Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma

Yan, Feng; Roy, Amit; Masson, Éric; Chen, Tai-Tsang; Humphrey, Rachel; Weber, Jeffrey S.

doi:10.1158/1078-0432.ccr-12-3243

Cited by 165 publications

(153 citation statements)

References 17 publications

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“…With ipilimumab treatment in melanoma patients, C minss was identified as a significant predictor for the occurrence of an immune-related AE (irAE). 94 The probability of experiencing grade ࣙ3 irAEs increased with increasing ipilimumab exposure at the median C minss for doses of 0.3, 3, and 10 mg/kg; however, analyses of the relationship between exposure and safety with approved PD-1 and PD-L1 inhibitors have found a flat relationship. In patients with melanoma who received nivolumab 0.1 to 10 mg/kg every 2 weeks, the risk of time to first grade ࣙ3 drug-related AEs S37 and AEs leading to discontinuation did not increase with average concentration at steady state (C avgss ).…”

Section: Exposure-safety Relationshipmentioning

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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Section: Exposure-safety Relationshipmentioning

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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“…[67][68][69][70] A meta-analysis including 1265 patients from 22 clinical trials found that the risk of developing an immune-related adverse event (any grade) was threefold higher with ipilimumab 10 mg/kg versus 3 mg/kg. 68 In EORTC 18071, grade 3 to 4 adverse events were more common with ipilimumab versus placebo (54% vs 25%), as were immune-related adverse events (grade 3, 37% vs 2%; grade 4, 6% vs <1%).…”

Section: High-dose Ipilimumabmentioning

confidence: 99%

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

Coit¹,

Thompson²,

Algazi³

et al. 2016

J Natl Compr Canc Netw

219

167

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OverviewIn 2016, an estimated 76,380 patients will be diagnosed with and approximately 10,130 patients will die of melanoma in the United States.1 However, these figures for new cases may represent a substantial underestimate, as many superficial and in situ melanomas treated in the outpatient setting are not reported. The incidence of melanoma continues to increase dramatically, at an overall rate of 33% for men and 23% women from 2002 to 2006.2 Melanoma is increasing in men more rapidly than any other malignancy, and in women more rapidly than any other malignancy except lung cancer. AbstractThis selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and highdose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted reassessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections. J Natl Compr Canc Netw 2016;14(4):450-473 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.All recommendations are category 2A unless otherwise noted.Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please NoteThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines ® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network ® (NCCN ® ) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way. The full NCCN Guidelines for Melanoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.© National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. Disclosures for the NCCN Melanoma ...

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“…The cut-off for maximal binding for CD80 and CD86 has been reported as target concentrations of 20 μg/mL and 3 μg/mL, respectively. [34] Recent data have also shown that the activity of ipilimumab may also involve selective depletion of regulatory T cells within tumor lesions, which suggests that target concentrations may not reflect the clinical endpoints sufficiently. [35] The results from the phase III trial (ClinicalTrials.gov registry number NCT01515189) will help us fully understand the mechanism of action and dose-effect relationship for ipilimumab.…”

Section: Transl Clin Pharmacolmentioning

confidence: 99%

Clinical pharmacologic aspects of immune checkpoint inhibitors in cancer therapy

Kim

Jung

2016

Transl Clin Pharmacol

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During the past two years, three immune checkpoint inhibitors, ipilimumab, nivolumab and pembrolizumab, have been approved and revolutionized cancer immunotherapy. Translational and clinical pharmacology of these agents have contributed in identifying patients who will receive benefit, dose effect relationship and surrogate endpoints of clinical benefit. In addition, population pharmacokinetics/pharmacodynamics have facilitated scientific clinical development, which has led to accelerated approval of these agents. This paradigm may show how early phase studies may allow identification of subgroup of patients who can benefit and subsequent approval of drugs based on smaller patient population. This may speed the access of effective treatment for patients with lifethreatening diseases. IntroductionColey had reported the shrinkage of sarcoma after the bacterial infection erysipelas in the late 19th century.[1] The low rate of response portrayed two important issues: the potential of harnessing the immune system against cancer and the importance of selecting the right patients. These issues are persistent despite recent breakthroughs of cancer immunotherapy. In addition, many clinical pharmacology issues have risen regarding optimum dose and response evaluation. This review is a tutorial on the development of recently approved immune checkpoint inhibitors focused on clinical pharmacology and translational research. T lymphocytes are pivotal in immunologic surveillance a process critical for the identification and elimination of tumor cells.[2] T cell receptor (TCR) is the key molecule that is related to the recognition of tumor cells. [3] After the TCR binds with the major histocompatibility complex (MHC) on the cell surface of tumor cells, various other ligand-receptors interactions come into place, which are co-stimulatory and co-inhibitory. The latter are often called "immune checkpoints" and include cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), T-cell immunoglobulin domain and mucin domain 3 (TIM3), and lymphocyte-activation gene 3 (LAG3).During the past two years, the three drugs, ipilumumab, nivolumab and pembrolizumab, have revolutionized cancer immunotherapy. These immune checkpoint inhibitors block the co-inhibitory signals related to tumors, which subsequently leads to an immune response against tumors. [4] Pathology of Cancer ImmunotherapyPathology has been a cornerstone in identifying patients who might respond to immune checkpoint inhibitors. Pathologic evaluation reveals patients' characteristics that suggest "immune targetable lesion" that include inflamed tumor environment, gene mutation load and molecular markers related with immune escape mechanisms. Inflamed tumor environment are comprised of T cells which are tumor-infiltrating lymphocytes (TILs) recruited into the tumor. TILs are seen in various entities including melanoma, breast cancer and colorectal cancer and the quantity of TILs at diagnosis is often associated with prognosis.[5] Further stratificati...

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Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma

Cited by 165 publications

References 17 publications

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

Clinical pharmacologic aspects of immune checkpoint inhibitors in cancer therapy

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