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 v1.1. A subset of patients displays a 30% reduction in the sum of lesion diameters in the post-progression period (melanoma 24.4%, NSCLC 11.6%, 12.6% GC, 8.9% HNSCC, 15.7% ccRCC, and 13.2% UC). Most patients show stable target lesion dynamics in the post-progression period (melanoma, 64.8%; NSCLC, 72.6%; GC, 69.0%, 75.9% HNSCC, 72.5% ccRCC, 75.3% UC). Pembrolizumab generates meaningful efficacy in a subset of patients treated beyond RECIST v1.1 progression.

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.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically-based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.

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. First, randomized dose finding admittedly slows down clinical development. To reduce the size of dose finding study, trend in exposure vs. tumor-size analysis can be assessed, instead of a statistical test for non-inferiority between multiple doses. Second, investment in testing a lower dose when benefit-risk at the higher dose is sufficient for regulatory approval (i.e., efficacy at the higher dose is better than standard of care and safety is acceptable) is perceived as low priority. Changing regulatory landscape must be considered to optimize dose in pre-marketing setting as post-marketing changes in dose can be commercially costly. Third, the risk of exposing patients to subtherapeutic exposures with a lower dose should be assessed scientifically instead of assuming a monotonic relationship between dose and efficacy. Only the doses which are expected to be at the plateau of dose/exposure-response curve should be investigated in Phase 1b/2. Overall, changing the perceptions that have been impeding investment in dose finding in oncology requires pragmatic discourse among biopharmaceutical industry, regulatory agencies and academia. These perceptions should also not deter dose finding for recently emerging modalities, including BITEs and CART cell therapies.

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 in vitro and in vivo 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. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t1/2 = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.

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., specifically, waterfall plot showing target lesion response and overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), which additionally considers nontarget lesion growth and appearance of new metastatic lesions. We then used the model to predict waterfall and RECIST version 1.1 for combination treatment reported in Long et al. A key insight from this work was that nontarget lesions growth and appearance of new metastatic lesion contributed significantly to disease progression, despite reduction in target lesions. Further, the lesion level simulations of combination therapy show substantial efficacy in warm lesions (intermediary immunogenicity) but limited advantage of combination in both cold and hot lesions (low and high immunogenicity). Because many patients with metastatic disease are expected to have a mixture of these lesions, disease progression in such patients may be driven by a subset of cold lesions that are unresponsive to checkpoint inhibitors. These patients may benefit more from the combinations which include therapies to target cold lesions than double checkpoint inhibitors.

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). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically-based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well-vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose.

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

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. Instead, dose selection should be informed by the pharmacology of immune signaling. Engaging an IMR is a key initial step to triggering pharmacologic effects, and turnover (i.e., the rate of protein synthesis) of the IMR is a key property to determining the dose level needed to engage the IMR. Here, we applied the stable isotope labeling mass spectrometry technique using 13 C6 -leucine to measure the in vivo turnover rates of IMRs in humans. The 13 C6 -leucine was administered to 10 study participants over 15 hours to measure 13 C6 -leucine enrichment kinetics in 2 IMR targets that have been clinically pursued in oncology: GITR and PD-1. We report the first measurements of GITR and PD-1 median half-lives associated with turnover to be 55.6 and ≥ 49.5 hours, respectively. The approach outlined here can be applied to other IMRs and, more generally, to protein targets.

First-in-human phase 1 study of MK-1248, an anti-glucocorticoid-induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors.

