Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study.

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles.

Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression.

While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progressive disease (PD) per RECIST v1.

Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.

Assessment of Clinical Response to V937 Oncolytic Virus After Intravenous or Intratumoral Administration Using Physiologically-Based Modeling.

Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.

Dose Finding in Oncology: What is Impeding Coming of Age?

After a drug molecule enters clinical trials, there are primarily three levers to enhance probability of success: patient selection, dose selection and choice of combination agents. Of these, dose selection remains an under-appreciated aspect in oncology drug development despite numerous peer-reviewed publications. Here, we share practical challenges faced by the biopharmaceutical industry that reduce the willingness to invest in dose finding for oncology drugs.

Semi-Mechanistic Model for the Antitumor Response of a Combination Cocktail of Immuno-Modulators in Non-Inflamed (Cold) Tumors.

Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors.

Mechanistic Modeling of a Novel Oncolytic Virus, V937, to Describe Viral Kinetic and Dynamic Processes Following Intratumoral and Intravenous Administration.

V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated and data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration.

Beyond the single average tumor: Understanding IO combinations using a clinical QSP model that incorporates heterogeneity in patient response.

A quantitative systems pharmacology model for metastatic melanoma was developed for immuno-oncology with the goal of predicting efficacy of combination checkpoint therapy with pembrolizumab and ipilimumab. This literature-based model is developed at multiple scales: (i) tumor and immune cell interactions at a lesion level; (ii) multiple heterogeneous target lesions, nontarget lesion growth, and appearance of new metastatic lesion at a patient level; and (iii) interpatient differences at a population level. The model was calibrated to pembrolizumab and ipilimumab monotherapy in patients with melanoma from Robert et al.

Modulation of intratumoural myeloid cells, the hallmark of the anti-tumour efficacy induced by a triple combination: tumour-associated peptide, TLR-3 ligand and α-PD-1.

Background: Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment.

Pivotal Dose of Pembrolizumab: A Dose-Finding Strategy for Immuno-Oncology.

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs).

Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients.

Letermovir is indicated for prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Two-stage population pharmacokinetic (PK) modeling of letermovir was conducted to support dose rationale and evaluate the impact of intrinsic/extrinsic factors. Data from healthy phase I study participants over a wide dose range were modeled to evaluate the effects of selected intrinsic factors, including pharmacogenomics; next, phase III HSCT-recipient data at steady-state following clinical doses were modeled.

Experimental Medicine Study to Measure Immune Checkpoint Receptors PD-1 and GITR Turnover Rates In Vivo in Humans.

Development of monoclonal antibodies (mAbs) targeting immune-checkpoint receptors (IMRs) for the treatment of cancer is one of the most active areas of investment in the biopharmaceutical industry. A key decision in the clinical development of anti-IMR mAbs is dose selection. Dose selection can be challenging because the traditional oncology paradigm of administering the maximum tolerated dose is not applicable to anti-IMR mAbs.

A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.

Background: Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens.

Methods: The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses.

Progress and Opportunities to Advance Clinical Cancer Therapeutics Using Tumor Dynamic Models.

There is a need for new approaches and endpoints in oncology drug development, particularly with the advent of immunotherapies and the multiple drug combinations under investigation. Tumor dynamics modeling, a key component to oncology "model-informed drug development," has shown a growing number of applications and a broader adoption by drug developers and regulatory agencies in the past years to support drug development and approval in a variety of ways. Tumor dynamics modeling is also being investigated in personalized cancer therapy approaches.

Model Informed Drug Development: Novel Oncology Agents are Lost in Translation.

Excitement around and investment in oncology drug development are at unprecedented levels. To maximize the health impact and productivity of this research and development investment, quantitative modeling should impact key decisions in early clinical oncology including Go/No-Go decisions based on early clinical data, and dose selection for late stage studies..

Immunogenicity of pembrolizumab in patients with advanced tumors.

Background: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study.

Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance.

Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC).

Patients And Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL), were assessed per indication and study.

Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab.

The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS).

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use.

Quantitative pharmacology (QP) applications in translational medicine, drug-development, and therapeutic use were crowd-sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial-burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model-informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy.