35% objective response rate (ORR) in second-line colorectal cancer (CRC)
patients treated with sirexatamab (DKN-01) plus bevacizumab and
chemotherapy, compared to 23% ORR
in the control arm
DKK1 levels
highly correlated with clinical activity in CRC population
ORR benefit
with sirexatamab observed across multiple potential Phase
3 CRC populations
Preparations will begin for a registrational
Phase 3 study in second-line CRC patients
DisTinGuish Part C study in gastric cancer
demonstrates activity in biomarker populations, but not
the signal necessary to advance into Phase 3
Leap to host a conference call to present
clinical data today, January 28,
2025, at 8:00 a.m. ET
CAMBRIDGE,
Mass., Jan. 28, 2025 /PRNewswire/ -- Leap
Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused
on developing targeted and immuno-oncology therapeutics, today
announced positive initial data from Part B of the DeFianCe study
evaluating sirexatamab (DKN-01) in combination with bevacizumab and
chemotherapy as a second-line treatment for patients with advanced
colorectal cancer (CRC), and initial data from Part C of the
DisTinGuish study evaluating sirexatamab in combination with
tislelizumab and chemotherapy in first-line patients with advanced
gastroesophageal junction (GEJ) and gastric cancer.
Key Findings from Part B of the DeFianCe
study:
"Data from Part B of the DeFianCe study closely
mirror the findings from Part A, and together they demonstrate the
potential of sirexatamab to provide a compelling treatment option
for second-line CRC patients who do not benefit from current
standard of care," said Cynthia
Sirard, M.D., Chief Medical Officer of Leap. "Along with
consistently achieving higher response rates than the control arm,
the data also point to a favorable safety profile. While not yet
fully mature, we are encouraged by the progression-free survival
data thus far across key subgroups in the study. We look forward to
reporting additional data from Part B as it matures over the coming
months and beginning our planning for Phase 3 registrational
studies."
"The patient population in second-line CRC is
heterogeneous, and there is a true unmet need for new treatment
options that are safe and effective. The latest findings from
DeFianCe Part B are highly encouraging, as sirexatamab combination
therapy is outperforming bevacizumab and chemotherapy alone in
ORR in the intent-to-treat
analysis and across key subgroups of interest," said Zev Wainberg, M.D., Professor of Medicine and
Co-Director of the GI Oncology Program at UCLA. "Initial results also show increased response
rates in patients with high DKK1
levels, directly correlating with sirexatamab's novel mechanism of
action. These data support moving forward into Phase 3
registrational studies to further explore a unique treatment option
for patients in need."
The DeFianCe study (NCT05480306) is a Phase
2, open-label, global study of sirexatamab in combination with
bevacizumab and chemotherapy in patients with advanced
microsatellite stable (MSS) CRC who have received one prior
systemic therapy for advanced disease. Part B of the study is a 188
patient randomized controlled trial, with the primary objective
being progression-free survival (PFS) in patients with left-sided
cancers and in all patients. Key secondary and exploratory
objectives include objective response rate (ORR), duration of response, and overall
survival across tumor, treatment, and biomarker subgroups.
- Across the intent-to-treat (ITT) population with second-line
MSS CRC (n=188):
- Patients treated with sirexatamab plus bevacizumab and
chemotherapy (Experimental Arm, n=94) had ORR of 35% and disease control rate (DCR) of
86%, compared to an ORR of 23% and
DCR of 84% in patients treated with bevacizumab and chemotherapy
alone (Control Arm, n=94)
- Across the population with left-sided primary tumors (n=144):
- Patients treated in the Experimental Arm (n=71) had an ORR
of 38%, compared to an ORR of 25%
in the Control Arm (n=73)
- Plasma DKK1 highly correlated
with clinical activity:
- Patients in the Experimental Arm with DKK1 levels above the median (n=49) had
an ORR of 39%, compared to 22% ORR in the Control Arm (n=36)
- Patients in the upper-quartile of DKK1 levels in the Experimental Arm (n=25) had
an ORR of 48%, compared to 11% ORR in the Control arm (n=18)
- Key patient subgroups demonstrated higher ORR in the
Experimental Arm:
- No prior anti-VEGF therapy: Patients in the Experimental
Arm (n=49) had an ORR of 51%,
compared to 29% ORR in the Control
Arm (n=45)
- Prior anti-EGFR therapy: Patients in the Experimental Arm
(n=28) had an ORR of 54%, compared
to 27% ORR in the Control Arm
(n=22)
- RAS wildtype (RAS-wt) tumors: Patients in the Experimental Arm
(n=35) had an ORR of 43%, compared
to 32% ORR in the Control Arm
(n=25)
- With only 3 months follow-up on the final patients enrolled and
mean duration on study of approximately 6 months, PFS is not
yet mature. Eighty-two patients are still on study, 46 in the
Experimental Arm and 36 in the Control Arm. Early separation in the
Kaplan-Meier PFS curves is being seen in many of the key patient
subgroups, including DKK1 biomarker,
anti-VEGF-naïve, anti-EGFR-experienced, and RAS-wt patients. Leap
expects to report additional data as it matures in 2025.
