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Cancer remains one of the fields of medical research with many unmet
needs. Tremendous private and public resources have been committed
to address the devastating healthcare impact of the myriad of individual
diseases that comprise cancer. This has resulted in a revolution
in our understanding of these diseases at the cellular level and
is now leading to innovative advances in the treatment of cancer.
Recently, targeted therapeutics have emerged as one of the most
significant advancements in cancer research in decades. We have
entered into a modern era of targeted therapy for cancer as medications
that can target cancer cells with only a limited impact on the rest
of the body have become an important part of oncology’s cutting
edge. At OSI, we are contributing greatly to the evolution of this
new era by pioneering and developing anti-cancer drugs that target
the multiple underlying mechanisms of cancer.
Many of these novel anti-cancer drugs are designed to target growth-regulating
genes that can cause cancer when they are either over-expressed
or mutated in cancer cells. One of the most important of these oncogenes
is the epidermal growth factor receptor (HER1/EGFR). HER1/EGFR is
mutated or over-expressed in a variety of tumor types that impact
a significant number of the approximately 1.3 million patients newly
diagnosed with cancer in the United States each year.
Our most advanced drug candidate, Tarceva™, is a small molecule
inhibitor of the epidermal growth factor receptor, or HER1/EGFR.
Tarceva™ is designed as a once-a-day pill to inhibit the tyrosine
kinase activity of the HER1 signaling pathway inside the cell, which
blocks tumor cell growth. We are developing Tarceva™ in a
global alliance with Genentech and Roche. Our co-development plan
is designed to obtain an effective registration for Tarceva™
while maintaining a competitive position against other EGFR inhibitors.
Tarceva™ has been developed both as a monotherapy (based on
a series of positive Phase II trials) and in combination with cytotoxic
chemotherapy where we built a Phase III program in front-line non-small
cell lung cancer (NSCLC) in response to a competitor’s program
in this setting. The failure of the competitor’s trials in
2002, and the subsequent and anticipated failure of Tarceva™
in similar trials has shown us that the concurrent dosing of oral
EGFR inhibitors with cytotoxic chemotherapy regimens in NSCLC is
ineffective and that we still have much to learn in this area.
The focal point of our registration program is a worldwide 730 patient
Phase III trial testing monotherapy Tarceva™ versus placebo
in a second/ third-line NSCLC setting with survival as the primary
endpoint, while secondary endpoints include progression-free survival,
time to symptomatic deterioration and response rate. We are conducting
this trial in collaboration with the National Cancer Institute of
Canada’s Clinical Trial Group. This is the most advanced single-agent,
controlled Phase III study of an EGFR-targeted agent designed to
detect a survival advantage. Tarceva™ has demonstrated encouraging
indications of activity in multiple disease settings (including
advanced NSCLC) when used as a single agent and we remain optimistic
about our potential for success with this study and expect data
in early 2004.
Another Phase III trial being conducted by the alliance is evaluating
Tarceva™ in front-line pancreatic cancer comparing Tarceva™
in combination with standard chemotherapy versus chemotherapy alone.
Enrollment was complete in January 2003 with top-line results expected
in mid-2004. It should be noted that due to the failure of Tarceva™
when used with concurrent chemotherapy in NSCLC, we consider this
pancreatic front-line study to be high-risk. The near-term focus
for ongoing Tarceva™ development is on its use as a monotherapy
and in combination with novel targeted therapies.
Encouraging data in this regard was presented at the 2003 American
Society of Clinical Oncology (ASCO) and NCI/EORTC meetings, suggesting
that Tarceva™ has a broad range of activity in a number of
solid tumor types including bronchioloalveolar cell carcinoma (BAC),
hepatobiliary carcinoma and glioblastoma (brain cancer). These cancers
are generally considered difficult to treat and unresponsive to
chemotherapy.
In the BAC Phase II trial, 50 patients were treated with Tarceva™.
Of these 50 patients, 13 (26%) achieved a partial response. The
median duration of response has not yet been reached and the study
has been expanded to 100 patients.
In a glioblastoma multiforme Phase I study, out of a total of 49
evaluable patients, 8 partial responses (16%), 3 minor responses
(6%) and 11 stable disease (22%) were observed. As a result of this
encouraging data, Genentech in collaboration with the Accelerate
Brain Cancer Cure (ABC2) Clinical Network initiated a Phase II trial
in patients with malignant glioma in August 2003. Top-line data
for this ongoing trial is expected in 2004. Tarceva™ was also
granted orphan drug status by the FDA in this setting.
In all Tarceva™ trials, an acneiform rash is the most commonly
reported side effect. We have now observed a strong correlation
between rash and survival in three single-agent Phase II trials
using 150 mg/day of Tarceva™ and totaling over 200 patients
with refractory NSCLC, head and neck and ovarian cancers that were
retrospectively analyzed. The incidence of rash in these studies
was approximately 80%. In all trials, patients with rash had longer
survival than those without rash. This analysis supports our belief
that our higher dose strategy (Tarceva™ induces more rash
than a competitive agent at its recommended dose) may translate
into an improved survival benefit in larger, randomized and controlled
Phase III studies. In November 2003, we announced the initiation
of a Phase II dose-to-rash escalation study designed to evaluate
the feasibility of safety and effectively dose escalating Tarceva™
to induce tolerable rash.
We have also explored combinations of novel targeted therapies.
Studies in NSCLC with Tarceva™ used in combination with the
anti-angiogenic agent Avastin™ have demonstrated an encouraging
initial response rate in the early stages of an ongoing study and
a similar study in renal cancer is under way. These studies form
part of an extensive clinical program investigating Tarceva™
use in over 100 clinical trial initiatives. Thirty-two of these
studies are being conducted in collaboration with the National Cancer
Institute’s CTEP program and 81 trials are currently approved
as part of the alliance’s Investigator-Sponsored Trial program.
These trials will be supplemented with additional company-sponsored
studies as we seek to broaden Tarceva™’s utility to
chemotherapy-naive, front-line NSCLC patients, explore adjuvant
use of Tarceva™ subsequent to radiotherapy or chemotherapy,
examine Tarceva™’s utility in combination with other
novel targeted therapies and explore all-oral cancer drug regimens
therapy. This extensive clinical development program is designed
to position the product on the forefront of cutting-edge cancer
therapy.
In Tarceva™ we continue to believe that we have a cancer blockbuster
product in the making with the potential of providing a real difference
to the lives of millions of cancer patients around the world.
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Targeted therapy represents
an exciting and important new chapter in cancer treatment. At OSI,
we are at the hub of this revolution in discovering, developing
and commercializing anti-cancer drugs that can target cancer cells
while having minimal side effects on the rest of the body.
“The observed correlation between
rash and survival previously reported with Tarceva™ and some
other agents targeting the HER1/EGFR pathway is intriguing and of
particular interest to the oncology community. The preliminary data
suggest that it may provide an opportunity to maximize the clinical
benefit of Tarceva™ in cancer patients.”
Eric Rowinsky, M.D.
Institute for Drug Development
Director of Clinical Research
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