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Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non-small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time-to-event model for progression-free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero-order increase and first-order elimination (19.7/day, 95% confidence interval [CI] 14.9-23.6/day) of ctDNA concentrations. In addition, time-dependent development of resistance (5.0 × 10 -4 , 95% CI 2.0 × 10 -4 -7.0 × 10 -4 /day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression (p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time-to-event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis., Methods: Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied., Results: Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14)., Conclusions: Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis., Competing Interests: J. H. Beijnen (partly) holds a patent on oral taxane formulations and is a part-time employee and stockholder of Modra Pharmaceuticals, a spin-out company developing oral taxanes. This is not related to the manuscript. N. Steeghs provided consultation or attended advisory boards for AIMM Therapeutics, Boehringer Ingelheim, and Ellipses Pharma and received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, InteRNA, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, and Takeda (outside the submitted work). R. B. Verheijen reports share ownership and employment at Johnson & Johnson, prior share ownership and employment at AstraZeneca, and share ownership of Galapagos and Chinook Tx (outside of the submitted work). The other authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Fixed dosing of oral targeted therapies is inadequate in the era of precision medicine. Personalized dosing, based on pharmacokinetic (PK) exposure, known as therapeutic drug monitoring (TDM), is rational and supported by increasing evidence. The purpose of this perspective is to discuss whether randomized studies are needed to confirm the clinical value of precision dosing in oncology. PK-based dose adjustments are routinely made for many drugs and are recommended by health authorities, for example, for patients with renal impairment or for drug-drug interaction management strategies. Personalized dosing simply extrapolates this paradigm from selected patient populations to each individual patient with suboptimal exposure, irrespective of the underlying cause. If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials. We propose a path forward to demonstrate the clinical relevance of individualized dosing of molecularly-targeted anticancer drugs., (©2021 American Association for Cancer Research.)

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149-200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib ( ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells ( p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

Background: Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs., Objective: To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies., Patients and Methods: In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition., Results: Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients., Conclusions: The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib., Trial Registration: Clinicaltrials.gov; NCT02143466; 21 May 2014.

Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, bioavailable, selective MET-tyrosine kinase inhibitor. This randomized, double-blind, 3-way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placebo-evaluated effects on the QT interval after a single savolitinib dose. Healthy non-Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time-matched, placebo-adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula (ΔΔQTcF). Secondary end points included 12-lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600-mg dose, the highest least-squares mean ΔΔQTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2-sided 90% confidence interval for ΔΔQTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3-6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive ΔΔQTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of adverse events. In this thorough QT/QTc study, QTcF prolongation was observed with a single savolitinib 600-mg dose. ECG monitoring will be implemented in ongoing and future studies of savolitinib to assess the clinical relevance of the observed QT changes from this study., (© 2021, The American College of Clinical Pharmacology.)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Savolitinib is an oral, potent, and highly selective MET-tyrosine kinase inhibitor under investigation in various tumor types. A thorough QT study evaluated effects on QT interval after a 600-mg single savolitinib dose in healthy subjects. We report exposure-response (E-R) modeling from this study to characterize the effects of savolitinib and its metabolites, M2 and M3, on QTc changes. In a novel application, in vitro potencies against hERG current provided mechanistic support to model the metabolites' effects. The hERG IC50 estimates (95% CI) were 25.8 (22.2-29.9) and 22.6 (14.7-34.6) μM for parent and M2, respectively. The E-R was described by both linear and E max models, with exposure captured by an active moiety that consisted of savolitinib and M2 concentrations, weighted by the hERG IC50 ratio (1.14). The maximal increase in ΔΔQTcF and EC50 estimates (95% CI) was 18.5 (9.2-27.7) ms and 5709 (2889-8529) nM, respectively. Ignoring M2 contribution resulted in under prediction of QTcF prolongation in the hypothetical case of inhibited M2 clearance; at 300 mg C max , the mean (90% CI) of ∆∆QTcF was 9.0 (5.7-12.6) and 5.9 (2.9-8.9) ms using the hERG-informed and parent-only linear models, respectively. Simulations in normal setting confirmed modest QTcF prolongation with 600 mg, but not 300 mg. Using the linear model, the mean (90% CI) maximum ΔΔQTcF were 12.3 (8.6-16.2) and 5.5 (2.6-8.5) ms for 600 and 300 mg, respectively. Further clinical studies will monitor cardiac safety to assess the clinical significance of QT-interval prolongation with savolitinib.

