Clinical Therapeutics/Volume 43, Number 6, 2021 Original Research Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors Victor Moreno, MD, PhD1 ; Richard Greil, MD2 ; Jeffrey Yachnin, MD, PhD3 ; Margarita Majem, MD, PhD4 ; Martin Wermke, MD5 ; Hendrik-Tobias Arkenau, MD, PhD6,7 ; Jean-Rene Basque, PhD8 ; Prasanna Kumar Nidamarthy, MSc9 ; Shruti Kapoor, MD9 ; Xiaoming Cui, PhD10 ; and Monica Giovannini, MD11 1 START Madrid-FJD, Hospital Fundación Jímenez Díaz, Madrid, Spain; 2 IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute, Salzburg, Austria; 3 Department of Oncology–Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden; 4 Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5 Medical Clinic I, University Hospital Carl Gustav Carus, NCT/UCC Early Clinical Trial Unit, Dresden, Germany; 6 Medical Oncology, Sarah Cannon Research Institute UK, London, United Kingdom; 7 Cancer Institute, University College London, London, United Kingdom; 8 Novartis Pharma AG, Basel, Switzerland; 9 Novartis Healthcare Private Limited, Hyderabad, India; 10 Novartis Institutes for BioMedical Research, East Hanover, New Jersey; and 11 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey ABSTRACT the tolerated study doses and assess PK variables, with a secondary objective of safety. Purpose: In the Phase II GEOMETRY mono-1 study, Findings: Overall, 35 patients (300 mg BID, n = 8; the potent and selective mesenchymal-epithelial tran- 400 mg BID, n = 27) with MET-dysregulated advanced sition (MET) inhibitor capmatinib exhibited consider- solid tumors were enrolled; all patients had received able efficacy in MET exon 14 skipping (METex14)– prior antineoplastic therapy, and the most common mutated metastatic non–small cell lung cancer at a dose primary site was lung (45.7%). Among PK-evaluable of 400 mg BID. The current recommended dose is 400 patients, the median Tmax for capmatinib after mg BID in tablet formulation, with or without food. administration with a high-fat meal (on C1D1/C1D7) This article reports the pharmacokinetic (PK) profile, was 4.0 to 5.6 hours across doses. At steady state safety, and tolerability of capmatinib 300 and 400 mg (C1D7), capmatinib accumulation was low across dose BID given with food in MET-dysregulated advanced levels (geometric mean of accumulation ratios, 1.29– solid tumors. 1.69), with an increase in exposure (AUCtau and Cmax ) Methods: This multicenter, open-label, Phase I from 300 to 400 mg BID. There were no occurrences of study enrolled adult patients with MET-dysregulated dose-limiting toxicity. All patients experienced at least advanced solid tumors. In the dose escalation phase, 1 adverse event, and treatment-related adverse events capmatinib tablets were orally administered at a dose occurred in 28 patients (80%; 300 mg BID, n = 6; of 300 mg BID with food; if tolerated, the dose 400 mg BID, n = 22), the most frequent of which were escalation cohort of 400 mg BID was to be opened to fatigue (37.1%) and nausea (34.3%). enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal Accepted for publication April 11, 2021 https://doi.org/10.1016/j.clinthera.2021.04.006 type, except on cycle 1 day 1 (C1D1) and cycle 1 day 0149-2918/$ - see front matter 7 (C1D7), when they were given with a high-fat meal. © 2021 The Authors. Published by Elsevier Inc. The primary objectives were to determine the higher of This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) 1092 Volume 43 Number 6 V. Moreno et al. Implications: Capmatinib tablet formulation at a are an independent prognostic factor that can predict dose of up to 400 mg BID with food is well tolerated poor outcomes.24 ,25 in patients with MET-dysregulated advanced solid Capmatinib is an orally bioavailable, adenosine tumors, with safety observations consistent with the triphosphate (ATP)–competitive, reversible, highly po- existing profile under fasted conditions. These findings tent, and selective inhibitor of the MET tyrosine support the capmatinib dosing recommendation of kinase domain that inhibits downstream signaling 400 mg BID with or without food. ClinicalTrials.gov and subsequent tumor growth and progression.26 identifier: NCT02925104. (Clin Ther. 2021;43:1092– In preclinical studies, capmatinib exhibited high 1111.) © 2021 The Authors. Published by Elsevier Inc. selectivity for MET relative to other kinases in large This is an open access article under the CC BY-NC- screening panels and had potent activity in vitro ND license (http://creativecommons.org/licenses/by- (50% inhibition, 0.13 nM) and against a range of nc-nd/4.0/) MET-dependent lung cancer (50% inhibition, 0.3– Key words: Capmatinib, Food, MET, Pharmacoki- 0.7 nM) and METex14-mutated cancer (half maximal netics, Phase I. inhibitory