The FDAs Oncologic Drugs Advisory Committee (ODAC) recommended
the approval of topotecan hydrochloride for injection (Hycamtin) for
the second-line treatment of sensitive small-cell lung cancer (SCLC).
The favorable recommendation was based on a review of data from four
clinical trials conducted in patients with relapsed SCLC. In a
randomized, phase III, comparative clinical trial, topotecan as a
single agent showed comparable efficacy to CAV (cyclophosphamide,
Adriamycin, and vincristine), a triple-drug combination therapy
commonly used for the treatment of relapsed SCLC. Median survival and
time to progression were comparable for both treatment groups.
Topotecan is currently approved by the FDA for use in the treatment
of ovarian cancer after failure of initial or subsequent chemotherapy.
"Since most small-cell lung cancer patients will eventually
relapse and become difficult to treat, there is a need for new agents
such as topotecan that can be used to treat patients, particularly
those who have failed first-line therapy. There is currently no
standard treatment for this malignancy, which is one of the most
deadly cancers among both men and women," said Joan Schiller,
MD, associate professor, University of Wisconsin Comprehensive Cancer
Center in Madison, Wisconsin, and the lead US study investigator for
the phase III clinical trial. "Results from several clinical
trials involving patients treated with topotecan have been very encouraging."
Phase III Trial Results
The panel based its decision, in part, on a large phase III,
randomized clinical trial that was conducted at 44 centers in North
America, Europe, and South Africa and involved 211 patients who had
relapsed at least 60 days after their initial treatment. Patients
received either an intravenous infusion of topotecan (1.5 mg/m²)
as a single agent for 5 consecutive days every 3 weeks or CAV
(cyclophosphamide, 1,000 mg/m², Adriamycin, 45 mg/m², and
vincristine, 2 mg) administered intravenously on day 1 every 3 weeks.
A greater percentage of topotecan-treated than CAV-treated patients
responded to treatment (24.3% vs 18.3%), although this difference was
not statistically significant. Tumors were assessed by radiologic
evaluation and required independent confirmation. Median survival and
time to progression were comparable in the two treatment groups.
More topotecan-treated patients than CAV recipients reported
improvement in disease-related symptoms. A significantly higher
percentage of patients who were treated with topotecan vs CAV
reported an improvement in the following symptoms: shortness of
breath (P = .002), fatigue (P = .032), hoarseness (P = .043), and
anorexia (P = .042). Improvement was defined as improvement over
baseline sustained for at least two consecutive courses. In addition,
significantly fewer topotecan-treated patients (P = .023) experienced
interference with daily activities.
Of the other four symptoms measured, improvements in three symptoms
(chest pain, cough, insomnia) were numerically superior for
topotecan-treated patients, while improvement in hemoptysis was
numerically superior for patients treated with CAV, although this
symptom was not very frequent in either group.
Data from Open-Label, Noncomparative Trials
Data were also reviewed from three open-label, noncomparative trials
involving 319 patients with recurrent or progressive SCLC cancer
after treatment with first-line chemotherapy. These three studies
supported the results of the phase III study.
"We are extremely pleased with the committees positive
decision today," said Scott Z. Fields, MD, group director,
Oncology, Clinical Research, Development and Medical affairs North
America, SmithKline Beecham Pharmaceuticals, developers of topotecan.
"Topotecan has been one of the most extensively studied new
agents for the treatment of relapsed small-cell lung cancer, a very
deadly disease for which there are limited options."
As with many chemotherapeutic agents, the main side effect
experienced by topotecan in clinical trials was neutropenia, which
was predictable, noncumulative, and manageable. Nonhematologic side
effects were generally mild. The most commonly observed events were
low-grade nausea, vomiting, and diarrhea.
A Look Ahead
Topotecan was the first of the topoisomerase I class of drugs. It has
undergone extensive study as a single agent and in combination with
other drugs in clinical trials in the United States and Europe for
first and second-line treatment for SCLC. Topotecan is under clinical
investigation for a number of other cancers, including non-small-cell
lung, breast, colorectal, and pediatric cancers, lymphoma, myeloma,
and leukemia. It is also being studied as first-line combination
chemotherapy in patients with ovarian cancer.