Model-Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non-Small Cell Lung Cancer.
ABSTRACT: 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.
Project description:LESSONS LEARNED:Nivolumab treatment at doses of 3 mg/kg once every 2 weeks (Q2W), 240 mg Q2W, and 360 mg once every 3 weeks was well tolerated in the Chinese population, with no new safety signals identified.Comparison of intensive pharmacokinetic profiles of nivolumab at 3 mg/kg Q2W in Chinese versus global populations revealed no ethnic differences of nivolumab treatment.Nivolumab shows promising preliminary antitumor activity in nasopharyngeal carcinoma. BACKGROUND:This phase I/II study investigated the safety and pharmacokinetics (PK) of nivolumab (anti-programmed cell death-1 monoclonal antibody) in Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors. METHODS:A dose evaluation phase (3 mg/kg once every 2 weeks [Q2W]) was followed by a cohort expansion phase (3 mg/kg Q2W or flat doses of 240 mg Q2W or 360 mg once every 3 weeks). RESULTS:In the dose evaluation phase, 8/8 patients completed one cycle with no dose-limiting toxicities. At data cutoff, 46/51 patients were evaluable for safety (all cohorts). Treatment-related adverse events (TRAEs) occurred in 35 (76%) patients and were primarily grade 1-2; one patient (3 mg/kg Q2W) discontinued because of study drug toxicity. Intensive PK profiles at 3 mg/kg, 240 mg, and 360 mg were well characterized at single and multiple doses of nivolumab. An objective response was determined in six (6/46) patients, four (4/32) of whom had NPC tumors. CONCLUSION:Nivolumab monotherapy at 3 mg/kg and flat doses of 240 mg and 360 mg were well tolerated in this Chinese patient population, with PK profiles at 3 mg/kg being similar to those of global patients. Preliminary efficacy results showed promising antitumor activity of nivolumab in advanced NPC.
Project description:Nivolumab 3?mg/kg every 2?weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology.A flat dose of 240?mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ?80?kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240?mg was evaluated by comparing exposures at 3?mg/kg Q2W and 240?mg Q2W across BW and tumor types; clinical safety at 3?mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240?mg Q2W relative to 3?mg/kg Q2W in melanoma, NSCLC, and RCC.The median nivolumab exposure and its distribution at 240?mg Q2W were similar to 3?mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3?mg/kg Q2W or 240?mg Q2W flat dose.Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240?mg Q2W was comparable to 3?mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.
Project description:BACKGROUND:The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial. METHODS:The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed. RESULTS:The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs. CONCLUSIONS:Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy. CLINICAL TRIAL REGISTRATION:NCT02105636.
Project description:This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.
Project description: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.
Project description:Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors.
Project description:Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years' minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.
Project description:BACKGROUND:Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. METHODS:We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. FINDINGS:Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1% PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients treated with nivolumab, compared with 5% (3-7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12-0·27) for nivolumab and 0·43 (0·29-0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37-0·71) for nivolumab and 0·80 (0·61-1·04) for docetaxel. Long-term data did not show any new safety signals. INTERPRETATION:Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. FUNDING:Bristol-Myers Squibb.
Project description:Background: The CheckMate 227 trial has indicated that nivolumab plus ipilimumab compared with chemotherapy significantly increases long-term survival in the first-line setting of advanced non-small-cell lung cancer (NSCLC). Methods: A Markov model was built to estimate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy as the first-line therapy in patients with advanced NSCLC based on outcomes data from the CheckMate 227 trial. We calculated the cost and health outcomes at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in populations with different programmed death ligand 1 (PD-L1) expression levels (?50, ?1, and <1%) or a high tumor mutational burden (TMB) (?10 mutations per megabase). Sensitivity analysis were used to test the model stability. Results: The outcomes showed that the incremental costs and QALYs by using nivolumab plus ipilimumab were $124180.76 and 1.16, $70951.42 and 0.53, $144093.63 and 0.83 for the advanced NSCLC patients with a PD-L1 expression ?50%, ?1%, and <1%, which led to an incremental cost-effective ratio (ICER) of $107403.72, $133732.20, and $172589.15 per QALY, respectively. For patients with a high TMB, nivolumab plus ipilimumab contributed an extra 2.04 QALYs at a cost of $69182.50 per QALY. Conclusion: Nivolumab plus ipilimumab as first-line therapy makes a better cost-effective strategy than chemotherapy in advanced NSCLC patients with PD-L1 expression levels ?50% and ?1% or a high TMB, at a willingness-to-pay threshold of $150,000 per QALY, but not in the patients with a PD-L1 expression <1%.
Project description:BACKGROUND AND OBJECTIVE:The economic assessment of immuno-oncology agents in Chinese patients is limited despite a need for new therapies. Nivolumab is the first immune checkpoint inhibitor approved for the second-line treatment of non-small cell lung cancer (NSCLC) in China, and it significantly prolongs overall survival. However, considering the high cost of nivolumab, it is urgent to assess its value in China in terms of both efficacy and cost. The objective of this study was to investigate the cost-effectiveness of nivolumab vs docetaxel in the second-line setting for NSCLC patients from the Chinese healthcare system perspective. METHODS:A Markov model consisting of three health states, was designed to evaluate the lifetime cost and effectiveness of nivolumab vs docetaxel in the second-line treatment of NSCLC patients. Clinical data was derived from the CheckMate 078 phase III clinical trial, which included 504 patients predominantly from China. Parametric survival models to fit and extrapolate survival data were chosen based on clinical rationality, visual fit and statistical goodness-of-fit. Lifetime costs and health outcomes were calculated, and US$28,899 and $63,564 per quality-adjusted life-year (QALY) were selected as the willingness-to-pay (WTP) threshold values for general regions and affluent regions, respectively. One-way and probabilistic sensitivity analyses were undertaken to explore the robustness of the model. Additional subgroup analyses were performed. RESULTS:In base case analysis, Nivolumab yielded an additional 0.24 QALYs, at a cost of $93,307 per QALY. Sensitivity analyses suggested that the results to be most sensitive to the price of nivolumab per kg (mean $60.00; range $26.00-$60.00) and the mean patient weight (65 kg, range 52-78 kg). Utility values in progression-free survival state (mean 0.804; range 0.643-0.965) and overall survival hazard ratio (0.68; 97.7% CI 0.52-0.90) had moderate impact on the model results. Subgroup analyses indicated that nivolumab was most cost-effective for patients who were 65 years of age or older ($85,171/QALY), followed by female patients ($85,273/QALY) and patients with tumor PD-L1 expression at least 1% ($90,309/QALY). CONCLUSIONS:Nivolumab is unlikely to be cost-effective compared with docetaxel for patients with previously treated advanced NSCLC in China. Ensuring that nivolumab is included in the National Reimbursement Drug List (NRDL) may be a valid mean of meeting extensive treatment demands in China.