Aurélie Lombard (1,2), Hitesh Mistry (2,3), Leon Aarons (1,2), Kayode Ogungbenro (1,2)
(1) Centre for Applied Pharmacokinetic Research, (2) Division of Pharmacy and Optometry, (3) Division of Cancer Sciences, University of Manchester
Objectives: For most of chemotherapies, patients will receive the same dose/m2 on the 1st cycle. However, the interindividual variability in the pharmacokinetics of chemotherapy does generally not only rely on the body surface area. This dosing regimen contributes to a variability in chemotherapy exposure and leads to underdosed patients, who will not benefit from the optimal drug efficacy and to overdosed patients, who will develop toxicities. Neutropenia is one of the 1st causes of dose reduction with chemotherapy because of its damaging effect on neutrophil progenitors. In case of toxicity, the dose will generally be reduced in a similar way for all patients and will rarely be individualised. Mild chemotherapy-induced neutropenia has been associated with an increase in overall survival in non-small cell cancer patients [1] in an empirical manner. Therefore, neutrophil counts could be an interesting biomarker for chemotherapy efficacy that is directly linked to toxicities. Here, we explore the relationship between neutrophil metrics and patient survival. Once the association has been established we will perform dosing optimisation for patients with severe toxicities without compromising drug efficacy at a population level.
Methods: Comparator arm data of a phase III clinical was collected for this analysis (NCT00076388 trial extracted from ProjectDataSphere [2]). Patients with non-small cell lung cancer were treated with docetaxel (75 mg/m2 infusion every 3 weeks). The 1st cycle neutrophil profile was described using the Friberg model [3] where drug effect was driven by docetaxel concentrations derived from the Fukae et al. population pharmacokinetic model [4] using a linear model. Individual parameter estimates of docetaxel effect on neutrophils (Slope) were derived using the posthoc option of the nlmixr package in the R software (version 3.5.2). Other neutrophil metrics were also derived from the neutrophil profiles, such as neutrophil counts at baseline. (1) Cox proportional hazards model was used to explore the relationship between pre-treatment patient characteristics, docetaxel effect on neutrophils (Slope*Cmax) and overall survival. (2) An algorithm for dosing optimisation was developed to perform dose reduction without compromising drug efficacy (overall survival/risk score) for patients with severe toxicities (neutropenia). Individual risk scores, representing the risk of patients’ death, were computed using the final survival model and patient characteristics using Slope*Cmax as a marker of patients’ response. Simulations were performed to predict individual neutrophil nadir following docetaxel administration for a range of doses (45-70 mg/m2). The algorithm was parametrized to identify an individual dose leading closer to a neutrophil nadir target of 1.0 109/L without increasing the risk score more than 10%. As safety comes first, a neutrophil nadir of 0.5 109/L was defined as the minimum threshold to not go under whatever the increase in the risk score. The simulated individual 1-year survival probability associated with the original dose and the reduced dose were compared.
Results: (1) The following pre-treatment patient characteristics were associated with patient survival and were included in the final survival model: ECOG performance status; smoking status; liver metastasis; tumour burden; neutrophil counts and albumin. After taking into account these prognostic factors, docetaxel effect on neutrophil (Slope*Cmax) was found to be associated with patient survival (p=0.005). (2) According to the algorithm, 197 out of 366 patients would have benefited from a dose reduction. The simulated individual 1-year survival probabilities associated with the original dose and the reduced dose were not different (p=0.19).
Conclusion: The strong relationship between docetaxel effect on the 1st cycle neutrophil profile and patient survival suggests that this marker of patients’ response could be used to individualise the dose. The algorithm highlights that doses can be reduced without compromising overall survival in case of severe toxicities.
References:
[1] Di Maio et al. Lancet Oncol. (2005);6(9):669-77.
[2] www.projectdatasphere.org (Assessed 2020).
[3] Friberg et al. J Clin Oncol. (2002);20(24):4713-21.
[4] Fukae et al. Cancer Chemother Pharmacol. (20160;78(5):1013-23.
Reference: PAGE () Abstr 9311 [www.page-meeting.org/?abstract=9311]
Poster: Oral: Clinical Applications