concentration [IC50 ], 0.6 nM) cell lines; it also induced tumor regression in MET-driven mouse models harboring MET amplification and/or overexpression at tolerable doses.26–28 Preliminary INTRODUCTION efficacy signals were observed in a range of MET- Upon binding of its high-affinity ligand hepatocyte dysregulated advanced solid tumors, including as growth factor (HGF), the receptor tyrosine kinase a single agent in hepatocellular carcinoma29 and mesenchymal-epithelial transition (MET) orchestrates NSCLC,13 ,30 and in combination with gefitinib in an invasive growth program through the unique EGFR-mutant, MET-dysregulated NSCLC harboring coordination of signaling cascades involved in cell resistance to EGFR tyrosine kinase inhibitors.31 proliferation, survival, motility, and invasion, in- In the open-label, multicohort, Phase II GEOME- cluding the RAS–mitogen-activated protein kinase TRY mono-1 study, capmatinib (400 mg BID tablet) and phosphatidylinositol 3-kinase–protein kinase B exhibited a clinically meaningful overall response rate pathways.1–3 The MET–HGF pathway is frequently (ORR) when administered under fasting conditions dysregulated in several solid tumors, notably non– in treatment-naive and previously treated patients small cell lung cancer (NSCLC)4 and gastrointestinal with METex14-mutated advanced NSCLC, and had cancers,5 in which MET dysregulation is a biomarker a manageable toxicity profile across all cohorts.32 of poor prognosis and constitutes an oncogenic Importantly, deep and durable responses were observed driver implicated in metastatic progression and drug in the majority of patients, irrespective of the line of resistance. therapy. On the basis of these findings, the US Food MET can be aberrantly activated through a number and Drug Administration (FDA) granted accelerated of mechanisms, including overexpression (via gene approval in May 2020 to capmatinib for treatment of amplification or transcriptional upregulation), genetic adult patients with metastatic NSCLC whose tumors mutation, and autocrine/paracrine HGF signaling.6 harbor a METex14 mutation (as determined by an MET amplification, which leads to constitutive ligand- FDA-approved test).33 In June 2020, the Japanese independent activation, correlates with response to Ministry of Health, Labor, and Welfare granted MET inhibitors in vitro7 ,8 and in patients with approval in the same indication. MET-amplified lung and gastric cancers,9–13 and In a global Phase I dose escalation study in patients acquired MET amplification confers clinical resistance with MET-dysregulated solid tumors, capmatinib was to epidermal growth factor receptor (EGFR)-targeted well tolerated with an acceptable safety profile at therapy in NSCLC.14–16 MET exon 14 skipping the recommended Phase II dose of 400 mg BID (METex14) mutations, which lead to removal of the in tablet formulation under fasted conditions, and juxtamembrane domain and, consequently, stabiliza- the maximum tolerable dose was not reached.13 ,33 tion and oncogenic activation of MET,17 have been Furthermore, preliminary findings from cohort 6 reported in NSCLC at a frequency of ˜3% to 4%,18 of GEOMETRY mono-1, in which capmatinib was are predictive of response to MET inhibitors,19–23 and administered without fasting restrictions, showed that  2021 1093 Clinical Therapeutics capmatinib at the dose of 400 mg BID had a additional patients (a minimum of 15 PK-evaluable manageable safety profile in patients with METex14- patients and 20 patients for safety considerations) were mutated advanced NSCLC after one line of treat- to be enrolled in the expansion phase at the higher of ment.34 In an absorption, distribution, metabolism, the tolerated doses. and excretion study in healthy male volunteers, 14 C- Irrespective of the dose level, capmatinib tablets labeled capmatinib (a single 600 mg oral dose, capsule were administered orally on a continuous BID dosing formulation) had substantial systemic availability, was schedule, on a flat scale of milligrams per day and extensively metabolized, and was mainly distributed to not individually adjusted by weight or body surface the peripheral tissue, with a mean elimination t1/2 of area. The treatment period began on C1D1 and a 7.84 hours.35 The highest tested dose of capmatinib treatment cycle was defined as 21 days. Patients were in tablet formulation reported in the literature is 400 treated with capmatinib until investigator-determined mg BID,13 ,32 ,36 and all published pharmacokinetic (PK) disease progression (per Response Evaluation Criteria studies have been conducted under fasted conditions. in Solid Tumors [RECIST] version 1.1); unaccept- In the present study (NCT02925104; A Dose able toxicity precluding further