Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

PURPOSE: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. METHODS: Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. RESULTS: To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. CONCLUSION: The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

AIMS: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. METHODS: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. RESULTS: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year. CONCLUSIONS: The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

Model-Informed Clinical Pharmacology Profile of a Novel Fixed-Dose Combination of Nivolumab and Relatlimab in Adult and Adolescent Patients with Solid Tumors.

PURPOSE: Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination (FDC) every 4 weeks (Q4W) versus nivolumab alone in patients with previously untreated advanced melanoma in RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response with nivolumab plus relatlimab in previously treated patients. Here, we evaluate the clinical pharmacology profile (CPP) of nivolumab plus relatlimab to support the approved regimen for adult and adolescent patients with advanced melanoma and its continued clinical development in solid tumors. EXPERIMENTAL DESIGN: The pharmacokinetics (PK) and immunogenicity of relatlimab and nivolumab were assessed using data from RELATIVITY-047 and RELATIVITY-020. Patients with advanced solid tumors received relatlimab alone or nivolumab plus relatlimab as single-agent vials (SAV) or FDC. PK was characterized using a population PK (popPK) model. RESULTS: Relatlimab demonstrated nonlinear and time-varying PK. Nonlinearity in relatlimab PK represented approximately 31% of total CL of relatlimab 160 mg Q4W. Relatlimab PK was dose proportional at doses ≥160 mg Q4W. Geometric mean exposures were similar for SAV and FDC cohorts receiving equivalent dosing regimens. No dose adjustment was required for covariates. Incidence of relatlimab antidrug antibodies was <6% for nivolumab plus relatlimab and had no clinically meaningful impact. There was no PK-related drug interaction of nivolumab plus relatlimab. CONCLUSIONS: The CPP of relatlimab alone or in combination with nivolumab supports the approved dosing in advanced melanoma and the continued evaluation of nivolumab and relatlimab across other solid tumors. See related commentary by Gopalakrishnan and Amaria, p. 2862.

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PK of nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials.

BACKGROUND: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. METHODS: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. RESULTS: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). CONCLUSIONS: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. TRIAL REGISTRATION NUMBER: NCT02538666; NCT02267343.

Exposure-Response Analysis to Support Nivolumab Once Every 4 Weeks Dosing in Combination with Cabozantinib in Renal Cell Carcinoma.

PURPOSE: A benefit:risk assessment for a less-frequent nivolumab 480 mg every 4 weeks + cabozantinib 40 mg every day dosing regimen was predicted using modeling and simulation of clinical trial data from nivolumab monotherapy studies and from the nivolumab 240 mg every 2 weeks + cabozantinib 40 mg every day dosing regimen, which demonstrated clinical benefit versus sunitinib in previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 9ER trial (NCT03141177). PATIENTS AND METHODS: Multivariable Cox proportional hazards analyses were conducted using nivolumab monotherapy data in previously treated aRCC and data from CheckMate 9ER to evaluate progression-free survival (PFS), overall survival (OS), and grade ≥2 immune-mediated adverse events (IMAE). RESULTS: Nivolumab 240 mg every 2 weeks + cabozantinib versus nivolumab monotherapy showed improvement in PFS (HR, 0.38; 95% CI, 0.31-0.47), OS (HR, 0.63; 95% CI, 0.46-0.85), and increased risk of grade ≥2 IMAEs (HR, 2.19; 95% CI, 1.79-2.67). Nivolumab exposure was not a predictor of PFS/OS or grade ≥2 IMAEs. Lower nivolumab clearance, male sex, higher baseline bodyweight, and Karnofsky performance (100) were each associated with PFS/OS improvements. Region and International Metastatic Renal Cell Carcinoma Database Consortium poor score were negative OS predictors. Age, baseline albumin, and programmed death ligand 1 status were not significant PFS/OS predictors. Cabozantinib was a significant grade ≥2 IMAE predictor, driven by diarrhea and hepatic events. Model-predicted PFS/OS and grade ≥2 IMAE rates were similar (<2.5% difference) for nivolumab 240 mg every 2 weeks + cabozantinib and 480 mg every 4 weeks + cabozantinib. CONCLUSIONS: Comparable benefit:risk was predicted for nivolumab 480 mg every 4 weeks + cabozantinib and nivolumab 240 mg every 2 weeks + cabozantinib.

A Machine-Learning Approach to Identify a Prognostic Cytokine Signature That Is Associated With Nivolumab Clearance in Patients With Advanced Melanoma.

Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy).

Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: translational PK/PD analysis in patients with renal cell carcinoma.

BACKGROUND: Although several therapeutic options for patients with renal cell carcinoma (RCC) have been approved over recent years, including immune checkpoint inhibitors, considerable need remains for molecular biomarkers to assess disease prognosis. The higher pharmacokinetic (PK) clearance of checkpoint inhibitors, such as the anti-programmed death-1 (PD-1) therapies nivolumab and pembrolizumab, has been shown to be associated with poor overall survival (OS) across several tumor types. However, determination of PK clearance requires the collection and analysis of post-treatment serum samples, limiting its utility as a prognostic biomarker. This report outlines a translational PK-pharmacodynamic (PD) methodology used to derive a baseline composite cytokine signature correlated with nivolumab clearance using data from three clinical trials in which nivolumab or everolimus was administered. METHODS: Peripheral serum cytokine (PD) and nivolumab clearance (PK) data from patients with RCC were analyzed using a PK-PD machine-learning model. Nivolumab studies CheckMate 009 (NCT01358721) and CheckMate 025 (NCT01668784) (n = 480) were used for PK-PD analysis model development and cytokine feature selection (training dataset). Validation of the model and assessment of the prognostic value of the cytokine signature was performed using data from CheckMate 010 (NCT01354431) and the everolimus comparator arm of CheckMate 025 (test dataset; n = 453). RESULTS: The PK-PD analysis found a robust association between the eight top-ranking model-selected baseline inflammatory cytokines and nivolumab clearance (area under the receiver operating characteristic curve = 0.7). The predicted clearance (high vs low) based on the cytokine signature was significantly associated with long-term OS (p < 0.01) across all three studies (training and test datasets). Furthermore, cytokines selected from the model development trials also correlated with OS of the everolimus comparator arm (p < 0.01), suggesting the prognostic nature of the composite cytokine signature for RCC. CONCLUSIONS: Here, we report a PK-PD translational approach to identify a molecular prognostic biomarker signature based on the correlation with nivolumab clearance in patients with RCC. This composite biomarker signature may provide improved prognostic accuracy of long-term clinical outcome compared with individual cytokine features and could be used to ensure the balance of patient randomization in RCC clinical trials.

Linking Tumor Growth Dynamics to Survival in Ipilimumab-Treated Patients With Advanced Melanoma Using Mixture Tumor Growth Dynamic Modeling.

Early tumor assessments have been widely used to predict overall survival (OS), with potential application to dose selection and early go/no-go decisions. Most published tumor dynamic models assume a uniform pattern of tumor growth dynamics (TGDs). We developed a mixture TGD model to characterize different patterns of longitudinal tumor sizes. Data from 688 patients with advanced melanoma who received ipilimumab 3 or 10 mg/kg every 3 weeks in a phase III study (NCT01515189) were used in a TGD-OS analysis. The mixture model described TGD profiles using three subpopulations (no-growth, intermediate, and fast). The TGD model showed a positive exposure/dose-response (i.e., a higher proportion of patients in no/intermediate growth subpopulations and a lower tumor growth rate with ipilimumab 10 mg/kg relative to the 3 mg/kg dose). Finally, the mixture TGD model-based measures of tumor response provided better predictions of OS compared with the nonmixture model.

Model-Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non-Small Cell Lung Cancer.

