British Journal of Clinical Pharmacology

Exposure–response relationships of mirvetuximab soravtansine in patients with folate receptor‐α‐positive ovarian cancer: Justification of therapeutic dose regimen

AimsThis study aimed to investigate exposure–response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first‐in‐class antibody–drug conjugate approved for the treatment of folate receptor‐α‐positive platinum‐resistant ovarian cancer.MethodsMIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV‐treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy‐controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).ResultsIn the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression‐free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration–time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.ConclusionThe trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor‐α positive ovarian cancer: The antibody–drug conjugate, payload and metabolite

AimsMirvetuximab soravtansine is a first‐in‐class antibody–drug conjugate recently approved for the treatment of folate receptor‐α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration–time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S‐methyl‐DM4).MethodsMirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum‐resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed‐effects modelling approach. Stepwise covariate modelling was performed to identify covariates.ResultsWe developed a semi‐mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S‐methyl‐DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated.ConclusionThere is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

A quantitative model‐based approach for adavosertib dose selection in patients with uterine serous carcinoma

Aims Adavosertib, a WEE1 inhibitor, has been studied for safety and efficacy as monotherapy and in combination therapy. The phase 2b ADAGIO trial (NCT04590248) evaluated adavosertib monotherapy for uterine serous carcinoma with a recommended dose of 300 mg administered on days 1–5 and 8–12 of a 21‐day cycle. However, reports of severe neutropaenia and dose reduction in approximately half of patients at 300 mg raised potential tolerability concerns. Methods We conducted a model‐based benefit–risk analysis, including an exposure‐safety analysis, pooling data from all AstraZeneca‐sponsored monotherapy studies. Analysis focussed on the relationship between adavosertib exposure and incidence of adverse events (AEs) such as haematological and gastrointestinal toxicities. A preliminary exposure–efficacy analysis was conducted based on available efficacy data from the ADAGIO study. Results A strong correlation was observed between adavosertib exposure and predicted probability of developing neutropaenia. In addition, baseline creatinine clearance (bCL Cr ) was identified as an independent factor for severe neutropaenia development. Patients with bCL Cr  ≥ 50 ml/min were less likely to experience severe neutropaenia than those with bCL Cr  < 50 ml/min. The model showed that a dose reduction from 300 to 250 mg reduced the predicted probability of neutropaenia by 55% when compared at the 95th percentile exposure range at these doses. Contrary to exposure safety, the exposure–efficacy relationship was similar across doses. Conclusion The approach identifies risk factors that can aid in the decision to use a 250‐mg monotherapy dose. This regimen may manage haematological toxicities across studies. A quantitative model‐based approach predicts that reducing adavosertib doses minimizes risks, underscoring the need for dose adjustment.

Population pharmacokinetics and exposure–response relationships of dostarlimab in primary advanced or recurrent endometrial cancer in part 1 of RUBY

AimsDostarlimab‐gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein‐1 (PD‐1) receptor and blocks its ligands. RUBY (NCT03981796) is a two‐part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure–efficacy/safety (ER) relationships.MethodsA PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure–safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure–efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression‐free survival (PFS).ResultsFor the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure–safety or exposure–PFS relationships.ConclusionsThe addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure–safety or exposure–PFS relationships.