treatment; death; Escalation Study to Assess PK, Safety and Tolerability or discontinuation. Patients were followed up for of INC280 When Taken With Food in cMET safety until 30 days after the last dose, regardless Dysregulated Advanced Solid Tumors), we present of the reason for discontinuation. If discontinuation study, we evaluated the PK profile, safety, and occurred for reasons other than progression or tolerability of the 300 and 400 mg BID capmatinib withdrawal of consent, patients were followed up tablet regimens administered with food in patients with for tumor assessments until progression, start of new MET-dysregulated advanced solid tumors. anticancer therapy, or death. Patients in ongoing study treatment at the end of the study could be enrolled PARTICIPANTS AND METHODS into a rollover study. Details on dose modification, Study Design and Treatment treatment interruption, and treatment discontinuation This was a multicenter, open-label, Phase I study are provided in the Appendix. of capmatinib (tablet formulation) administered with The primary objectives of the present study were to food in patients with MET-dysregulated advanced solid determine the higher of the tolerated doses (between tumors, comprising dose escalation and expansion the 300 mg and 400 mg BID tablet) and to assess the PK phases. In the dose escalation part, capmatinib variables of capmatinib when administered with food. treatment was initiated in a minimum of 6 patients Accordingly, the related primary end points were the at a dose of 300 mg BID with food on a continuous incidence, frequency, and category of DLT in the dose dosing schedule. With the exception of the mornings escalation phase during the first 28 days of treatment, of cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), and the plasma concentration and PK parameters for when it was administered with a high-fat meal (to capmatinib. The secondary objective was to assess the capture the maximum impact of food on PK exposure), safety of capmatinib tablet formulation when taken capmatinib was taken within 30 minutes of an with food, with a related secondary end point of the unrestricted meal type. If the 300 mg BID dose was frequency and severity of adverse events (AEs). The tolerated during a minimum of the first 28 days of exploratory objective was to evaluate the preliminary treatment (the minimum exposure criterion), the dose antitumor activity of capmatinib when taken with escalation cohort of 400 mg BID with food was to food, with an exploratory end point of investigator- be opened to enroll a minimum of 6 patients. Dose determined ORR (per RECIST 1.1). escalation decisions were guided by the escalation with overdose control criteria based on the Bayesian logistic Patients regression model,37 ,38 as well as by clinical judgment Patients (aged ≥18 years) with MET-dysregulated regarding safety, tolerability, and PK variables. The advanced solid tumors whose disease had progressed dose escalation rules applied in this study are provided despite standard therapy, or for whom no standard in the Appendix, and the study criteria for dose- therapy existed, were included in this study. Eligible limiting toxicity (DLT) are provided in Appendix Table patients were required to have an Eastern Cooperative S1. At the completion of the dose escalation phase, Oncology Group performance status of ≤1, at least 1094 Volume 43 Number 6 V. Moreno et al. one measurable lesion (per RECIST 1.1), and adequate conditions on C1D1/C1D7; have taken 3 consecutive organ function. Key exclusion criteria included: prior doses of capmatinib before steady-state PK collection treatment with crizotinib or a MET/HGF-targeted on C1D7; and have not vomited within 4 hours of agent; symptomatic central nervous system metastases capmatinib administration on C1D1 and C1D7. that were neurologically unstable or required increas- For the measurement of the capmatinib plasma ing doses of steroids within 2 weeks of study entry; concentrations, predose (0 h) and postdose (0.5, 1, 2, clinically significant uncontrolled heart diseases; major 4, 6, 8, and 12 hours) blood samples were collected on surgery within 4 weeks of starting capmatinib (or C1D1 and C1D7, and predose samples were collected within 2 weeks for resection of brain metastases); on cycle 1 day 15, cycle 2 day 1, and cycle 3 day prior treatment with medications that strongly induce 1; unscheduled collection was permitted at any time cytochrome P450 3A4 and that cannot be discontinued thereafter. In addition, meal records were collected on at least 1 week before starting capmatinib and for C1D1 and C1D7. the duration of the study; pregnancy or breastfeeding Capmatinib plasma concentrations were determined (lactation); and childbearing potential. by using a validated LC-MS/MS assay, which has been At molecular prescreening, MET dysregulation was described elsewhere.35 The assay used a lower limit determined cytopathologically or histopathologically of quantitation of ˜1 ng/mL using 100 μL of plasma (either by local or central assessment) and was sample in di-potassium EDTA. Sample preparation defined as at least one of the following criteria: in 96-well plates comprised addition of a 100 μL MET amplification determined by fluorescent in situ aliquot of the samples, a 50 μL aliquot of the hybridization, defined by a gene copy number (GCN) internal standard working solution, and a 300 μL of ≥4; MET overexpression determined by MET aliquot of 0.5% ammonium hydroxide solution to immunohistochemistry (IHC), defined by intensity the designated wells. Determination of the capmatinib score of +3 in ≥50% of tumor cells; and METex14 concentration comprised solid-phase extraction of the mutation. Not all patients were screened for both samples and evaporation of the extract to dryness; amplification and overexpression if at least one diluted samples (with 300 μL of 20% acetonitrile) criterion was met. were subsequently analyzed by injecting a 10 μL aliquot of each sample into the LC-MS/MS system in Clinical Assessments multiple reaction monitoring, positive ion mode using Clinical assessments were conducted at the screening electrospray ionization as the ionization technique. visit; on days 1, 7, and 15 of cycles 1 and 2; at The LC-MS/MS system consisted of a CAPCELL PAK every 21 days thereafter starting on cycle 3 day MG C18 column (50 × 2 mm, 5 μm particle size; 1; and at the end of treatment (within 7 days Osaka Soda Co, Ltd, Osaka, Japan) and an API of the last dose). Safety monitoring consisted of 4000 mass spectrometer (Applied Biosystems/Sciex, collecting DLTs, all AEs, and serious AEs (SAEs), Framingham, Massachusetts). Chromatographic elu- along with their severity and relationship to capmatinib tion was performed using 0.1% formic acid 1.0 treatment. Patients were regularly monitored for mmol/L ammonium acetate in water (mobile phase hematology and blood chemistry, and assessed for A) and 0.1% formic acid 1.0 mmol/L ammonium vital signs and physical parameters. All safety and acetate in 95% acetonitrile (mobile phase B). The tolerability assessments were conducted at predose, MS transitions observed were m/z 413.1 to 354.2 for unless otherwise specified. Tumor response and disease capmatinib and m/z 417.2 to 382.0 for the internal progression per RECIST 1.1 was assessed locally by standard. the investigator. Archival or newly obtained biopsy Key PK parameters assessed included area under specimens or slides were required as part of the the plasma concentration–time curve from time zero molecular prescreening. to the end of a dosing interval (AUCtau ), Cmax , and Tmax , with additional PK parameters of accumulation PK Assessments ratio (Racc), total body apparent clearance of drug To be considered PK evaluable, patients were from the plasma at steady state (CLss/F), and required to have taken capmatinib according to effective half life (T1/2 ) (t1/2, eff ). Because the 12-hour the originally assigned dose with assigned prandial postdose PK sampling period was not long enough to  2021 1095 Clinical Therapeutics Figure 1. Geometric mean and arithmetic mean (SD) concentration–time profiles for capmatinib according to treatment (full pharmacokinetic analysis set). The graphs depict the arithmetic and geometric mean concentration–time profiles for capmatinib in the 300 mg BID (solid lines) and 400 mg BID (dotted lines) dose levels on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7). Error bars denote the mean (SD) for the arithmetic mean and the mean for the geometric mean at each time point. Both linear and semi- logarithmic views of the data are presented. The full pharmacokinetic analysis set was used for analysis. Zero concentrations at individual time points are excluded from geometric mean computation. capture the elimination phase of capmatinib for most The full analysis set (FAS) comprised all patients patients (Figure 1), PK parameters derived from the who received at least 1 dose, with patients analyzed elimination phase (terminal half life (T1/2 ), elimination according to the planned treatment assigned. The safety rate constant, and volume of distribution) were not set included all patients who received at least 1 dose, reported. Instead, t1/2, eff was calculated based on Racc: with patients analyzed according to the study drug they τ × ln2/ln[Racc/(Racc − 1)].39 In this study, Racc actually received. The dose-determining set consisted of was calculated as AUCtau,ss /AUCtau,sd , where AUCtau,ss all patients in the dose escalation phase from the FAS refers to AUCtau at steady-state, AUCtau,sd refers to who had taken capmatinib for at least 21 days during AUC tau after single dosing, and tau refers to the dosing the first 28 days (the minimum exposure criterion) and interval. had sufficient safety evaluations, or experienced a DLT during the first 28 days of dosing. The full PK analysis Statistical Analysis set (full PAS) included all patients who provided an For the final analysis, all available data from all evaluable PK profile for at least 1 period (C1D1 or patients at the end of the study (May 16, 2018) were C1D7). used, with all dose escalation and expansion phase For the primary end point of probability of DLT arms combined for the same dose level. SAS version 9.4 in the first 28 days, the dose-determining set was (SAS Institute, Inc, Cary, North Carolina) was used to used. For the primary PK end points, the full PAS perform all analyses. was used, and PK parameters were estimated from Patients were classified into different analysis sets each individual plasma concentration time profile us- according to the assigned or received dose level. ing noncompartmental analysis (WinNonlin software 1096 Volume 43 Number 6 V. Moreno et al. version 6.4; Certara L.P. [Pharsight], Princeton, New RESULTS Jersey). Descriptive statistics were presented at each Recruitment and Patient Characteristics scheduled time point and on C1D1 and C1D7 for all At the conclusion of the study (May 16, 2018), a noncompartmental PK parameters (including AUCtau , total of 35 patients (300 mg BID, n = 8; 400 mg BID, Cmax , Tmax , CLss/F, and Racc). Descriptive statistics for n = 27) with a median age of 63 years (range, 31– the secondary end points were presented according to 75 years) were enrolled; among the 27 patients in the dose group, and the safety set was used for analysis. For 400 mg BID dose level, 12 were enrolled in the dose the exploratory objective, ORR, best overall response escalation phase and 15 were enrolled in the expansion (BOR), and disease control rate (DCR) were described phase. in the FAS, with the exact 95% CI. Most patients had stage IV disease at initial For this study, no formal statistical power calcu- diagnosis (n = 24 [68.6%]), and the most common lations were performed to determine sample size. A primary site was the lung (n = 16 [45.7%]) (Table I). minimum of 6 patients were estimated to be enrolled The majority of tumors were adenocarcinomas (n = 25 at the starting dose level of capmatinib 300 mg BID [71.4%]), and most were either poorly differentiated with food. Pending the dose escalation decision, an arm (n = 15 [42.9%]) or of unknown histologic grade of at least 6 patients would be enrolled at capmatinib (n = 13 [37.1%]). All 35 (100%) patients had received 300 mg BID or 400 mg BID with food. For further prior antineoplastic medication, 19 (54.3%) had prior assessment of safety and PK parameters, additional radiotherapy, and 23 (65.7%) had prior surgery. The patients were to be enrolled to have ˜15 PK-evaluable median time since initial diagnosis (of the primary site) patients at the higher of the tolerated dose levels was 27.6 months (range, 2.7–283.2 months), and the assessed in this study with food. In addition, for median time since the most recent recurrence/relapse safety considerations, a sample size of 20 patients who was 1.8 months (range, 0.4–7.7 months). At baseline, received at least one dose of the higher tolerated dose all patients had measurable disease according to level was estimated to result in a 90% probability RECIST 1.1; most patients (n = 29 [82.9%]) had both of detecting an AE with an incidence of >10%. This target and nontarget lesions, and 6 (17.1%) had only sample size of 20 patients for expansion at the higher target lesions. The extent of disease was consistent tolerated dose level was selected on the basis of the with that expected among patients with advanced consideration of acceptable safety signal detection and solid tumors with metastasis, comprising liver (n = 21 operational feasibility. [60%]), lung (n = 20 [57.1%]), and bone lesions (n = 8 [22.9%]). Ethics All patients had met at least one confirmed MET This study was designed, conducted, and reported dysregulation criterion (METex14 mutation, n = 1 according to the International Council for Harmoni- [2.9%]; MET amplification with GCN ≥4, n = 23 sation of Technical Requirements for Pharmaceuticals [65.7%]; MET overexpression with IHC score +3 in for Human Use Harmonized Tripartite Guidelines ≥50% of tumor cells, n = 14 [40%]) at prescreening, for Good Clinical Practice, with applicable local with 3 patients having concurrent amplification and regulations (including European Directive 2001/20/EC overexpression. At the 300 mg BID dose level, 5 and US Code of Federal Regulations Title 21), and (62.5%) and 4 (50%) patients had MET amplification with the ethical principles of the Declaration of and MET overexpression, respectively. At the 400 mg Helsinki. The study protocol and all amendments BID dose level, 18 (66.7%) and 10 (37%) patients were reviewed by the independent ethics committee or had MET amplification and MET overexpression; the institutional review board for each center, and written single patient (3.7%) with METex14 mutation was informed consent was provided by all patients before enrolled at the 400 mg BID dose level. conducting any molecular prescreening or protocol- defined study procedures. The study was designed by Exposure and Disposition the sponsor (Novartis Pharmaceuticals Corporation, All patients received the planned dose of capmatinib, East Hanover, New Jersey); data were collected and with a median relative dose intensity of 100% at analyzed by the sponsor in conjunction with the both the 300- and 400 mg BID dose levels. Overall, authors. the median duration of capmatinib exposure was  2021 1097 Clinical Therapeutics Table I. Baseline demographic and disease characteristics (full analysis set). Characteristic Capmatinib Capmatinib All Patients 300 mg BID 400 mg BID (N = 35) (n = 8) (n = 27) Age, y Mean (SD) 59.5 (9.56) 61.1 (11.16) 60.7 (10.70) Median 61.5 64.0 63.0 Minimum–maximum 38–68 31–75 31–75 Age ≥65 y, no. (%) 2 (25.0) 11 (40.7) 13 (37.1) Male sex, no. (%) 4 (50.0) 16 (59.3) 20 (57.1) Race, no. (%) White 8 (100) 21 (77.8) 29 (82.9) Unknown 0 6 (22.2) 6 (17.1) ECOG PS, no. (%) 0 5 (62.5) 9 (33.3) 14 (40.0) 1 3 (37.5) 18 (66.7) 21 (60.0) Primary site of cancer, no. (%) Lung 5 (62.5) 11 (40.7) 16 (45.7) Rectum 1 (12.5) 2 (7.4) 3 (8.6) Colon 1 (12.5) 1 (3.7) 2 (5.7) Esophagus 0 2 (7.4) 2 (5.7) Pancreas 0 2 (7.4) 2 (5.7) Other∗ 0 8 (29.6) 8 (22.9) Adenocarcinoma of unknown primary 1 (12.5) 0 1 (2.9) Unknown 0 1 (3.7) 1 (2.9) ECOG PS = Eastern Cooperative Oncology Group performance status. ∗ Other organ sites (n = 1 each in the Capmatinib 400 mg BID and All Patients columns) include breast, cervix, gallbladder, gallbladder ducts, kidney, skin melanoma, small intestine, and thyroid. 11.8 weeks (range, 2–27 weeks) at the 300 mg BID [2.9%]; 300 mg BID, 0%; 400 mg BID, n = 1 [3.7%]). dose level and 6 weeks (range, 0–36 weeks) at the 400 All patients discontinued capmatinib, mostly due to mg BID dose level. Three patients from the 400 mg progressive disease (n = 23 [65.7%]; 300 mg BID, n = 6 BID dose level whose treatments were ongoing at the [75%]; 400 mg BID, n = 17 [63%]), followed by AEs time of study completion continued on to the rollover (n = 4, 11.4%), physician’s decision (n = 3 [8.6%]), study; the duration of exposure for these patients study termination (n = 3 [8.6%]), death due to study before rollover was 18.1, 25.6, and 36.1 weeks. A total indication (n = 1 [2.9%]), or patient/guardian decision of 3 patients (8.6%; 300 mg BID, n = 1 [12.5%]; (n = 1 [2.9%]). 400 mg BID, n = 2 [7.4%]) required at least one dose reduction due to AEs, and 19 patients (54.3%; PK Variables 300 mg BID, n = 5 [62.5%]; 400 mg BID, n = 14 In total, 7 patients in the 300 mg BID dose level [51.9%]) required at least one dose interruption, due and 24 patients in the 400 mg BID dose level were to AEs (n = 16 [45.7%]; 300 mg BID, n = 3 [37.5%]; evaluable for PK analysis. Fig. 1 depicts the geometric 400 mg BID, n = 13 [48.1%]), physician’s decision and arithmetic mean concentration–time profiles for (n = 4, 11.4%; 300 mg BID, n = 3 [37.5%]; 400 capmatinib on C1D1 and C1D7 (steady state) by mg BID, n = 1 [3.7%]), or dosing errors (n = 1 treatment dose level in the full PAS, with descriptive 1098 Volume 43 Number 6 V. Moreno et al. statistics for PK parameters shown in Table II. After experienced grade 3 or higher TRAEs, whereas 6 administration with a high-fat meal, the median Tmax patients (22.2%) in the 400 mg BID dose level for capmatinib ranged from 4.00 to 5.6 hours across experienced grade 3 or higher TRAEs. Overall, 13 dose levels (C1D1 300 mg BID, 5.6 hours; C1D1 400 patients (37.1%) experienced at least one SAE of mg BID, 4.01 hours; C1D7 300 mg BID, 4.04 hours; any grade, the most frequent of which were general C1D7 400 mg BID, 4.0 hours), followed by a decline physical health deterioration, abdominal pain, and in concentration over time. The geometric mean of dyspnea (n = 2 [5.7%] each) (see Appendix Table S3). AUCtau and Cmax increased with capmatinib dose. At Twelve patients (34.3%) had at least one grade 3 or steady-state (C1D7), the geometric means of AUCtau higher SAE, which were deemed treatment-related in 2 and Cmax were 9370 ng × h/mL (%CV 24.3) and 1550 patients (7.4%) in the 400 mg BID arm. No fatal SAEs ng/mL (%CV 22.6) in the 300 mg BID dose level, and occurred. 