Purpose: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib., Methods: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored., Results: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation., Conclusion: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.

Background: The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions., Objective: Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk., Methods: A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out., Results: The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions., Conclusion: This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction.

Importance: Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group., Objective: To determine whether savolitinib is a better treatment option for this patient population, vs standard of care, sunitinib., Design, Setting, and Participants: The SAVOIR phase 3, open-label, randomized clinical trial was a multicenter study carried out in 32 centers in 7 countries between July 2017 and the data cutoff in August 2019. Overall, 360 to 450 patients were to be screened to randomize approximately 180 patients. Patients were adults with MET-driven (centrally confirmed), metastatic PRCC, with 1 or more measurable lesions. Exclusion criteria included prior receipt of sunitinib or MET inhibitor treatment. Overall, 254 patients were screened., Interventions: Patients received 600 mg of savolitinib orally once daily (qd), or 50 mg of sunitinib orally qd for 4 weeks, followed by 2 weeks without treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS, assessed by investigator and confirmed by blinded independent central review). Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety/tolerability., Results: At data cutoff, 60 patients were randomized (savolitinib n = 33; sunitinib n = 27); most patients had chromosome 7 gain (savolitinib, 30 [91%]; sunitinib, 26 [96%]) and no prior therapy (savolitinib, 28 [85%]; sunitinib, 25 [93%]). For savolitinib and sunitinib, 4 (12%) and 10 (37%) patients were women, and the median (range) age was 60 (23-78) and 65 (31-77) years, respectively. Following availability of external data on PFS with sunitinib in patients with MET-driven disease, study enrollment was closed. Progression-free survival, OS, and ORR were numerically greater with savolitinib vs sunitinib. Median PFS was not statistically different between the 2 groups: 7.0 months (95% CI, 2.8-not calculated) for savolitinib and 5.6 months (95% CI, 4.1-6.9) for sunitinib (hazard ratio [HR], 0.71; 95% CI, 0.37-1.36; P = .31). For savolitinib and sunitinib respectively, grade 3 or higher adverse events (AEs) were reported in 14 (42%) and 22 (81%) of patients and AE-related dose modifications in 10 (30%) and 20 (74%). After discontinuation, 12 (36%) and 5 (19%) of patients on savolitinib and sunitinib respectively, received subsequent anticancer therapy., Conclusions and Relevance: Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy vs sunitinib, with fewer grade 3 or higher AEs and dose modifications. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT03091192.

Background and Objective: Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16-20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure., Methods: We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules., Results: Nine evaluable patients were included. At the 800 mg QD dosing schedule, median minimum plasma concentration (C min ), area under the concentration-time curve from 0 to 24 h (AUC 0-24h ), and maximum plasma concentration (C max ) were 23.2 mg/L (interquartile range 18.5-27.6), 773 mg h/L (557-1009), and 40.6 mg/L (36.4-56.4) compared with 41.6 mg/L (30.5-55.8, p = 0.004), 942 mg h/L (885-1419, p = 0.027), and 50.2 mg/L (46.8-72.5, p = 0.074) at 400 mg twice daily. One patient experienced a grade 3 event (i.e., diarrhea)., Conclusions: This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in C min , with acceptable tolerability. Therefore, this new dosing schedule offers a cost-neutral opportunity to optimize treatment in patients with low exposure., Clinical Trial Registration: NL6137 ( http://www.trialregister.nl ).

Background: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study., Methods: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466., Findings: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D., Interpretation: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes., Methods: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase., Discussion: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure-response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: minimum plasma concentration (C min ) 4.1 ng/mL and enzalutamide: C min 11.4 mg/L). However, for most drugs, exposure-efficacy analyses could be translated into specific targets (abiraterone: C min 8.4 ng/mL, anastrozole: C min 34.2 ng/mL, and letrozole: C min 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure-efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.

Background/aim: Pazopanib is approved for advanced soft tissue sarcoma (STS) patients. The aim of the study was to examine the usefulness of ( 18 F)-Fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) imaging for early evaluation of the response of STS patients to pazopanib, as well as the association between pazopanib pharmacokinetics and early metabolic response., Patients and Methods: Twenty STS patients underwent FDG-PET scans at baseline, two- and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks., Results: After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis., Conclusion: In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor., Objective: Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity., Patients and Methods: The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies., Results: Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease., Conclusions: BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS., Gov Identifier: NCT01335269.

