14 CLINICAL STUDIES
14.1 Small Cell Lung Cancer
The efficacy of topotecan was studied in 426 patients with recurrent or progressive SCLC in a randomized, comparative trial and in 3 single-arm trials.
Randomized Comparative Trial
In a randomized, comparative trial, 211 patients were randomized 1:1 to received topotecan (1.5 mg/m2 once daily intravenously for 5 days starting on Day 1 of a 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, vincristine 2 mg administered sequentially on Day 1 of a 21-day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression and overall survival (OS).
The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 2.
| Parameter | Topotecan (n = 107) | CAV* (n = 104) | |
|---|---|---|---|
| Abbreviations: CI = confidence interval. | |||
| Overall response rate (95% CI) | 24% (16% to 32%) | 18% (11% to 26%) | |
| Complete response rate | 0% | 1% | |
| Partial response rate | 24% | 17% | |
| Response duration† (months) | |||
| Median (95% CI) | 3.3 (3.0 to 4.1) | 3.5 (3.0 to 5.3) | |
| Time to progression (months) | |||
| Median (95% CI) | 3.1 (2.6 to 4.1) | 2.8 (2.5 to 3.2) | |
| Hazard ratio (95% CI) | 0.92 (0.69 to 1.22) | ||
| Overall survival (months) | |||
| Median (95% CI) | 5.8 (4.7 to 6.8) | 5.7 (5.0 to 7.0) | |
| Hazard ratio (95% CI) | 1.04 (0.78 to 1.39) | ||
The median time to response was similar in both arms: topotecan 6 weeks (2.4 weeks to 3.6 months) versus CAV 6 weeks (5.1 weeks to 4.2 months).
Changes on a disease-related symptom scale are presented in Table 3. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 cycles. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.
| Symptom | Topotecan (n = 107) | CAV† (n = 104) | ||
|---|---|---|---|---|
| n‡ | % | n‡ | % | |
| Shortness of breath | 68 | 28 | 61 | 7 |
| Interference with daily activity | 67 | 27 | 63 | 11 |
| Fatigue | 70 | 23 | 65 | 9 |
| Hoarseness | 40 | 33 | 38 | 13 |
| Cough | 69 | 25 | 61 | 15 |
| Insomnia | 57 | 33 | 53 | 19 |
| Anorexia | 56 | 32 | 57 | 16 |
| Chest pain | 44 | 25 | 41 | 17 |
| Hemoptysis | 15 | 27 | 12 | 33 |
Single-Arm Trials
Topotecan was also studied in 3 open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all 3 trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all 3 trials and the comparative trial.