Assessment of nivolumab benefit–risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors

Zhao, Xiaochen; Suryawanshi, Satyendra; Hruska, Matthew; Feng, Yufei; Wang, X.; Shen, Jun; Vezina, Heather; McHenry, M. Brent; Waxman, Ian M.; Achanta, A.; Bello, Akintunde; Roy, Amit; Agrawal, Shruti

doi:10.1093/annonc/mdx235

Cited by 169 publications

(183 citation statements)

References 14 publications

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“…However, for most of these antibodies, the estimated effect of BW on CL in their respective PopPK analyses had a coefficient ranging from 0.4 to 0.6, indicating the effect was less than proportional and both flat or BW‐based dosing will be suitable for these mAbs. Additionally, modelling and simulation studies using a range of mAbs have now suggested that BW‐based and flat dosing resulted in similar PK or pharmacodynamic variability, so BW‐based dosing does not always offer an advantage over flat dosing …”

Section: Discussionmentioning

confidence: 99%

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Bajaj

Suryawanshi

Roy

et al. 2019

Brit J Clinical Pharma

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Aims The development of monoclonal antibodies (mAbs) requires an understanding of the interindividual variability (IIV) in pharmacokinetics (PK) at the population level facilitated by population PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare the effect of covariates on PK parameters for mAbs in oncology and identify the most commonly used covariates affecting PK parameters. Methods All 25 mAbs approved for therapeutic use in oncology until December 2017 by the Food and Drug Administration and the European Medicines Agency were selected for study. Literature searches revealed 23 available PopPK models for these mAbs. To understand the magnitude and types of covariate effect on PK parameters, all covariates included in the final PopPK model for each mAb were summarized. Results The most commonly identified covariates were baseline body weight (BW; 17 mAbs), baseline serum albumin (8 mAbs), and sex (7 mAbs) on clearance; and BW (16 mAbs) and sex (12 mAbs) on central volume of distribution. A reduced PopPK model was developed for nivolumab and ipilimumab using these covariates, and the percentage of explained IIV from the reduced model (20.3% and 16.8%, respectively) was compared with that from the full model (24.5% and 27.9%, respectively). Conclusions This analysis provides a uniform platform for selecting covariates and suggests that the effect of BW, albumin and sex should be included during the development of PopPK models for mAbs in oncology. The reduced model was able to explain IIV to a similar extent as the full model.

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Section: Discussionmentioning

confidence: 99%

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Bajaj

Suryawanshi

Roy

et al. 2019

Brit J Clinical Pharma

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“…Nivolumab monotherapy was originally approved at a BWT‐ based dose of 3 mg/kg q2w, but the approved dose has recently been revised to 240 mg q2w or 480 mg q4w across multiple indications . Flat and less frequent dosing regimens can reduce the burden of frequent, lengthy intravenous treatments and allow combination of nivolumab with other agents with various dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Flat and less frequent dosing regimens can reduce the burden of frequent, lengthy intravenous treatments and allow combination of nivolumab with other agents with various dosing regimens. Based on PopPK modeling and exposure–response analyses for efficacy and safety, the benefit‐risk profile of the 240 mg q2w dose was determined to be comparable to the 3 mg/kg q2w dose . We extended this assessment in AdjMEL, and BIC post hoc estimates of exposures demonstrated that model predictions for the flat 240 mg q2w and the 480 mg q4w doses achieved comparable C avg ss (<1%) as the 3 mg/kg q2w dose.…”

Section: Discussionmentioning

confidence: 99%

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

Hamuro

Statkevich

Bello

et al. 2019

Clin Pharma and Therapeutics

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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.

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“…2 Following the initial body weight-based approvals, the need for this type of dosing was reassessed for both pembrolizumab and nivolumab based on population PK modeling and therapeutic window information derived from exposure-response analyses, as well as demonstrated clinical safety at doses up to 10 mg/kg. 62,63 These assessments showed that 200-mg and 2 mg/kg doses provided similar exposure distributions for pembrolizumab and that the benefitrisk profile of nivolumab 240 mg every 2 weeks was comparable to 3 mg/kg every 2 weeks. Pembrolizumab was approved as a flat dose for all indications subsequent to melanoma, whereas in the case of nivolumab, modification of the initially approved 3 mg/kg every-2-week regimen to 240 mg every 2 weeks was approved by the FDA for melanoma, NSCLC, urothelial cancer, and RCC indications.…”

Section: Dosing Strategy (Flat Dosing Versus Body Weight-based Dosing)mentioning

confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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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. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

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Assessment of nivolumab benefit–risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors

Cited by 169 publications

References 14 publications

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

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

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

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