BACKGROUND: Ligation of glucocorticoid-induced tumor necrosis factor receptor (GITR) decreases regulatory T cell-mediated suppression and enhances T-cell proliferation, effector function, and survival. MK-1248 is a humanized immunoglobulin G4 anti-GITR monoclonal antibody agonist. METHODS: In patients with advanced solid tumors, MK-1248 (starting dose, 0.12 mg) was tested alone and with pembrolizumab (200 mg) according to a 3 + 3 dose escalation design (ClinicalTrials.gov identifier NCT02553499); both treatments were administered intravenously every 3 weeks for ≤4 and ≤35 cycles, respectively. The safety and tolerability, maximum tolerated dose, and pharmacokinetics/pharmacodynamics were explored. RESULTS: Twenty patients received MK-1248 monotherapy; 17 received combination therapy. The most frequent tumor types were colorectal cancer (n = 8), melanoma (n = 6), and renal cell carcinoma (n = 4). MK-1248 was generally well tolerated at the maximum tested doses of 170 (monotherapy) and 60 mg (combination). No dose-limiting toxicities (DLTs) or treatment-related deaths occurred. Adverse events (AEs) occurred in 36 of the 37 patients (97%); the most common were vomiting (n = 13 [35%]), anemia (n = 10 [27%]), and decreased appetite (n = 10 [27%]). Grade 3 to 5 AEs occurred in 19 of the 37 patients (51%). Treatment-related AEs occurred in 18 of the 37 patients (49%): 9 of the 20 patients (45%) on monotherapy and 9 of the 17 patients (53%) on combination therapy. Among the 17 patients receiving combination therapy, 1 achieved a complete response and 2 achieved a partial response, for an objective response rate of 18%; no patients achieved an objective response with monotherapy. The disease control rate (stable disease or better) was 15% with monotherapy and 41% with combination therapy. CONCLUSIONS: MK-1248 was generally well tolerated at doses up to 170 (monotherapy) and 60 mg (combination), with no DLTs or treatment-related deaths. Combination therapy provided limited antitumor responses.

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. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose. RESULTS: The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean âˆ¼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose. CONCLUSIONS: Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.

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.See related article by Bottino et al., p. 6633.

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. PATIENTS AND METHODS: Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. RESULTS: Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies. CONCLUSIONS: The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).

Clinical outcomes with therapies for previously treated recurrent/metastatic head-and-neck squamous cell carcinoma (R/M HNSCC): A systematic literature review.

OBJECTIVES: A wide range of objective response rates (ORRs: 0-53%) among available treatments in patients with R/M HNSCC with progression on or after platinum-based chemotherapy (PBT) renders treatment selection a challenge. This systematic literature review (SLR) was intended to aid clinical decision-making by classifying historical studies to accurately characterize the response in second-line (progression on/after platinum-based therapy), and third-line (progression on/after platinum and cetuximab/other drug) settings. METHODS: SLR was performed to characterize the ORR, duration of response (DOR), progression-free survival (PFS) and overall survival (OS) with therapies recommended by the National Comprehensive Cancer Network (NCCN) guidelines. Clinical trials published in English between January 1, 1985, and September 30, 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: The SLR identified 34 key studies in second-line R/M HNSCC patients, and one of these included a third-line patient cohort. However, several studies did not enrol a strictly second-line population. Response in a true second-line setting was elucidated by categorizing the studies using a novel framework defined according to the extent to which enrolled patients were second-line. Only seven studies were strictly second-line, with an estimated pooled ORR of 4% (95% CI = 2-8%; N = 414) for methotrexate and 11% (95% CI = 7-15%; N = 235) for cetuximab, and a reported ORR of 14% (N = 78) from a single study of paclitaxel. The median DOR was limited with cetuximab (∼4 months) and paclitaxel (∼7 months), and not reported for methotrexate. Median PFS or time to progression (TTP) ranged from 1.7 to 3.5 months, and median OS from 4.3 to 6.7 months. The ORR in the only third-line study was 0% (95% CI = 0-7; N = 53) for the platinum + cetuximab combination. CONCLUSION: These findings emphasize the historically bleak prognoses in patients with R/M HNSCC following PBT progression. Anti-PD-1 therapies, namely pembrolizumab and nivolumab, represent novel treatment options that may improve clinical outcomes.

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 (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups. RESULTS: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94-1.02] and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL0-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0-OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC). CONCLUSIONS: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.See related commentary by Coss et al., p. 5787.

Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example.

One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an "effect marker." An effect marker could be a target engagement, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher-than-optimal dosing can increase toxicity in later trials (and in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose.

Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.