Nivolumab is the first anti-programmed death-1 agent approved in China for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Here, we characterize the population pharmacokinetics (PPK) of nivolumab monotherapy in Chinese patients with previously treated advanced/recurrent solid tumors, including NSCLC and nasopharyngeal cancer (NPC), using data from 2 predominantly Chinese (CheckMate 077 and 078), and 5 global (MDX1106-01, CA209-003, and CheckMate 017, 057, and 063) studies. The PPK model was developed by reestimating parameters of a prior global population model with Chinese patient data. Model reestimates showed nivolumab pharmacokinetics (PK) to be linear and dose proportional. Race did not have a clinically meaningful effect on nivolumab clearance. Body weight, Asian race, sex, and performance status had significant effects on clearance. Baseline clearance was 9% lower in the Asian versus the global population but not considered clinically relevant. Change in time-varying clearance and predicted nivolumab exposures with 3 mg/kg every 2 weeks (Q2W) were similar in Chinese, non-Chinese Asian, and non-Asian patients. In Chinese patients, the predicted nivolumab exposure with a 240-mg Q2W regimen was ∼25% higher than with 3 mg/kg Q2W, but ∼62% lower than that of a previously evaluated, well-tolerated regimen of 10 mg/kg Q2W (global population). Differences in nivolumab baseline clearance and exposures between patients with NPC and NSCLC were not clinically meaningful (<20%). Overall, PPK analysis demonstrated that nivolumab was not sensitive to race when evaluated in Chinese and non-Asian patients and exhibited similar PK in NSCLC and NPC.

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time-Varying Clearance.

Nivolumab clearance (CL) in patients with advanced melanoma (MEL) decreases over the treatment duration, with change in CL associated with improved disease status, measured by reduced tumor burden. Here, we characterize the pharmacokinetics of nivolumab administered as adjuvant therapy for patients with MEL (AdjMEL) whose tumors were removed by surgical resection. A population pharmacokinetic model was developed using data from 1,773 patients with AdjMEL, MEL, non-small cell lung cancer, and other solid tumors who received nivolumab over a dose range of 0.1-20 mg/kg every 2 weeks. In patients with AdjMEL, the geometric mean nivolumab CL of 6.0 mL/hour was 40% lower at baseline and did not vary with time and 20% lower at steady state compared with patients with MEL. Lower nivolumab CL in patients with AdjMEL and absence of time dependence support the hypothesis that changes in nivolumab CL in the metastatic setting are associated with disease status after treatment.

Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.

PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies. METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W. RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight. CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.

Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma.

Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure-response (E-R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E-R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ≥3 drug-related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E-R safety relationship, nivolumab demonstrated a favorable benefit-risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model-based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.

The Clinical Pharmacology of Elotuzumab.

Novel treatment options are needed to improve long-term outcomes for patients with multiple myeloma (MM). In this article, we comprehensively review the clinical pharmacology of elotuzumab, a first-in-class monoclonal anti-SLAMF7 antibody approved in combination with lenalidomide and dexamethasone (ELd) for the treatment of patients with MM and one to three prior therapies. Elotuzumab has a dual mechanism of action to specifically kill myeloma cells: binding SLAMF7 on myeloma cells facilitates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), and direct engagement of SLAMF7 on NK cells further enhances NK cell activity. Elotuzumab administration causes transient elevations of selected cytokines (tumor necrosis factor-α, interferon-γ-induced protein-10 and monocyte chemoattractant protein-1). The temporary nature of these elevations (greatest after the first dose, with a trend to return to baseline by day 7) suggests a low likelihood of facilitating clinically meaningful drug-drug interactions. Elotuzumab exposure increases more than proportionally to dose and >80% SLAMF7 receptor occupancy is achieved with the approved elotuzumab 10 mg/kg regimen. Population pharmacokinetic data from 375 patients demonstrated weight-based dosing is appropriate for elotuzumab, and that ethnicity and hepatic/renal function have minimal effects on exposure. Exposure-response analysis of patients treated with ELd demonstrated that increased elotuzumab exposure does not elevate the risk of grade 3+ adverse events (AEs) or AEs leading to discontinuation/death. Elotuzumab antidrug antibodies occurred in 18.5% of patients treated with ELd or elotuzumab plus bortezomib and dexamethasone, but were generally transient and did not affect elotuzumab efficacy or safety. A monotherapy study indicated elotuzumab does not have clinically relevant effects on QT intervals.

