Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of ~15–40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro , abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2‐K transporters with a half‐maximal inhibitory concentration of 0.4–3.8 μM. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase‐associated lipocalin (NGAL), serum cystatin‐C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule‐1.

The human inflammatory response can result in the alteration of drug clearance through effects on metabolizing enzymes or transporters. In this article we briefly review the theory of how cancer can lead to indirect changes in drug metabolism, review acute phase proteins and cytokines as markers of changes in cytochrome P450 (CYP) activity in cancer patients, and provide clinical case examples of how the inflammation in advanced cancer patients can lead to altered CYP-mediated drug clearance.

Background and ObjectivesAbemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels.MethodsA phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model.ResultsThe pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted.ConclusionThe proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight.Trial registrationNCT01394016 (ClinicalTrials.gov).Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0559-8) contains supplementary material, which is available to authorized users.

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGFdependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab.Experimental Design: The study comprised a 3þ3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ! grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab þ erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab þ erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression.Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W.

1019 Background: Abemaciclib is an oral selective CDK4 and CDK6 inhibitor administered on a continuous dosing schedule, which has demonstrated clinical activity and an acceptable safety profile in patients (pts) with heavily pre-treated HR+ metastatic breast cancer (MBC). Abemaciclib has been shown preclinically to cross the blood-brain barrier, providing rationale for testing this agent in pts with BM. Furthermore, as previously presented, levels of abemaciclib similar to plasma were detected in resected BM in a subset of pts with HR+, HER2- MBC in this study. Methods: Study I3Y-MC-JPBO is an open-label, Phase 2, Simon 2-Stage trial evaluating the safety and efficacy of abemaciclib 200 mg BID in pts with new or progressive BM secondary to HR+ MBC, NSCLC, or melanoma. Eligible pts in Part B (the focus of this presentation) include pts with HR+, HER2- MBC who have ≥1 measurable brain lesion. The primary objective was objective intracranial (IC) response rate as defined by Response Assessment in Neuro-Oncology BM response criteria. Secondary objectives (IC related) include best overall response, duration of response, disease control rate, and clinical benefit rate. Exploratory objectives include assessment of drug concentrations in resected tumors. Safety, tolerability, and PK of abemaciclib were also assessed. Stage 1 includes 23 pts; if < 2 of the 23 pts respond to abemaciclib, futility is met. However, if ≥2 respond, 33 additional pts are to be enrolled to Stage 2. Results: This Stage 1 efficacy analysis included 23 pts; 32 pts were included in the safety analysis. Although 5 pts were considered nonevaluable, 2 pts (8.7%) had confirmed partial response (PR) (meeting the predefined threshold for advancement to Stage 2); enrollment is ongoing. At the time of the analysis, the 2 pts with PR had completed 14 and 15 cycles each (21d cycles) of therapy. The majority of adverse events were gastrointestinal in nature, consistent with previous studies of abemaciclib. Conclusions: This study has provided preliminary evidence that abemaciclib penetrated BM in pts with HR+, HER2- MBC and had antitumor activity in this population. Final results will be presented following Stage 2 analyses. Clinical trial information: NCT02308020.