- Sirexatamab plus bevacizumab and chemotherapy was
well-tolerated, without additive toxicity to the standard of
care.
The strong signal in CRC from the DeFianCe study
supports Leap moving forward to plan a registrational Phase 3
clinical trial to evaluate sirexatamab plus bevacizumab and
chemotherapy in second-line MSS CRC patients with high unmet need,
subject to regulatory discussions. Potential Phase 3 patient
populations include: DKK1
biomarker-selected, anti-VEGF naïve, anti-EGFR experienced, or
RAS-wt patients. While the data matures, Leap intends to conduct
global commercial and regulatory strategic analysis to select the
optimal population.
Key Findings from Part C of the DisTinGuish
study:
Leap also reported data from Part C of the
DisTinGuish study evaluating sirexatamab in combination with
tislelizumab, BeiGene's anti-PD-1 antibody, and chemotherapy in
first-line patients with advanced GEJ and gastric cancer. While
demonstrating activity in biomarker populations, the study did not
generate a clear positive signal and will be negative on the
primary PFS endpoints when the study completes, resulting in the
decision not to move forward with Phase 3 studies in gastric
cancer.
"Sirexatamab plus tislelizumab and chemotherapy
demonstrated improved confirmed response rates compared to the
control arm in the ITT, DKK1-high,
and PD-L1 negative patients by Blinded Independent Central Review
(BICR). However, gastric cancer is a difficult tumor to assess
radiologically, and unfortunately, there was a high level of
discordance between investigator assessment (IA) and BICR," said
Dr. Sirard. "Therefore, we have decided to focus our internal
effort and resources on advancing sirexatamab in CRC and will
explore strategic partnership opportunities to advance sirexatamab
plus anti-PD-1 antibodies in gastric cancer and other indications
where there is high DKK1
expression."
Part C of the DisTinGuish study (NCT0436380) is a
Phase 2, randomized, open-label, multicenter study of sirexatamab
in combination with tislelizumab and chemotherapy in first-line
patients with advanced GEJ and gastric cancer. Part C enrolled 170
first-line, HER2-negative patients. Patients were randomized 1:1 to
evaluate sirexatamab in combination with tislelizumab and
chemotherapy, compared to tislelizumab and chemotherapy alone. The
primary objective is PFS by IA in all patients and in DKK1 TPS > 20 (DKK1-high) patients. Secondary objectives include
ORR, duration of response, and
overall survival as measured by BICR and IA in all patients and in
DKK1-high patients.
- Across the ITT population (n=170), patients treated
with sirexatamab plus tislelizumab and chemotherapy
(Experimental Arm, n=85) had a confirmed ORR of 52% by both IA and BICR, while patients
treated with tislelizumab and chemotherapy alone (Control Arm,
n=85) had a confirmed ORR of 56%
by IA and 42% by BICR.
- Based on BICR:
- Patients in the Experimental Arm with DKK1-high tumors (n=22) had a confirmed ORR
of 59%, compared to 36% in the Control Arm (n=22)
- Patients in the Experimental Arm with PD-L1-negative tumors
(n=18) had a confirmed ORR of 44%, compared to 32% in the
Control Arm (n=19)
- In the ITT population, preliminary median PFS in the
Experimental Arm was 9.72 months by BICR and 7.66 months by IA
compared to 11.99 months by BICR and 10.41 months by IA in the
Control Arm. The median PFS for tislelizumab plus chemotherapy in
the Phase 3 Rationale-305 study was 6.9 months (95% CI: 5.7,
7.2).
- In the DKK1-high population,
preliminary median PFS in the Experimental Arm was 7.72 months
by BICR and 7.43 months by IA compared to 7.79 months by BICR and
11.14 months by IA in the Control Arm. The hazard ratio for PFS by
BICR was 0.68, representing a trend in favor of the Experimental
Arm in the overall time to event analysis.
- Sirexatamab plus tislelizumab and chemotherapy was well
tolerated, without additive toxicity to the standard of care.
