Mark Stroh(1), Michelle Green(2), Ed Cha(1), Nancy Zhang(2), Russ Wada(2), and Jin Jin(1)
(1) Genentech, Inc., (2) Quantitative Solutions, Inc.
Objectives: Meta-analysis of published trial data for docetaxel monotherapy was undertaken to elucidate its efficacy and safety profile in second-line non-small-cell lung cancer (NSCLC).
Methods: A literature database was constructed based on a review of published trials including docetaxel monotherapy treatment arms. Grade 3/4 neutropenia, overall response rate (ORR), and overall survival (OS) were selected for model-based meta-analysis (MBMA). In addition to assessing dose-response relationships, effects of treatment regimen and population characteristics were examined. Neutropenia and ORR were modelled using logistic regression. For OS, Kaplan-Meier curves were modelled based on a reference survival curve and benchmark prognostic factors[1]. The reference curve was derived from a published meta-analysis of individual data from second-line NSCLC (Di Maio analysis)[2].
Results: The literature database included 46 unique trials, with 57 treatment arms and summary-level data for 6085 NSCLC patients receiving docetaxel alone as second-line therapy. Doses ranged from 25 mg/m2 to 100 mg/m2 with 1036, 158, and 4891 subjects treated with QW, Q2W, and Q3W regimens, respectively. Neutropenia, ORR, and OS data were reported for 51, 52, and 52 of the 57 treatment arms.
Grade 3/4 neutropenia incidence was described as the inverse logit of a linear function of dose (odds ratio (OR) = 1.05 per unit increase in dose, 95% CI 1.04 to 1.06), with a Japanese study effect (OR = 17.1, 95% CI 6.05 to 48.4) capturing the substantial increase in neutropenia evident in the three Japanese studies included in the database. ORR was described as the inverse logit of a linear function of actual cumulative dose (OR = 1.004 per unit increase in cumulative dose, 95% CI 1.001 to 1.008) and median population age (OR=1.08 per year, 95% CI 1.02 to 1.15). For both neutropenia and ORR, docetaxel exposure (dose or cumulative dose) was a stronger predictor than regimen (Q3W versus QW). No dose-response relationship was detected for OS; however, a Japanese study effect (HR=0.65, 95% CI 0.51 to 0.84) was quantified in addition to the prognostic factors identified by the Di Maio model.
Conclusions: MBMA revealed dose-response relationships for neutropenia and ORR, as well as important population characteristics that influence the three endpoints examined. These findings can be used to support trial design and normalize results for patient prognostic factors in support of approval of new therapies.
References:
[1] Wada R. Technical Challenges in Modeling Kaplan-Meier Survival Curves. Presented at the American Conference on Pharmacometrics, May 2013; Ft. Lauderdale, FL.
[2] Di Maio M, Lama N, Morabito A, Smit EF, Georgoulias V, Takeda K, Quoix E, Hatzidaki D, Wachters FM, Gebbia V, Tsai CM, Camps C, Schuette W, Chiodini P, Piccirillo MC, Perrone F, Gallo C, Gridelli C. Clinical assessment of patients with advanced non-small-cell lung cancer eligible for second-line chemotherapy: a prognostic score from individual data of nine randomised trials. Eur J Cancer. 2010 Mar; 46(4):735-43. doi: 10.1016/j.ejca.2009.12.013. Epub 2010 Jan 4. PubMed PMID: 20045311.
Reference: PAGE 23 (2014) Abstr 3138 [www.page-meeting.org/?abstract=3138]
Poster: Drug/Disease modeling - Oncology