Population Pharmacokinetics of Nivolumab in Combination With Ipilimumab in Patients With Advanced Malignancies.

Nivolumab is a fully human monoclonal antibody that inhibits programmed cell death-1 activation. To assess covariate effects on nivolumab clearance (CL), a population pharmacokinetics model was developed using data from 6,468 patients with colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, or small cell lung cancer who received nivolumab as monotherapy or in combination with ipilimumab or chemotherapy across 25 clinical studies. Nivolumab CL was similar across the tumor types examined; CL was higher for ipilimumab 1 mg/kg every 6 weeks (by 17%) and 3 mg/kg every 3 weeks (by 29%) vs. nivolumab monotherapy. Nivolumab CL over time was partially explained by time-varying covariates. A greater decrease in nivolumab time-varying CL was associated with increased albumin and body weight and a responder status. Our findings support the observed association between nivolumab CL and disease severity.

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology.

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.

Current knowledge of Ipilimumab and its use in treating non-small cell lung cancer.

Introduction: The systemic treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the identification of actionable mutations and the use of targeted agents. Unfortunately, many tumors will acquire resistance and >75% of NSCLC cases lack for an actionable gene aberration. In this setting, immunotherapy rises as effective therapeutic where immune checkpoint inhibitors have entered or are entering the market in many neoplasms, including NSCLC. Ipilimumab is a monoclonal antibody targeting CTLA-4, promoting T-cell activation and its subsequent anti-tumoral immune effect. Ipilimumab might have a very important role in NSCLC as it does in melanoma because of its synergistic effect with PD-1/PDL-1 inhibitors. Areas covered: We summarize current results of clinical studies of ipilimumab for efficacy and safety in NSCLC and also the current knowledge about potential biomarkers for its efficacy. Expert Opinion: Combined use of PD-1/PDL-1 and anti-CTL4 inhibitors increases the efficacy against NSCLC and it is a very promising approach not only in NSCLC but also in small cell lung cancer (SCLC) for first or second-line therapy. It's very important to identify biomarkers that can better select the population of patients that benefit the most with these checkpoint inhibitors.

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to FDA approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018. Areas covered: The pharmacodynamics and pharmacokinetics of nivolumab and ipilimumab are reviewed. Clinical safety and efficacy results from pivotal phase I and III trials of the combination of nivolumab plus ipilimumab in mRCC are summarized, and the combination is reviewed in the context of other available systemic therapies for RCC. Ongoing clinical studies involving the combination of nivolumab plus ipilimumab in RCC are discussed. Expert opinion: The combination of nivolumab and ipilimumab has demonstrated superior efficacy for treatment-naïve patients with intermediate- and poor-risk mRCC with clear cell histology and is likely to replace anti-angiogenic therapies as the treatment-of-choice in this patient population in the United States. Development of additional combination strategies, novel trial designs, and predictive biomarkers of response will be important to further optimize therapeutic selection and clinical outcomes.

An open-label, multiple ascending dose study of the anti-CTLA-4 antibody ipilimumab in viremic HIV patients.

Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell function, is increased in chronic HIV-1 infection. It was hypothesized that CTLA-4 blockade may enhance immune response to HIV-1 and result in better control of viremia. This open-label, multiple ascending dose study (NCT03407105)-the first to examine ipilimumab in participants with HIV-1 infection-assessed the safety, tolerability, and pharmacokinetics of ipilimumab, as well as whether ipilimumab enhanced immune response to HIV-1 and improved control of viremia. Twenty-four participants received 2 or 4 doses of ipilimumab (0.1, 1, 3, or 5 mg/kg) every 28 days. No serious adverse events (AEs) or dose-limiting toxicities were reported; one participant discontinued ipilimumab for an AE of grade 2 facial palsy. Twenty participants (83.3%) had ≥1 AE; all but 1 were grade 1 or 2. Eight participants (33.3%) had potentially immune-related AEs (7 had grade 1 diarrhea not requiring corticosteroids; 1 who had diarrhea also had transient antinuclear antibody positivity; 1 had grade 2 facial palsy requiring corticosteroids). Two participants (8.3%), one each in the 0.1- and 1-mg/kg dose groups, had a decrease from baseline HIV-1 RNA of 0.85 and 1.36 log10 copies/mL. Fourteen participants (58.3%) had an increase from baseline HIV-1 RNA (mean, 0.87 log10 copies/mL; range, 0.59-1.29). Of these 14 participants, all but 1 were in the higher ipilimumab dose groups (3 or 5 mg/kg). No pattern was noted regarding change from baseline in CD4 or CD8 T cells; ex vivo assessments of immune response were precluded because of inadequate cell viability. Serum concentration data for ipilimumab showed biphasic disposition, with steady state reached by dose 3. Ipilimumab treatment was well tolerated and was associated with variations in HIV-1 RNA in excess of expected repeat measures in most participants, but these were not related to combination antiretroviral therapy status or CD4 counts. The mechanism(s) underlying the increased variation in HIV-1 RNA is unclear and needs further study.

Ipilimumab for the treatment of metastatic prostate cancer.

INTRODUCTION: Immunotherapy with checkpoint inhibitors is beginning to be recognized as a valid weapon for the treatment of metastatic prostate cancer (PCa) when chemotherapy fails. Ipilimumab (ipi) is a fully humanized monoclonal antibody that blocks the activity of CTLA4. It also has a molecular weight of 148 kDa and is water-soluble at physiological pH. Ipi was first approved by the FDA for the treatment of malignant melanoma and is currently being studied in metastatic castration-resistant prostate cancer, with promising early results. Areas covered: The aim of this review is to collate the most significant preclinical and clinical studies available that look at ipi to propose new strategies for the future. Expert opinion: Additional studies are required to reduce toxicity and increase the activity of ipi in PCa. A possible strategy is to combine ipi with standard anti-cancer therapeutics such as vaccines, PDL1 inhibitors, antiandrogen drugs, and chemotherapy agents. Several initial results have suggested that combination strategies are useful to increase the activity in mCRPC, even if the toxicity of the treatment can increase. The activity of combined treatments is still not predictable, but considering the ongoing studies, we believe that they have good potential that will lead to the discovery of an optimal therapeutic strategy.

Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma.

BACKGROUND: Ipilimumab is approved for the treatment of advanced melanoma in adults; however, little information on the efficacy and safety of ipilimumab in younger patients is available. METHODS: Patients aged 12 to <18 years with previously treated or untreated, unresectable stage III or IV malignant melanoma received ipilimumab 3 or 10 mg/kg every 3 weeks. Primary end-points were 1-year overall survival and safety. RESULTS: Over a period of 3.5 years, 12 patients received ipilimumab at either 3 mg/kg (n = 4) or 10 mg/kg (n = 8). The median number of ipilimumab doses was four for 3 mg/kg and three for 10 mg/kg. At 1 year, three of four patients on 3 mg/kg and five of eight patients on 10 mg/kg were alive. Two patients on 10 mg/kg had partial response, and one on 3 mg/kg had stable disease. One patient had durable partial response at 3 years without further treatment, at time of this report. There was one grade 3/4 immune-mediated adverse reaction with 3 mg/kg and five with 10 mg/kg. There were no treatment-related deaths. The study was stopped due to slow accrual. CONCLUSIONS: At >1 year follow-up, ipilimumab demonstrated activity in melanoma patients aged 12 to <18 years, with a similar safety profile as that seen in adults. Our trial highlights the difficulties of enrolling younger patients with rare diseases in clinical trials for treatments that are approved in adults, suggesting adolescents with cancer types occurring predominantly in adults should be considered for inclusion in adult trials of promising new drugs. CLINICAL TRIAL REGISTRATION: NCT01696045.