16,800 ng × h/mL (%CV 26.7) and 3050 ng/mL (%CV Regarding AEs of special interest (AESIs), 5 39.5) in the 400 mg BID dose level, respectively. On patients (14.3%) experienced liver toxicity (grade C1D7, the accumulation of capmatinib was low, with 3, n = 1), 3 (8.6%) experienced central nervous the geometric mean of Racc ranging from 1.29 (400 system toxicity, 3 (8.6%) experienced renal toxicity, mg BID) to 1.69 (300 mg BID). Geometric means of 2 (5.7%) experienced pancreatitis (grade 3, n = 2), CLss/F ranged from 23.8 to 32 L/h, and geometric 1 (2.9%) experienced pneumonitis (grade 3), and means of t1/2, eff ranged from 5.97 to 10.7 hours across 1 (2.9%) experienced QT prolongation (grade 3). dose levels. Among these AESIs, pneumonitis was the only AE reported as an SAE (n = 1 [2.9%]) (see Appendix Safety Table S4). AESIs were deemed to be related to The 300- and 400 mg BID capmatinib tablets were treatment in a total of 5 patients (pancreatitis, well tolerated when administered with food, and there n = 2 [5.7%]; liver toxicity, n = 2 [5.7%]; renal were no DLTs during the first 28 days of treatment in toxicity, n = 1 [2.9%]), all in the 400 mg BID dose either the 300- or 400 mg BID dose cohort. On the basis level. of Bayesian logistic regression model considerations Five patients (14.3%) died during the study, (posterior probability of excessive toxicity 0% for including 2 patients (25.0%) at the 300 mg BID dose both dose levels) and an overall safety assessment, level and 3 patients (11.1%) at the 400 mg BID dose the dose escalation cohort for 400 mg BID with food level. All of the deaths were due to the study indication was opened to enrollment. The 400 mg BID dose was (disease progression) and were unrelated to the study selected as the higher of the tolerated doses evaluated treatment. in this study. Four patients (11.4%) experienced at least 1 AE Table III provides a summary of AEs and treatment- leading to capmatinib discontinuation, including 1 related AEs (TRAEs). All 35 patients experienced at patient (12.5%) at the 300 mg BID dose level least one AE, and grade 3 or higher AEs occurred in (grade 4 general physical health deterioration) and 4 patients (50%) in the 300 mg BID dose level and 3 patients (11.1%) at the 400 mg BID dose level 16 (59.3%) in the 400 mg BID dose level. The most (grade 3 hypersensitivity, myocardial infarction, and frequently reported AEs (incidence of ≥20% across thrombocytopenia) (Table III). TRAEs leading to all grades) were fatigue (45.7%), nausea (40.0%), discontinuation (grade 3 or higher hypersensitivity and peripheral edema (28.6%), and dyspnea (20.0%) (see myocardial infraction) occurred in only 2 patients Appendix Table S2). A total of 28 patients (80%) (5.7%). A total of 15 patients (42.9%) experienced experienced TRAEs, including 6 (75.0%) in the 300 at least one AE leading to dose adjustment and/or mg BID dose level and 22 (81.5%) in the 400 mg interruption, including 2 patients (25.0%) at the 300 BID dose level; the most frequent TRAEs (incidence mg BID dose level and 13 patients (48.1%) at the 400 of ≥10% across all grades) were fatigue (n = 13 mg BID dose level. [37.1%]), nausea (n = 12 [34.3%]), peripheral edema One patient met the laboratory criteria for drug- (n = 5 [14.3%]), vomiting (n = 5 [14.3%]), and induced liver injury (Hy’s Law), which was not decreased appetite and diarrhea (n = 4 [11.4%] deemed to be related to the study treatment, and each). No patients in the 300 mg BID dose level the patient discontinued study treatment due to  2021 1099 Clinical Therapeutics Table II. Capmatinib pharmacokinetic parameters according to treatment dose level (full pharmacokinetic analysis set). Parameter Cycle 1 Day 1 Cycle 1 Day 7 Capmatinib Capmatinib Capmatinib Capmatinib 300 mg BID 400 mg BID 300 mg BID 400 mg BID (n = 7) (n = 24) (n = 7) (n = 24) AUCtau , ng × h/mL n∗ 3 14 4 15 Mean (SD) 6910 (1690) 14,000 (3880) 9580 (2350) 17,300 (4330) %CV 24.5 27.7 24.5 24.9 Geometric mean 6760 13,500 9370 16,800 %CV 27.2 28.0 24.3 26.7 Cmax , ng/mL n∗ 7 24 6 23 Mean (SD) 1330 (946) 2850 (1270) 1590 (382) 3260 (1130) %CV 71.3 44.4 24.1 34.8 Geometric mean 1110 2580 1550 3050 %CV 66.9 49.8 22.6 39.5 Tmax , h n∗ 7 24 6 23 Median 5.60 4.01 4.04 4.00 Minimum– 1.87–8.00 0.5–8.17 1.17–6.12 1.07–8.28 maximum Racc n∗ NA NA 6 19 Mean (SD) NA NA 1.78 (0.610) 1.33 (0.355) %CV NA NA 34.3 26.6 Geometric mean NA NA 1.69 1.29 %CV NA NA 36.7 26.0 CLss/F, L/h n∗ NA NA 4 15 Mean (SD) NA NA 32.7 (7.47) 24.6 (6.78) %CV NA NA 22.9 27.6 Geometric mean NA NA 32.0 23.8 %CV NA NA 24.3 26.7 Effective t1/2 , h n∗ NA NA 5 16 Mean (SD) NA NA 11.4 (4.57) 6.58 (3.07) %CV NA NA 40.0 46.7 Geometric mean NA NA 10.7 5.97 %CV NA NA 42.1 47.4 AUCtau = area under the plasma concentration–time curve from time zero to the end of a dosing interval; CLss/F = total body apparent clearance of drug from the plasma at steady state; NA = not applicable; Racc = accumulation ratio. ∗ Number of patients with corresponding evaluable pharmacokinetic parameters. 