Nivolumab Exposure-Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non-Small Cell Lung Cancer.

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394-405. ©2017 AACR.

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors.

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches.

An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab.

Elotuzumab is a humanized, immunostimulatory anti-signaling lymphocytic activation molecule F7 (SLAMF7) IgG1 monoclonal antibody indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma (MM) who have received 1-3 prior therapies. We assessed the immunogenicity of elotuzumab as a monotherapy and in combination with bortezomib/dexamethasone and lenalidomide/dexamethasone in patients with MM in five clinical studies, including the pivotal ELOQUENT-2 trial (NCT01239797). Anti-drug antibody (ADA) prevalence was determined using a validated bridging assay. The prevalence of neutralizing antibodies (NAbs) was assessed in ADA-positive samples from ELOQUENT-2. Data from four trials of elotuzumab combined with lenalidomide/dexamethasone or bortezomib/dexamethasone (n = 390 evaluable patients) demonstrated that nine (2.3%) patients were ADA positive in baseline assays, 72 (18.5%) were ADA positive on-treatment or during follow-up, and two (0.5%) developed persistent ADAs. Patients treated with elotuzumab monotherapy had a higher incidence of elotuzumab ADAs than those on the combination therapy. In general, ADAs developed early and resolved after 2-4 months. Of 45 on-treatment ADA-positive patients in ELOQUENT-2, 19 had NAbs. Population pharmacokinetic modeling demonstrated an apparent increase in target-mediated elimination (higher V max, lower K M) in ADA-positive versus ADA-negative patients. ADAs were associated with lower elotuzumab steady-state exposure; however, this result may have been confounded by differential myeloma protein levels. ADAs/NAbs were not associated with hypersensitivity, infusion reactions, or loss of elotuzumab efficacy. Using a novel visualization, we also demonstrate that there is no clear relationship between the occurrence and titer values of ADA/NAbs and progression-free survival and best overall response status in patients treated with elotuzumab.

Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVES: Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. METHODS: The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. RESULTS: No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. CONCLUSIONS: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily.

Clinical Implications of the Pharmacokinetics of Crizotinib in Populations of Patients with Non-Small Cell Lung Cancer.

PURPOSE: We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUCss) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer. EXPERIMENTAL DESIGN: A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes. RESULTS: Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/minute; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/minute; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCss were not predicted to be clinically relevant. CONCLUSIONS: Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin ≤ 2.1 mg/dL or AST ≤124 U/L). Clin Cancer Res; 22(23); 5722-8. ©2016 AACR.

Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma.

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody in development for the treatment of patients with multiple myeloma who have received one or more prior therapies. In this work, 6958 elotuzumab serum concentrations from 375 patients enrolled in four Phase 1 to 3 clinical trials were used to analyze the pharmacokinetics (PK) of elotuzumab. A population PK model with parallel linear and Michaelis-Menten elimination from the central compartment and limited-capacity target-mediated elimination from the peripheral compartment described the elotuzumab concentration-time course. Clearance of elotuzumab increased with increasing body weight and weight-based dosing generated uniform exposures across a range of body weights. Coadministration of lenalidomide/dexamethasone background therapy decreased elotuzumab nonspecific clearance by 35 %. Target-mediated elimination of elotuzumab increased with increasing baseline serum M-protein, resulting in lower exposure in patients with high baseline serum M-protein concentration. Age, race, sex, renal and hepatic function, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, albumin and ß2-microglobulin had less than 20 % effect on model parameters and are unlikely to have clinically meaningful effects. Impact of anti-drug antibodies (ADAs) on the PK of elotuzumab was assessed as an ad hoc analysis. In the majority of ADA-positive patients, immunogenicity started early, was transient and resolved by 2-4 months. Since the majority of patients had ADAs detected early, this resulted in a corresponding transient increase in nonspecific clearance at these time points. Nonspecific clearance appeared to return to baseline at later time points when ADAs were no longer detected.