-- At 2 years, 25% RINTEGA survival rate versus
0% for control -- -- Hazard ratio of 0.53 (p=0.0137) indicates a
significant overall survival advantage for recurrent GBM patients
-- -- Clinical benefit continues to be observed across multiple
endpoints, including PFS, OS, ORR and steroid requirement with all
OS subgroup analyses favoring RINTEGA treatment --
Celldex Therapeutics, Inc. (NASDAQ:CLDX) today presented mature
survival data from the Company's randomized, double-blind Phase 2
study of RINTEGA® (rindopepimut) in patients with
EGFRvIII-positive, recurrent glioblastoma (GBM) at the 20th Annual
Scientific Meeting of the Society for Neuro-Oncology (SNO). The
data were presented in a podium presentation by David A. Reardon,
M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber
Cancer Institute; Associate Professor of Medicine, Harvard Medical
School; and President of the Society for Neuro-Oncology, as well as
the lead investigator of the ReACT study. RINTEGA is an
investigational EGFRvIII specific therapeutic vaccine and was
granted Breakthrough Therapy Designation in February 2014. Patients
with recurrent glioblastoma that express the EGFRvIII mutation
typically have a worse prognosis than the overall glioblastoma
population, including poor long-term survival (median time from
recurrence to death for EGFRvIII-positive patients is 8.7 months1).
As previously reported, the primary endpoint of the study,
progression-free survival at six months (PFS6) has been met.
- Mature overall survival (OS) data continue to show a marked
benefit [hazard ratio = 0.53 (0.32, 0.88); p=0.0137] with a
long-term survival benefit clearly seen in the RINTEGA arm. In May,
the Company reported a hazard ratio of 0.57 (0.33, 0.98) (p=0.0386)
for OS in the study.
- Nine of 10 patients (one patient lost to follow up) on the
RINTEGA arm remain alive since the Company last presented data in
May compared to only two out of five patients on the control
arm.
- At two years, the survival rate for RINTEGA patients is 25%
versus 0% for control patients in the intent to treat (ITT)
population, with five patients extending beyond two
years.
- Five patients in the RINTEGA arm continue survival follow-up
without progression per central review, compared to only one
patient on the control arm.
- A clear advantage continues to be demonstrated across multiple,
clinically important endpoints including overall survival (OS),
long-term progression-free survival (PFS), objective response rate
(ORR) and need for steroids.
- 33% of patients on the RINTEGA arm who were receiving steroids
at baseline were able to stop steroids for six months or
longer compared to none on the control arm.
"The results of the ReACT study change the way we think about
glioblastoma—offering patients and their families new hope in the
face of one of the most difficult to treat cancers and upending the
notion that the brain, masked behind the blood brain barrier, is
beyond the reach of the promise of immunotherapy," said David A.
Reardon, M.D. "The long-term survival benefit observed in this
study is unprecedented as it is exceedingly rare for patients with
highly aggressive, EGFRvIII-positive glioblastoma—even in the newly
diagnosed setting—to live beyond two years. Most striking perhaps
is that not only are patients living considerably longer, they are
also living better, with minimal side effects and a reduced need
for steroids. The ReACT data also build considerable anticipation
for the ACT IV study in newly-diagnosed glioblastoma as these
patients typically present with much stronger immune systems and
stand to derive an even greater benefit."
"Patients with glioblastoma—especially those who are
EGFRvIII-positive—face a staggering diagnosis, and in the face of
this news, making the decision to participate in a clinical
trial—especially a randomized study—is never an easy decision,"
said Thomas Davis, M.D., Executive Vice President and Chief Medical
Officer of Celldex. "To this end, we are extremely gratified on
behalf of our ReACT patients, their families and physicians that
RINTEGA continues to tell a very consistent, impressive story
across multiple, clinically relevant endpoints including, most
importantly, long-term survival. These results replicate what we
have seen in earlier RINTEGA studies conducted in newly-diagnosed
patients, supporting our belief that RINTEGA will be an important
treatment option for all patients with EGFRvIII-positive
glioblastoma."
Presentation Details
ReACT is a randomized, controlled Phase 2 exploratory study
designed to determine if adding RINTEGA to standard of care
bevacizumab (BV; Avastin®) improves outcomes for patients with
EGFRvIII-positive, recurrent glioblastoma across multiple measures.
Patients [n=73, intent to treat (ITT)] were bevacizumab-naïve at
study entry. Tumor responses were evaluated in accordance with RANO
criteria by an independent expert review committee blinded to
treatment group assignment. Data for this long-term update included
study results through September 1, 2015.
- PFS6: As previously reported, the primary
endpoint of PFS6 was met. 10 out of 36 (28%) patients were alive at
six months without progression on the RINTEGA arm compared to 6 out
of 37 (16%) on the control arm (p=0.1163). Given the exploratory
nature and size of the trial, the ReACT study required a PFS6
1-sided p-value of 0.2 (powered at 80%) for positivity.
