DISCUSSION
hepatic impairment, nausea, neutropenia, diarrhea, CML, thrombocytopenia, vomiting, rash, myelosuppression
HEPATIC IMPAIRMENT, NEUTROPENIA, THROMBOCYTOPENIA, SOLID TUMORS, CML
The exposure–response efficacy analysis demonstrated that cumulative MMR and CCyR were similar in patients who received a bosutinib starting dose of 400 mg QD in the BFORE and B1871048 trials and those who received a starting dose of 500 mg QD in the BELA trial. With regard to the relationships between metrics of bosutinib exposure and key efficacy and safety outcomes, the present analysis found that the log(For safety exposure–response analysis, the risks of experiencing the eight prespecified, clinically relevant AEs were correlated with bosutinib exposure, with higher exposures associated with greater risks of diarrhea, nausea, and vomiting early in the treatment period, and greater risks of experiencing rash, elevated ALT, and elevated AST at any time. The reason for the finding that higher levels of bosutinib exposure were associated with reduced risks of neutropenia and thrombocytopenia is unclear. One hypothetical possibility is that the more rapid suppression of the Ph + cell clone may allow for a more rapid recovery of normal hematopoiesis, minimizing periods of significant myelosuppression. A bosutinib exposure–response relationship was identified with time‐to‐event for diarrhea, nausea, and vomiting, whereas no demographic covariates (e.g., age, sex, Asian vs. non‐Asian) were statistically significant for any of these safety endpoints. Interestingly, as bosutinib exposure increases, the incidence of any AE grade is much lower with time on treatment for diarrhea, nausea, and vomiting. In the final model, a statistically significant relationship between In the population PK analysis, age and body weight were statistically significant covariates on bosutinib VAccording to the NCI ODWG criteria for hepatic impairment (in patients with solid tumors and CML), bosutinib CL did not appear to be altered by mild (B1 and B2) hepatic impairment. However, due to the limitations of the data used in this analysis, caution should be applied when trying to interpret the effect of hepatic impairment on bosutinib exposure. Hence, the current dosing adjustments should be followed based on the results of the dedicated hepatic impairment study (B1871003).The analyses presented here fulfill a commitment to the European Medicines Agency and the Committee for Medicinal Products for Human Use to update the population PK and exposure–response model with additional PK and safety data from Japanese patients with newly diagnosed CP‐CML and to assess any impact for Asian patients. The relative importance of peak levels and cumulative exposures in determining the safety and efficacy of TKIs used in this clinical setting may differ depending on the specific agent used. Although plasma exposure to an agent would be expected to be lower with a reduced dose, which was the case in the present analysis, the clinical efficacy of the agent may be improved if the number and duration of dose interruptions is minimized over the course of a chronic dosing schedule. Indeed, the importance of a dosing regimen that avoids frequent interruptions has been emphasized by results from recent studies of TKIs other than bosutinib. For example, while several studies of high‐dose imatinib with a rather rigid dosing regimen failed to demonstrate clinical benefit,Population PK studies have been used with similar intent for other TKIs in the CML setting to better understand adequacy of dosing and correlation with efficacy and safety.An exposure–response analysis similar to the present study was conducted for nilotinib using data from the ENESTnd trial.An exposure–response analysis, based on a PK model constructed using data from seven clinical trials of dasatinib, compared the four dasatinib dosing groups included in the Phase 3 trial that contributed the majority of patient data used in the PK model.The results from the present analysis should be considered in light of its limitations. This analysis was a retrospective modeling study including data from two clinical trials designed to assess the safety and efficacy of bosutinib compared with imatinib and a single‐arm study of bosutinib alone, none of which were designed for the purpose of generating a PK model used for investigating relationships between metrics of bosutinib exposure and clinical outcomes. The presence of unknown confounders that may have affected the results of the analysis cannot be ruled out. Moreover, while our analysis demonstrates a positive correlation between log(In conclusion, a bosutinib exposure–response relationship with safety and efficacy was observed in adult patients with newly diagnosed CP‐CML. However, the predicted exposures achieved within the recommended dose range (400–500 mg QD) appear to be at or near the plateau for efficacy, which is supported by similar response rates at the 400 and 500 mg dose levels across studies. For safety, patients who received a bosutinib starting dose of 400 mg QD in the BFORE and B1871048 trials had a lower rate of permanent discontinuations due to AEs in some patient populations, while maintaining efficacy—measured by cumulative MMR and cumulative CCyR—at a similar level to those who received a dose of 500 mg QD in the BELA trial. Therefore, we conclude that a bosutinib starting dose of 400 mg QD improved tolerability without compromising efficacy in adult patients with newly diagnosed CP‐CML.