were observed, with
dose-proportional exposure and a half-life that is supportive of
once daily dosing. This preliminary PK data suggest that dose
levels of 50 mg QD or greater may provide increased coverage of
single and compound mutations in the CNS.
Preliminary pharmacodynamic findings by centrally confirmed
ctDNA analysis showed that treatment with NVL-655 induced clearance
of diverse ALK resistance mutation alleles across a wide dose
range. Notably, 100% clearance was observed in 14 of 16 patients
with centrally confirmed single or compound ALK G1202R or I1171X (X
= N or T) mutations, of which 13 had received prior lorlatinib.
Combined with the favorable preliminary activity observed as of
the data cut-off date, these data suggest that NVL-655 has
opportunity as a potential best-in-class therapy that may be able
to move up the treatment paradigm for patients with ALK-positive
NSCLC.
The ALKOVE-1 clinical trial is continuing to enroll patients in
the Phase 1 portion of the trial and is focused on further
characterizing the safety, PK, and pharmacodynamic profiles,
determining the RP2D, and if applicable, the MTD of NVL-655. Upon
RP2D selection, the trial is designed to transition directly into
the Phase 2 portion, which will evaluate the safety and activity of
NVL-655 in several expansion cohorts of patients defined based on
the number and type of prior anti-cancer therapies they have
received. The Phase 2 cohorts are intended to support potential
registration in patients with ALK-positive NSCLC who are both
lorlatinib-naïve and lorlatinib-treated.
In addition to the planned Phase 2 cohorts, Nuvalent intends to
use these preliminary data in patients with heavily pre-treated
ALK-positive NSCLC to guide discussions with physicians that will
inform development strategies in TKI-naïve ALK-positive NSCLC.
Webcast and Conference Call Information
A conference call with management will be held today at
8:00 am EDT. To access the
call, please dial +1 (866) 652-5200 (domestic) or +1 (412) 317-6060
(international) at least 10 minutes prior to the start time and ask
to be joined to the Nuvalent call. Accompanying slides and a live
video webcast will be available in the Investors section of the
Nuvalent website at https://investors.nuvalent.com/events. A replay
and accompanying slides will be archived on the Nuvalent website
for 30 days.
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 the
solvent front G1202R mutation or compound mutations G1202R / L1196M
("GRLM"), G1202R / G1269A ("GRGA"), or G1202R/L1198F ("GRLF").
NVL-655 has been designed for CNS penetrance to improve treatment
options for patients with brain metastases. NVL-655 has been
observed in preclinical studies to selectively inhibit wild-type
ALK 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/ALK inhibitors
and drive more durable responses for patients. NVL-655 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 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 preclinical and clinical development programs for
NVL-655; the potential clinical effect of NVL-655; the design and
enrollment of the ALKOVE-1 clinical trial; the potential of
NVL-655; the implications of the 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 ALKOVE-1 trial; 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 ALKOVE-1 clinical 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 ALKOVE-1;
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 ALKOVE-1 clinical 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 Nuvalent'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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