Abstract
PurposeThese exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk).MethodsLogistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose.ResultsEffect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range.ConclusionsThe relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk.Trial registrationClinicaltrials.gov: NCT02454972; registered May 27, 2015.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide
In the Small-cell lung cancer (SCLC) cohort, lurbinectedin was efficacious in increasing the median objective response rate (ORR) in patients with resistant (22% [95% CI 11.2–37.1] and sensitive disease 45.0% [95% CI 32.1–58.4], by Independent Review Committee [IRC]) (n = 96), and in extending the overall survival (OS) in patients with resistant (5.0 months [95% CI 4.1–6.3]) and sensitive disease (11.9 months [95% CI 9.7–16.2])
Exposure-efficacy analyses were based on available exposure and efficacy data from SCLC patients treated with single-agent lurbinectedin from study B-005 (n = 99), and exposure-safety analyses were based on all single-agent lurbinectedin studies in non-hematological malignancies when the agent was given q3wk (n = 644)
Summary
Lung cancer is the leading cause of cancer deaths worldwide. Small-cell lung cancer (SCLC) accounts for about 15% of lung cancers overall and is a aggressive neoplasm with a 5-year survival rate of < 5%. Little progress has been made in improving the outcome for patients with this malignancy over the past 30 years. When patients with SCLC relapse, few therapeutic options are available. Topotecan was the only approved drug for secondline treatment of patients with a chemotherapy-free interval (CTFI) longer than 60 days. Topotecan use is challenging because of its associated hematological toxicities
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