Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surgery. We report a nintedanib exposure-response relationship in the nintedanib arm.
Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar model-building strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings.
The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found.
An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM.
2011-006288-23.
ARCAGY-GINECO.
Boehringer Ingelheim.
N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.