Background: BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies., Objective: The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies., Patients and Methods: Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration-time curve from time zero to the last quantifiable concentration at t z [[Formula: see text]] and observed area under the plasma concentration-time curve extrapolated from time zero to infinity [AUC 0-∞,obs ]) and maximum plasma concentration (C max ) did not cross the 80-125% (bioequivalence) boundaries., Results: Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24-115.16), 98.17% (78.53-122.74), and 87.34% (71.04-107.38) for [Formula: see text], AUC 0-∞,obs , and C max , respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect [Formula: see text], AUC 0-∞,obs , or C max , resulting in adjusted GMRs (90% CIs) of 1.00 (0.92-1.09), 0.98 (0.90-1.07), and 0.93 (0.86-1.01), respectively., Conclusions: These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance., Clinical Trials Registration: ClinicalTrials.gov identifier: NCT01335269.

Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of various tumor types. Less invasive measurement of everolimus concentrations could facilitate pharmacokinetic studies and personalized dosing based on whole blood concentrations, known as therapeutic drug monitoring. Volumetric Absorptive Microsampling (VAMS) has been introduced as a patient friendly, less invasive sampling technique to obtain an accurate volume of whole blood regardless of hematocrit value. We describe the bioanalytical validation and clinical application of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to quantify everolimus using VAMS. For the quantification, 13 C 2 D 4 -Everolimus was used as internal standard (IS). Everolimus and the IS were extracted with methanol from the VAMS device, which was evaporated after ultrasonification and shaking. The residue was reconstituted in 20 mM ammonium formate buffer and methanol (50%, v/v) of which 5 μL was injected into the LC-MS/MS system. Quantification was performed for the ammonium adduct of everolimus in positive electrospray ion mode. The VAMS method met all pre-defined validation criteria. Accuracy and precision were within 11.1% and ≤14.6%, respectively. Samples were shown to be stable on the VAMS device for at least 362 days at ambient temperatures. Considerable biases from -20 to 31% were observed over a 30-50% hematocrit range. Although the method fulfilled all validation criteria, the perceived advantage of VAMS over dried blood spot sampling could not be demonstrated. Despite the effect of hematocrit, using an empirically derived formula the whole blood everolimus concentration could be back calculated with reasonable accuracy in the clinical application study., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor elacridar on brain uptake using 11 C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11 C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11 C-erlotinib PET scans before and after a 1,000-mg dose of elacridar. 11 C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (V T ) as the outcome parameter. In addition, 15 O-H 2 O scans to measure cerebral blood flow were acquired before each 11 C-erlotinib scan. Results: Brain uptake of 11 C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue ( P = 0.01). In WT mice, the addition of elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the V T of 11 C-erlotinib did not increase after intake of elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15 O-H 2 O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in V T with increased elacridar plasma exposure was found over the 271-619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11 C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11 C-erlotinib was not higher after administration of elacridar. The more pronounced role that ABCG2 appears to play at the human blood-brain barrier and the lower potency of elacridar to inhibit ABCG2 may be an explanation of these interspecies differences., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (C max ) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking., Methods: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28., Results: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, C max , minimum concentration (C min ), and area under the concentration-time curve from time zero to 24 h (AUC 24 ) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of C max to 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC 24 at 436 ng h/mL (CV% 34.8) (p = 0.952). C min increased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in C max was 21.2 ng/mL, or 32.7%. The C max /C min ratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001)., Conclusions: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces C max without negatively impacting C min or AUC 24 . These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy., Registration: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

Background: Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations., Methods: We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 → m/z 357 for pazopanib and m/z 442 → m/z 361 for the internal standard., Results: Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring., Conclusions: In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib.

Background: Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (C min ) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort., Patients and Methods: Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated C min values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed., Results: Sixty-one patients were included, of which 16.4% were underexposed (mean C min  < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis C min  > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis C min  > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis., Conclusion: This study confirms that pazopanib C min  > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. C min monitoring of pazopanib can help identify patients with low C min for whom individualized treatment at a higher dose may be appropriate.

Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.

