Gene Expression Profiling of Tumor is Correlated With Clinical Response CHICAGO, May 30
CHICAGO, May 30 /PRNewswire-FirstCall/ -- New data presented by
GlaxoSmithKline (GSK) today highlighted the potential of its investigational
MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) through results of
three studies evaluating highly targeted immunotherapy as a treatment for
metastatic melanoma and non-small cell lung cancer (NSCLC). These data were
presented at the 2008 American Society of Clinical Oncology (ASCO) Annual
Meeting in Chicago (Abstract Nos: 9065(1), 9045(2) and 7501(3)).
A randomized, open label Phase II study designed to evaluate two
different formulations of the MAGE-A3 ASCI in patients with metastatic
melanoma has been conducted. In this study, the ASCI, which is a combination
of MAGE-A3 recombinant protein and a GSK proprietary Adjuvant System, was
evaluated and resultant data suggest a positive trend for clinical response.
These data also demonstrate the induction of a desirable immune response,
including humoral and cellular responses. These study results represent a
second positive trend for clinical activity for the novel MAGE-A3 cancer
immunotherapeutic, following encouraging clinical results reported in a
separate double-blind, placebo-controlled Phase II study of patients with
NSCLC(4). The encouraging results from the Phase II NSCLC study have led to a
Phase III safety and efficacy trial in MAGE-A3-positive NSCLC patients (stage
IB, II and IIIA) who have undergone complete surgical resection (MAGRIT;
MAGE-A3 Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy).
At this year's ASCO, GSK also presented data regarding the use of the
genetic profiling of melanoma in predicting clinical outcomes of treatment
with MAGE-A3 ASCI. Biopsies performed on the melanoma tumors prior to
immunization were used to identify genetic markers expressed by the disease.
These markers enabled researchers to establish a correlation between the
expression of given genes and the clinical response induced by the MAGE-A3
ASCI in metastatic melanoma(2).
In addition, GSK presented data on the genetic profiling of patients with
NSCLC. In a retrospective analysis, a predictive gene signature similar to
that observed in melanoma was associated with a lower rate of disease
recurrence in the MAGE-A3 treated group(3).
"These phase II data mark another significant milestone for the
development of the MAGE-A3 ASCI as a potential novel cancer therapy.
Validation of a predictive gene signature, combined with selection of
patients who express cancer antigens of interest, may allow GSK to improve
predictions of a patient's clinical response to treatment with cancer
immunotherapeutics," said Johan Vansteenkiste, Professor of Internal
Medicine, Faculty of Medicine, Catholic University of Leuven, Belgium. "They
also provide further positive proof-of-concept Phase II data which highlight
the importance of the ongoing MAGRIT Phase III trial in Non-Small Cell Lung
Cancer."
Phase II Melanoma Data: abstract # 9065(1)
A randomized, open-label Phase II study designed to evaluate MAGE-A3
recombinant protein combined with two different Adjuvant Systems was
conducted. A total of 72 patients with measurable metastatic MAGE-A3-positive
cutaneous melanoma (unresectable or in transit stage III or stage IV M1a)
were randomized to receive immunization with MAGE-A3 protein combined with
either AS15 or AS02B as first-line metastatic treatment. Patients were to
receive a maximum of 24 immunizations over four years. Clinical activity is
assessed by the RECIST criteria, the international standards for evaluation
of solid tumors. Complete response (CR) and partial response (PR) i.e,
disappearance or significant reduction of tumor, were reported in four
patients in the AS15 group (3 CR and 1 PR) with two of these ongoing for more
than two years; in the AS02B arm, one patient showed a partial response which
lasted for 6 months.1 The safety profile was similar in both groups with the
majority of reported adverse events being mild or moderate local or systemic
reactions(1).
Gene Profiling in Melanoma: abstract # 9045(2)
Gene expression profiling by microarrays was used to identify markers
predictive of the clinical activity of the MAGE-A3 ASCI recorded in the phase
II melanoma study. Gene expression profiling was performed on tumor biopsies
taken prior to any immunization, leading to the identification of a gene
signature which reflects a specific immune micro-environment present prior to
any therapeutic intervention. This gene signature seems to be strongly
associated with MAGE-A3-induced clinical responses(2).
Gene Profiling in Non-Small Cell Lung Cancer: abstract # 7501(3)
These data show that it may be possible to identify patients that present
a high or low risk of relapse after surgery. A gene signature similar to that
observed in melanoma was associated in a retrospective analysis with a lower
rate of disease recurrence in the MAGE-A3 treated group. Another signature
that is predictive to clinical activity of the MAGE-3 ASCI treatment, which
increased clinical activity by a factor of 2, was also described(3).
This specific set of data follows the proof of concept Phase II data that
GSK reported at ASCO in 2007, which showed a 27% reduction in the relative
risk of NSCLC recurrence following surgery in patients treated with the
MAGE-A3 ASCI, compared to placebo(4). In the patients population selected for
the presence of the predictive gene signature, a 43% reduction in the
relative risk of relapse was observed(3). (Data on file).
Based on these encouraging data in NSCLC, GSK has initiated patient
recruitment to a randomized and controlled Phase III efficacy and safety
trial (MAGRIT) for this novel cancer immunotherapy. MAGE-A3 ASCI will be
evaluated as adjuvant therapy in about 2,270 MAGE-A3-positive patients with
completely resected stage IB, II or IIIA NSCLC in the large MAGRIT trial. The
gene profiling data presented at ASCO will be further validated during the
ongoing NSCLC MAGRIT Phase III trial.