Conference Call:
Leap's management team
will host a conference call today, January
28, 2025 at 8:00 a.m. Eastern
Time to further discuss the data. The conference call will
be broadcast live in listen-only mode and can be accessed via the
webcast URL: https://edge.media-server.com/mmc/p/t93pn2ke. A
replay of the event will be available for a limited time on the
Investors page of the Company's website at
https://investors.leaptx.com/.
About Leap Therapeutics
Leap
Therapeutics (Nasdaq: LPTX) is focused on developing targeted
and immuno-oncology therapeutics. Leap's most advanced clinical
candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody
targeting the Dickkopf-1 (DKK1)
protein. Sirexatamab is being studied in patients with colorectal,
esophagogastric, and gynecological cancers. Leap's pipeline also
includes FL-501, a humanized monoclonal antibody targeting the
growth and differentiation factor 15 (GDF-15) protein, in
preclinical development. For more information about Leap
Therapeutics, visit http://www.leaptx.com or view our
public filings with the SEC that are available via EDGAR at
http://www.sec.gov or via https://investors.leaptx.com/.
FORWARD-LOOKING STATEMENTS
This press
release contains forward-looking statements within the meaning of
the federal securities laws. Such statements are based upon current
plans, estimates and expectations of the management of Leap that
are subject to various risks and uncertainties that could cause
actual results to differ materially from such statements. The
inclusion of forward-looking statements should not be regarded as a
representation that such plans, estimates and expectations will be
achieved. Words such as "anticipate," "expect," "project,"
"intend," "believe," "may," "will," "should," "plan," "could,"
"continue," "target," "contemplate," "estimate," "forecast,"
"guidance," "predict," "possible," "potential," "pursue," "likely,"
and words and terms of similar substance used in connection with
any discussion of future plans, actions or events identify
forward-looking statements.
All statements, other than historical facts,
including statements regarding the potential safety, efficacy, and
regulatory and clinical progress of Leap's product candidates; the
anticipated timing for initiation or completion of clinical trials
and release of clinical trial data and the expectations surrounding
the outcomes thereof; Leap's future clinical or preclinical product
development plans for any of Leap's product candidates; Leap's
estimations of projected cash runway; and any assumptions
underlying any of the foregoing, are forward-looking statements.
Important factors that could cause actual results to differ
materially from Leap's plans, estimates or expectations could
include, but are not limited to: (i) the results of Leap's clinical
trials and pre-clinical studies, including whether the final data
from Part B of the DeFianCe study or Part C of the DisTinGuish
study are the same as the initial data reported, (ii) Leap's
ability to successfully finance or enter into new strategic
partnerships for sirexatamab or any of its other programs; (iii)
any regulatory feedback that Leap may receive from U.S. Food and
Drug Administration (FDA) or equivalent foreign regulatory
agency with respect to the registrational Phase III clinical trials
that Leap proposes to conduct using sirexatamab for the treatment
of patients with second-line CRC or with respect to any
other pre-clinical or clinical development activities that Leap
will be required to conduct in order to obtain regulatory approval
of sirexatamab for the treatment of second-line CRC; (iv)
whether any Leap products will receive approval from
the FDA or equivalent foreign regulatory agencies; and
(v) exposure to inflation and interest rate fluctuations, as well
as fluctuations in the market price of Leap's traded securities.
New risks and uncertainties may emerge from time to time, and it is
not possible to predict all risks and uncertainties. No
representations or warranties (expressed or implied) are made about
the accuracy of any such forward-looking statements. Leap may not
actually achieve the forecasts disclosed in such forward-looking
statements, and you should not place undue reliance on such
forward-looking statements. Such forward-looking statements are
subject to a number of material risks and uncertainties including
but not limited to those set forth under the caption "Risk Factors"
in Leap's most recent Annual Report on Form 10-K filed with
the SEC, as well as discussions of potential risks,
uncertainties, and other important factors in its subsequent
filings with the SEC. Any forward-looking statement speaks
only as of the date on which it was made. Neither Leap, nor any of
its affiliates, advisors or representatives, undertake any
obligation to publicly update or revise any forward-looking
statement, whether as a result of new information, future events or
otherwise, except as required by law. These forward-looking
statements should not be relied upon as representing Leap's views
as of any date subsequent to the date hereof.
CONTACT:
Douglas E. Onsi
President & Chief Executive Officer
Leap Therapeutics, Inc.
617-714-0360
donsi@leaptx.com
Matthew
DeYoung
Investor Relations
Argot Partners
212-600-1902
leap@argotpartners.com
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