- SURVIVAL: RINTEGA+BV demonstrated a
statistically significant, clinically meaningful overall survival
benefit compared to BV alone. Consistent with previous studies of
RINTEGA and the published data observed for immune-mediated
therapeutics, this survival benefit includes a "tail" on the
RINTEGA survival curve with multiple patients exceeding what is
customary survival for EGFRvIII-positive glioblastoma. Nine
patients on the RINTEGA arm continue to be followed for survival,
including five without disease progression per central review. Two
patients on the control arm continue to be followed for survival,
including one without disease progression per central review. At
two years, the survival rate for RINTEGA patients in the ITT
population is 25% versus 0% for control patients.
|
|
Overall Survival
(OS), Intent to Treat (ITT) Population |
|
|
|
Hazard Ratio (HR) |
HR = 0.53 (0.32, 0.88);
p=0.0137 |
|
|
|
|
Median (95% CI) |
OS 12 months |
OS 18 months |
OS 24 months |
RINTEGA + BV |
11.3 (9.9, 16.2) |
44% |
32% |
25% |
Control + BV |
9.3 (7.1, 11.4) |
32% |
13% |
0% |
- OBJECTIVE RESPONSE RATE (ORR): Nine out of 30
evaluable ITT patients (30%) on the RINTEGA arm experienced a
confirmed objective response versus six out of 34 evaluable
patients (18%) on the control arm. Five patients on the RINTEGA arm
experienced durable responses greater than six months, and three of
these patients experienced durable responses greater than 18 months
(range of 18.6+ to 22.2 months). In contrast, only two patients on
the control arm experienced a durable response greater than six
months, and none experienced a response greater than 7.4
months.
- STEROID USE: Further emphasizing the level of
disease control, 50% of the 18 patients on the RINTEGA arm who were
on steroids at the start of treatment were able to stop steroids
for at least two months during treatment versus only 26% of the 19
patients on the control arm who were on steroids at the start of
treatment. 33% of patients on the RINTEGA arm were able to stop
steroids for more than six months, and, of these, three were able
to stop for more than one year versus none on the control arm for
either time point.
- IMMUNE RESPONSE: Prolonged survival was
associated with high anti-EGFRvIII humoral responses that were
predominantly of the cell killing IgG1 isotype, and recent in vivo
experiments have shown those immune responses had tumor killing
function through antibody dependent cellular cytotoxicity (ADCC) of
EGFRvIII-expressing tumor cells. This biologic effector function is
rarely proven for immune therapies. Importantly, rapid generation
of anti-EGFRvIII humoral response correlated with longer survival;
however, even those with slower development of immune responses
benefitted. No patient in the control arm had detectable EGFRvIII
specific antibody response. This effect is consistent with
RINTEGA's proposed mechanism of action as a targeted
immunotherapeutic vaccine.
- OTHER: Multiple subgroup and adjusted analyses
have concluded that the consistent survival benefit observed in the
study was not influenced by potential imbalances in patient
demographics.
- SAFETY: RINTEGA was very well tolerated
without unexpected additive toxicity to bevacizumab.
RINTEGA® is a registered trademark of Celldex Therapeutics.
Avastin® is a registered trademark of Genentech, Inc. 1Data
provided the Radiation Therapy Oncology Group (RTOG).
About RINTEGA®
RINTEGA® is an investigational therapeutic vaccine that targets
the tumor specific oncogene EGFRvIII, a functional and permanently
activated variant of the epidermal growth factor receptor (EGFR), a
protein that has been well validated as a target for cancer
therapy. Expression of EGFRvIII correlates with increased
tumorigenicity in mouse models and poor long-term survival in
clinical studies of patients with glioblastoma (GBM). In addition,
EGFRvIII-positive cells are believed to stimulate proliferation of
non-EGFRvIII cells through IL-6 cell-to-cell signaling and to
release microvesicles containing EGFRvIII, which can merge with
neighboring cells, transferring tumor-promoting activity. EGFRvIII
expression may also be associated with tumor stem cells that have
been identified in GBM. These stem cells contribute to resistance
to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in
tumors in about 30% of patients with GBM. It has not been detected
at a significant level in normal tissues; therefore, targeting of
this tumor-specific molecule is not likely to impact healthy
tissues.
Three Phase 2 trials of RINTEGA—ACTIVATE, ACT II, and ACT
III—have been conducted in newly diagnosed EGFRvIII-positive GBM
and have shown consistent improvements in both overall survival and
progression-free survival compared to matched historical controls.
The most common adverse events for RINTEGA include injection site
reactions, fatigue, rash, nausea and pruritus. RINTEGA is currently
being studied in two clinical trials in EGFRvIII-positive GBM—an
international Phase 3 study called ACT IV in newly diagnosed GBM
and a Phase 2 study called ReACT in recurrent GBM. In February
2014, the U.S. Food and Drug Administration (FDA) granted RINTEGA
Breakthrough Therapy Designation for the treatment of adult
patients with EGFRvIII-positive glioblastoma. The first interim
analysis for ACT IV occurred in June 2015, and the study's Data
Safety and Monitoring Board recommended continuation of the study
as planned. The Company anticipates that ACT IV will reach the
required 75% of events (deaths) to perform the second interim
analysis in late 2015 and that the analysis will occur in early
2016.
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 Statement
This 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 RINTEGA® ("rindopepimut"; "rindo";
CDX-110), glembatumumab vedotin ("glemba"; CDX-011), varlilumab
("varli"; CDX-1127), CDX-1401, CDX-301 and other products and our
goals for 2015. 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 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 RINTEGA, 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 Breakthrough Therapy Designation for
RINTEGA, 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.
CONTACT: Company Contact
Sarah Cavanaugh, Vice President of Investor Relations & Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3161
scavanaugh@celldex.com
Media Inquiries
Dan Budwick, Pure Communications, Inc.
(973) 271-6085
dan@purecommunicationsinc.com
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