Background: Low trough imatinib concentration (C min ) values have been associated with poor clinical outcomes in gastrointestinal stromal tumour (GIST) patients. This study describes the pharmacokinetics of imatinib in a large cohort of GIST patients in routine clinical care., Methods: An observational study was performed in imatinib-treated GIST patients. Patient and tumour characteristics were derived from the Dutch GIST Registry and medical records. Imatinib concentrations were measured by liquid chromatography with tandem mass spectrometry. The analyses included the occurrence of a low imatinib C min (<1000 µg/L), the change in the C min over time and the correlation between exposure and response., Results: In total, 421 plasma samples were available from 108 GIST patients. Most patients (79.6 %) received an imatinib dose of 400 mg. The inter- and intrapatient variabilities in C min were 54 and 23 %, respectively. In the first steady-state sample, 44.4 % of patients presented with C min values <1000 µg/L; 32.4 % of patients had values <1000 µg/L in >75 % of their samples. Only 33.3 % of patients had C min values ≥1000 µg/L in all measured samples. No decrease in C min over time was found (P > 0.05). Fifty-seven (91.9 %) of 62 palliative-treated patients had a tumour response (median C min 1271 µg/L). Five palliative patients (8.1 %) did not respond (median C min 920 µg/L). Given the limited number of non-responders in this cohort, no statistically significant association with clinical benefit could be demonstrated., Conclusion: In routine clinical care, one third of GIST patients are systematically underexposed with a fixed dose of imatinib. Prospective clinical studies are needed to investigate the value of C min -guided imatinib dosing in GIST patients.

Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target C max was set at ≥ 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 ± 3.7 times higher compared to that from a crystalline powder mixture. C max and AUC 0-∞ increased linearly with dose over the explored range. The target C max of ≥ 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the C max and AUC 0-∞ were 326 ± 67 ng/mL and 13.4 ± 8.6 · 10 3  ng · h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (C min ). Therefore, patients with low C min might benefit from pharmacokinetically guided individualized dosing., Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib C min was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured C min was <20 mg/L and toxicity was min <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. C min in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all C min levels ≥20.0 mg/L. Of these, 9 patients with a high C min of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, C min remained above the threshold at 28.2 mg/L (25.3%)., Conclusions: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738-46. ©2016 AACRSee related commentary by Ornstein and Rini, p. 5626., (©2016 American Association for Cancer Research.)

Background: Pazopanib is approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Analyses show increased benefit in patients with plasma trough concentrations ≥20.5 μg/ml compared with patients with lower concentrations., Methods & Results: We developed a DBS assay as a patient friendly approach to guide treatment. The method was validated according to US FDA and EMA guidelines and European Bioanalysis Forum recommendations. Influence of spot homogeneity, spot volume and hematocrit were shown to be within acceptable limits. Analysis of paired clinical samples showed a good correlation between the measured plasma and DBS concentrations (R(2) of 0.872)., Conclusion: The method was successfully validated, applied to paired clinical samples and is suitable for application to therapeutic drug monitoring of pazopanib.

Unlabelled: Anticalins are a novel class of biopharmaceuticals, displaying highly desirable attributes as imaging agents. The anticalin PRS-110 was rationally engineered to target the oncogene MET with high affinity and specificity. The aim of this study was to visualize MET expression and analyze biodistribution of (89)Zr-labeled PRS-110 in human tumor-bearing mice., Methods: (89)Zr-PRS-110 was generated. For biodistribution studies (96 h after injection of tracer) 10 μg of (89)Zr-PRS-110 (with 0-490 μg of unlabeled PRS-110) were injected into BALB/c mice bearing high MET-expressing H441 non-small cell lung cancer xenografts. Further characterization with PET imaging was performed at 6, 24, 48, and 96 h after injection of 50 μg of (89)Zr-PRS-110 into mice bearing H441, primary glioblastoma U87-MG (intermediate MET), or ovarian cancer A2780 (low MET) xenografts. Drug distribution was also analyzed ex vivo using fluorescently labeled PRS-110., Results: Biodistribution analyses showed a dose-dependent tumor uptake of (89)Zr-PRS-110, with the highest fractional tumor uptake at 10 μg of (89)Zr-PRS-110, with no unlabeled PRS-110. Small-animal PET imaging supported by biodistribution data revealed specific tumor uptake of (89)Zr-PRS-110 in the MET-expressing H441 and U87-MG tumors whereas the MET-negative A2780 tumor model showed a lower uptake similar to a non-MET binder anticalin control. Tumor uptake increased up to 24 h after tracer injection and remained high, whereas uptake in other organs decreased over time. Ex vivo fluorescence revealed intracellular presence of PRS-110., Conclusion: (89)Zr-PRS-110 specifically accumulates in MET-expressing tumors in a receptor density-dependent manner. PET imaging provides real-time noninvasive information about PRS-110 distribution and tumor accumulation in preclinical models.