"This is an exciting time to be amongst those at the forefront of cancer
immunotherapy research," said Dr. Vincent Brichard, Vice-President, Head of
Cancer Immunotherapeutics at GSK Biologicals. "These data presented today and
the launch of the large MAGRIT trial are indicative of GSK's ongoing
commitment to researching new ways of treating cancer and focus on developing
the right medicine tailored to identify the patients most likely to benefit
from it. We are keenly anticipating the results of the Phase III trial and
what it may mean for the future of cancer treatment."
About ASCIs and MAGE-A3 ASCI
GSK's ASCIs represent a novel class of medicines designed to train the
immune system to recognize and eliminate cancer cells in a highly specific
manner. These novel cancer immunotherapeutics combine tumor antigens,
delivered as purified recombinant proteins, and GSK's proprietary Adjuvant
Systems which are specific combinations of immunostimulating compounds
selected to increase the anti-tumor immune response. ASCIs will be
investigated to support their use to reduce the risk of tumor recurrence
following surgery, or to impact tumor growth in an early metastatic setting.
The highly specific mode of action of GSK's ASCIs may not only avoid
harming the normal tissue but also aid in selecting patients eligible for the
treatment, depending on the expression of the tumor antigens.
MAGE-A3 is a tumor-specific antigen that is expressed in a large variety
of cancers, including Melanoma, Non-Small Cell Lung Cancer, Head and Neck
Cancer, Bladder Cancer, with no expression in normal cells. Expression of the
MAGE-A3 gene has been observed in testicular cells but without antigen
presentation capabilities.
MAGE-A3 protein has been in-licensed by GSK from the Ludwig Institute for
Cancer Research, the largest international academic institute dedicated to
understanding and controlling cancer. MAGE-A3 ASCI is an investigational
compound and it is not approved for use in any indication in any country at
this time.
About melanoma
Melanoma is a type of cancer which develops when melanocytes (pigment
cells in the skin) become malignant and start to grow and divide at an
abnormally quick pace, spreading into the surrounding surface layers of skin.
According to the World Health Organization (WHO), two to three million
non-melanoma skin cancers and 132,000 melanoma skin cancers occur globally
each year.(5)
About non-small cell lung cancer
According to the Global Lung Cancer Coalition, more than 1.2 million new
cases of lung cancer are diagnosed each year worldwide, and approximately 1.1
million deaths occur annually around the world.(6)
About GlaxoSmithKline and GlaxoSmithKline Biologicals
GSK Biologicals (GSK Bio), one of the world's leading vaccine
manufacturers, is headquartered in Rixensart, Belgium, where the majority of
GlaxoSmithKline's activities in the field of vaccine research, development
and production are conducted. GSK Bio employs more than 1,500 scientists, who
are devoted to discovering new vaccines and developing more cost-effective
and convenient combination products to prevent infections that cause serious
medical problems worldwide. GSK Bio is also developing innovative
immunotherapy compounds to treat cancer patients.
GlaxoSmithKline - one of the world's leading research-based
pharmaceutical and healthcare companies - is committed to improving the
quality of human life by enabling people to do more, feel better and live
longer. For company information please visit http://www.gsk.com.
Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities
Litigation Reform Act of 1995, the company cautions investors that any
forward-looking statements or projections made by the company, including
those made in this Announcement, are subject to risks and uncertainties that
may cause actual results to differ materially from those projected. Factors
that may affect the Group's operations are described under 'Risk Factors' in
the `Business Review' in the company's Annual Report on Form 20-F for 2007.
References:
(1) Kruit W, Suciu S, Dreno B, et al `Immunization with recombinant
MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with
unresectable and progressive metastatic cutaneous melanoma: a randomized
open-label phase II study of the EORTC Melanoma Group J Clin Oncol 26: 2008
(May 20 suppl; abstr 9065).
(2) Louahed J, Gruselle O, Gaulis S et al `Expression of defined genes by
identified by pre-treatment tumor profiling: association with clinical
responses to the GSK MAGE-A3 immunotherapuetic in metastatic melanoma
patients, J Clin Oncol 26: 2008 (May 20 suppl; abstr 9045).
(3) Vansteenkiste J, Zielinski M, Linder A et al `Association of gene
expression signature and clinical efficacy of MAGE-A3 antigen-specific cancer
immunotherapeutic (ASCI) as adjuvant therapy in resected stage IB/II
non-small cell lung cancer (NSCLC)' J Clin Oncol 26: 2008 (May 20 suppl;
abstr 7501).
(4) Vansteenkiste J, Zielinski M, Linder A et al `Final results of a
multi-center, double-blind, randomized, placebocontrolled Phase II study to
assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage
IB/II Non-Small Cell Lung Cancer (NSCLC)' Journal of Clinical Oncology, 2007
ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),
2007: 7554.
(5) http://www.who.int/uv/faq/skincancer/en/index1.html (Date of access:
May 6, 2008).
(6)
http://www.lungcancercoalition.org/files/File/90280%20GLCC%20English.pdf -
(Date of access May 2008).
SOURCE GlaxoSmithKline (GSK)
