Celldex Therapeutics, Inc. (NASDAQ:CLDX) today presented positive
results from the Company’s Phase 2 study of glembatumumab vedotin
in patients with stage III/IV checkpoint inhibitor-refractory, and,
if applicable, BRAF/MEK inhibitor-refractory metastatic melanoma
(n=62). Glembatumumab vedotin is a fully-human monoclonal
antibody-drug conjugate (ADC) that targets glycoprotein NMB
(gpNMB), a protein overexpressed by multiple tumor types, including
metastatic melanoma where greater than 80% of patients overexpress
the marker. High tumor expression of gpNMB is associated with
shorter metastasis-free survival and reduced overall survival.1
Study results were presented today at the ESMO 2016 Congress in
Copenhagen in poster titled “A Phase 2 study of glembatumumab
vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in
advanced melanoma.”
Study Highlights
- The primary endpoint of the study (6 or more objective
responses in the first 52 patients enrolled) was exceeded. 7 of 62
(11%) patients experienced a confirmed response, and an additional
3 patients also experienced single timepoint responses.
- Median duration of response in this heavily pre-treated patient
population was 6.0 months.
- 53% of patients experienced stable disease (with a minimum
duration of six weeks).
- A 52% disease control rate (patients without progression for
greater than three months) was demonstrated.
- 52% of patients experienced tumor shrinkage.
- Median progression-free survival (PFS) for all patients was 4.4
months.
- Patients who experienced rash in Cycle 1 experienced a 20%
confirmed response rate and a more prolonged PFS of 5.5 months
[p=0.054; HR=0.52 (0.27, 1.02)].
“While immune checkpoint inhibitors and BRAF targeted therapy
have dramatically changed outcomes for many patients with
metastatic melanoma, patients who either do not respond or progress
through these treatments are faced with very limited treatment
options,” said Patrick Ott, M.D., Ph.D., Clinical Director of the
Melanoma Center and the Center for Immuno-Oncology at Dana-Farber
Cancer Institute and an investigator in the study. “The
single-agent activity observed in this study and the corresponding
duration of response is highly encouraging. I am hopeful that
pursuing combination studies of glembatumumab vedotin, including
with checkpoint inhibition, could help us bring benefit to an even
larger number of melanoma and other cancer patients.”
“It’s clear based on these study results that refractory
metastatic melanoma is a responsive target indication for
glembatumumab vedotin,” said Thomas Davis, M.D., Executive Vice
President and Chief Medical Officer of Celldex Therapeutics. “gpNMB
is very highly expressed in melanoma with all tissue samples on
study testing positive, and almost 80% of tumors demonstrating 100%
expression in their epithelial cells. We’re encouraged by the
results we’ve seen to date in this advanced, checkpoint refractory
setting and believe leveraging the immune system through
combination therapy is a critical next step for patients in in this
indication.”
Study OverviewThis study was a Phase 2,
open-label study of glembatumumab vedotin in patients with
unresectable stage III (n=1; 2%) or stage IV (n=61; 98%) melanoma.
The median number of prior therapies was three (range of 1 to 6).
All patients had progressed after checkpoint therapy, and almost
all patients had received both ipilimumab (n=58; 94%) and
PD-1/PDL-1 (n=58; 94%) therapy. Twelve patients presented with BRAF
mutation, and eleven had prior treatment with BRAF or BRAF/MEK
targeted agents. Patients received glembatumumab vedotin every
three weeks until disease progression or intolerance. The safety
profile was consistent with prior studies of glembatumumab vedotin
with rash, neutropenia, and neuropathy experienced as the most
significant adverse events. Consistent with previous studies in
melanoma and breast cancer, rash was associated with greater
clinical benefit.
Clinical Efficacy |
|
Primary Endpoint: Confirmed Response Rate (ORR) Met |
7/62 (11%) |
Duration of Response |
Median: 6.0 months Range: 1.4 + to 8.6+ |
Any Response, Including Those not Confirmed at Subsequent
Assessment |
10/62 (16%) |
Stable Disease |
33/62 (53%) |
Disease Control Rate |
32/62 (52%) |
Patients with Tumor Shrinkage |
32/62 (52%) |
Progression-free Survival |
Median: 4.4 monthsRange: 0.4 to 15.8+ |
Tumor tissue (pre-treatment) was available for 58 patients at
the time of analysis. All samples were gpNMB positive, and 79% of
patients had tumors with 100% of their epithelial cells expressing
gpNMB. Given both the high level of expression and the intensity of
expression across this patient population, identifying a potential
population for gpNMB enrichment is not feasible; therefore, all
patients with metastatic melanoma could be evaluated as potential
candidates for treatment with glembatumumab vedotin in future
studies.
Next StepsIn August 2016, the Company announced
that the primary endpoint had been met in this Phase 2 single-agent
study of glembatumumab vedotin in metastatic melanoma
(post-progression on/after checkpoint therapy) and that the Company
was amending the protocol to add a second cohort of patients to a
glembatumumab vedotin and varlilumab combination. Varlilumab is
Celldex’s fully human monoclonal agonist antibody that binds and
activates CD27, a critical co-stimulatory molecule in the immune
activation cascade. This additional cohort is open to enrollment.
