• Topotecan (Hycamtin®) is a cytotoxic agent that works by inhibiting topoisomerase I, an enzyme involved in DNA replication. It is available as an injection for intravenous (IV) infusion and also as capsules; both are licensed for use in the second-line treatment of small cell lung cancer (SCLC) in patients for whom re-treatment with the firstline regimen is not considered appropriate.
• This review focuses on the data to support topotecan as a treatment for patients who would be considered unsuitable to receive an anthracycline (e.g. pre-existing cardiac conditions, as the standard second-line regimens for SCLC contain doxorubicin. The oral form is a treatment option for those who are considered in general to be inappropriate for IV therapy.
• NICE is currently reviewing topotecan for the second-line treatment of SCLC; a Final Appraisal Determination was issued in September 2009. This recommends oral topotecan as an option for people with relapsed SCLC for whom retreatment with the first-line regimen is not considered appropriate and the combination of cyclophosphamide, doxorubicin and vincristine (CAV) is contra-indicated. IV topotecan is not recommended for people with relapsed SCLC.
• Three Phase III trials evaluating topotecan in the second-line treatment of SCLC were identified; these provide information on the efficacy of topotecan compared with comparators of BSC and CAV, and of oral compared to IV topotecan, in the second-line setting.
• The main study (478) providing support for the use of topotecan monotherapy in the proposed indication included patients with SCLC who had progressed ≥45 days after completing first-line therapy, but who were deemed unsuitable for further IV chemotherapy. Initially this was restricted to those with a short treatment-free interval (risks and benefits of chemotherapy in this group are unproven) but further patients were permitted as the trial progressed (e.g. comorbidities, patient refusal). The primary endpoint was overall survival, which was a median of 13.9 weeks (95% CI 11.1 to 18.6) in the BSC arm (n=70) and 25.9 weeks (18.3 to 31.6) in the BSC plus oral topotecan arm ( 2.3mg/m2/day on days 1-5 every 21 days, n=71). This represented an absolute difference of 12 weeks (adjusted HR 0.61; 95% CI 0.43 to 0.87; p=0.01).
• An earlier Phase III study compared topotecan IV to CAV chemotherapy in patients with SCLC (limited or extensive) who had progressed ≥60 days following completion of first-line chemotherapy (study 090). Although this is not a relevant comparator for the subgroup of patients being considered here, it provides evidence that topotecan monotherapy results in similar response rates to the standard second-line therapy: 24.3% (95% CI 16.2 to 32.4) for IV topotecan and 18.3% (10.8 to 25.7) for CAV (difference of 6.0%, 95% CI -5.9 to 18.0%; p=0.285).
• Study 396, alongside an earlier Phase II study, is being used to support the assumption that oral and IV topotecan result in similar responses in this setting. In patients with SCLC who had progressed ≥ 90 days following completion of first-line chemotherapy, oral topotecan (2.3mg/m2 daily, days 1-5; n=153) resulted in a similar response rate to IV topotecan (1.5mg/m2 daily, days 1-5; n=151). The response rates were 18.3% (28/153) and 21.9% (33/151), respectively, with an inter-group difference (oral minus IV) of -3.6% (95% CI -12.6% to +5.5%). As the pre-defined lower non-inferiority bound of -10% was not met, non-inferiority of oral topotecan to IV topotecan was not demonstrated. The NICE Appraisal Committee accepted that oral and IV topotecan were similaar in terms of clinical efficacy.
• The addition of oral topotecan to BSC was associated with a higher incidence of all grade 3/4 serious adverse events, except for disease progression. Six patients (8.6%) in the topotecan group required IV antibiotics for fever, febrile neutropenia, or infections that were due to grade 4 neutropenia, compared to none in the BSC only group. The most frequent grade 3/4 non-haematological AEs in the oral topotecan plus BSC group were diarrhoea (6%), fatigue (4%), vomiting (3%) and dyspnoea (3%).
• The manufacturer's model estimated the incremental cost-effectiveness ratio (ICER) for oral topotecan plus BSC compared with BSC alone to be £26,833 per QALY gained, in patients for whom IV chemotherapy was considered unsuitable. The SMC submission notes that the ICER rose to over £30,000 if the assumptions made on quality of life values, drug administration costs, or costs associated with adverse events were changed.
• The company submission to the AWMSG estimated that 0.51 people with relapsed SCLC per 100,000 population would be eligible for topotecan therapy. Assuming a 50% uptake, the cost of topotecan can be broadly estimated as £1,482 per 100,000 population for IV topotecan (£5812 for 4 courses) and £612 per 100,000 population for oral topotecan (£2400 for 4 courses).