ODAC Recommends Approval of Topotecan for Second- Line Treatment of Small-Cell Lung Cancer

The FDA’s 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 committee’s 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.