Upon completion of enrollment in this cohort, the Company is
exploring opening a new arm in the study to assess a glembatumumab
vedotin and checkpoint combination. This rationale is strongly
supported by preclinical data that suggest that the anti-tumor
activity may be enhanced with the combination. In addition, due to
their direct cytotoxic properties, microtubule-depolymerizing
agents like MMAE also appear to convert tumor-resident tolerogenic
dendritic cells into active antigen-presenting cells.2 The Company
also intends to conduct exploratory analyses of pre-entry skin
biopsies in future patients to investigate potential predictors of
response to glembatumumab vedotin, given the association of rash
and outcome.
About Glembatumumab VedotinGlembatumumab
vedotin is a fully-human monoclonal antibody-drug conjugate (ADC)
that targets glycoprotein NMB (gpNMB). gpNMB is a protein
overexpressed by multiple tumor types, including breast cancer,
melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has
been shown to be associated with the ability of the cancer cell to
invade and metastasize and to correlate with reduced time to
progression and survival in breast cancer. The gpNMB-targeting
antibody, CR011, is linked to a potent cytotoxic, monomethyl
auristatin E (MMAE), using Seattle Genetics' proprietary
technology. Glembatumumab vedotin is designed to be stable in the
bloodstream but to release MMAE upon internalization into
gpNMB-expressing tumor cells, resulting in a targeted cell-killing
effect. Glembatumumab vedotin is in development for the treatment
of locally advanced or metastatic breast cancer with an initial
focus in triple negative disease, stage III and IV melanoma,
squamous cell lung cancer, uveal melanoma and osteosarcoma.
About Celldex Therapeutics, Inc.Celldex is
developing targeted therapeutics to address devastating diseases
for which available treatments are inadequate. Our pipeline is
built from a proprietary portfolio of antibodies and
immunomodulators used alone and in strategic combinations to create
novel, disease-specific therapies that induce, enhance or suppress
the body's immune response. Visit www.celldex.com.
Forward Looking StatementThis release contains
"forward-looking statements" made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995,
including those related to the Company's strategic focus and the
future development and commercialization (by Celldex and others) of
glembatumumab vedotin ("glemba"; CDX-011), varlilumab (“varli”;
CDX-1127) and other products and our goals for 2016.
Forward-looking statements reflect management's current knowledge,
assumptions, judgment and expectations regarding future performance
or events. Although management believes that the expectations
reflected in such statements are reasonable, they give no assurance
that such expectations will prove to be correct or that those goals
will be achieved, and you should be aware that actual results could
differ materially from those contained in the forward-looking
statements. Forward-looking statements are subject to a number of
risks and uncertainties, including, but not limited to, our ability
to successfully complete research and further development and
commercialization of glembatumumab vedotin and other drug
candidates; our ability to obtain additional capital to meet our
long-term liquidity needs on acceptable terms, or at all, including
the additional capital which will be necessary to complete the
clinical trials that we have initiated or plan to initiate; the
uncertainties inherent in clinical testing and accruing patients
for clinical trials; our limited experience in bringing programs
through Phase 3 clinical trials; our ability to manage and
successfully complete multiple clinical trials and the research and
development efforts for our multiple products at varying stages of
development; the availability, cost, delivery and quality of
clinical and commercial grade materials produced by our own
manufacturing facility or supplied by contract manufacturers, who
may be our sole source of supply; the timing, cost and uncertainty
of obtaining regulatory approvals; our ability to maintain and
derive benefit from the Fast Track designation for glembatumumab
vedotin which does not change the standards for regulatory approval
or guarantee regulatory approval on an expedited basis, or at all;
the failure of the market for the Company's programs to continue to
develop; our ability to protect the Company's intellectual
property; the loss of any executive officers or key personnel or
consultants; competition; changes in the regulatory landscape or
the imposition of regulations that affect the Company's products;
and other factors listed under "Risk Factors" in our annual report
on Form 10-K and quarterly reports on Form 10-Q.
All forward-looking statements are expressly qualified in their
entirety by this cautionary notice. You are cautioned not to place
undue reliance on any forward-looking statements, which speak only
as of the date of this release. We have no obligation, and
expressly disclaim any obligation, to update, revise or correct any
of the forward-looking statements, whether as a result of new
information, future events or otherwise.
References1. Rose, et al. Clin Cancer Res.
2010; 16(7):2147-56.2. Müller, Martin, von Bergwelt-Baildon, and
Zippelius, et al. Cancer Immunol. Res. 2014; 2(8):741-55.
Company Contact
Sarah Cavanaugh
Vice President of Investor Relations & Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3161
scavanaugh@celldex.com
Charles Liles
Associate Director of Investor Relations & Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3107
cliles@celldex.com
Media Inquiries
Dan Budwick
BrewLife
(973) 271-6085
dbudwick@brewlife.com
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