1100 Volume 43 Number 6 V. Moreno et al. Table III. Adverse event (AE) summary (safety set). Category Capmatinib 300 mg BID Capmatinib 400 mg All (n = 8) BID Patients (n = 27) (N = 35) All Grades Grade 3 or All Grades Grade 3 or All Grades Grade 3 or Higher Higher Higher Summary of AEs, no. (%) AEs 8 (100) 4 (50.0) 27 (100) 16 (59.3) 35 (100) 20 (57.1) TRAEs 6 (75.0) 0 22 (81.5) 6 (22.2) 28 (80.0) 6 (17.1) SAEs 3 (37.5) 3 (37.5) 10 (37.0) 9 (33.3) 13 (37.1) 12 (34.3) Treatment-related SAEs 0 0 2 (7.4) 2 (7.4) 2 (5.7) 2 (5.7) AEs leading to 1 (12.5) 1 (12.5) 3 (11.1) 3 (11.1) 4 (11.4) 4 (11.4) discontinuation TRAEs leading to 0 0 2 (7.4) 2 (7.4) 2 (5.7) 2 (5.7) discontinuation AEs requiring additional 7 (87.5) 4 (50.0) 26 (96.3) 12 (44.4) 33 (94.3) 16 (45.7) therapy AEs requiring dose 2 (25.0) 2 (25.0) 13 (48.1) 11 (40.7) 15 (42.9) 13 (37.1) adjustment/interruption TRAEs by preferred term,∗ no. (%) Fatigue 5 (62.5) 0 8 (29.6) 1 (3.7) 13 (37.1) 1 (2.9) Nausea 2 (25.0) 0 10 (37.0) 0 12 (34.3) 0 Peripheral edema 2 (25.0) 0 3 (11.1) 0 5 (14.3) 0 Vomiting 0 0 5 (18.5) 1 (3.7) 5 (14.3) 1 (2.9) Decreased appetite 0 0 4 (14.8) 0 4 (11.4) 0 Diarrhea 0 0 4 (14.8) 0 4 (11.4) 0 Muscle spasms 1 (12.5) 0 2 (7.4) 0 3 (8.6) 0 Rash 1 (12.5) 0 2 (7.4) 0 3 (8.6) 0 Dyspnea 1 (12.5) 0 1 (3.7) 1 (3.7) 2 (5.7) 1 (2.9) Pain 1 (12.5) 0 1 (3.7) 0 2 (5.7) 0 Chills 0 0 2 (7.4) 0 2 (5.7) 0 Constipation 0 0 2 (7.4) 0 2 (5.7) 0 Headache 0 0 2 (7.4) 0 2 (5.7) 0 Mucosal inflammation 0 0 2 (7.4) 0 2 (5.7) 0 SAE = serious adverse event; TRAE = treatment-related adverse event. ∗ TRAEs with incidence ≥5% of all grades are shown. disease progression (including worsened target lesions Efficacy in liver and new lesions in liver). Upon medical Table IV illustrates the BOR, ORR, and DCR per review, this case did not meet the clinical Hy’s Law investigator assessment (RECIST 1.1) in the FAS. No criteria; thus, no confirmed cases of drug-induced patients experienced a complete response. Two patients liver injury/Hy’s Law were observed in this study. No had a BOR of partial response. The first patient had other clinically significant hematology/clinical chem- stage IVA NSCLC with MET overexpression (IHC istry abnormalities or ECG/vital sign changes were score +3 in 90% of tumor cells) and experienced a observed. partial response (as per assessments on days 41, 82, and  2021 1101 Clinical Therapeutics Table IV. Best overall response (BOR) per investigator assessment (full analysis set). End point Capmatinib 300 mg Capmatinib 400 mg All BID BID Patients (n = 8) (n = 27) (N = 35) BOR, no. (%) Partial response∗ 2 (25.0) 0 2 (5.7) Stable disease† 1 (12.5) 6 (22.2) 7 (20.0) Progressive disease‡ 4 (50.0) 16 (59.3) 20 (57.1) Unknown 1 (12.5) 5 (18.5) 6 (17.1) ORR,§ no. (%) [95% CI] 2 (25.0) [3.2–65.1] 0 [0.0–12.8] 2 (5.7) [0.7–19.2] DCR, no. (%) [95% CI] 3 (37.5) [8.5–75.5] 6 (22.2) [8.6–42.3] 9 (25.7) [12.5–43.3] DCR = disease control rate; ORR = overall response rate. ∗ Defined (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, 40,41 ) as a ≥30% decrease in the sum of target lesion diameters (taking the baseline sum diameters as a reference). † Defined (per RECIST 1.1, 40,41 ) as an insufficient shrinkage (compared with baseline) to qualify for partial or complete response or an insufficient increase (taking the smallest sum diameters at baseline or while on study, whichever is smallest, as a reference) to qualify for progressive disease. ‡ Defined (per RECIST 1.1, 40,41 ) as a ≥20% increase in the sum of target lesion diameters (taking the smallest sum on study, including the baseline, as a reference); in addition, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesion is also considered progression. § Defined as the sum of complete responses and partial responses.  Defined as the sum of complete responses, partial responses, and stable disease events. 125); this patient was escalated to 400 mg BID (starting BID after cycle 4, two of whom had a BOR of partial on day 85) but subsequently experienced progressive response and one had a BOR of stable disease. The disease (as per assessment on day 163) and was single patient in the study with recorded METex14 permanently discontinued from the study on day 169. mutation (stage IV thyroid cancer with lung metastasis) The second patient had stage IV adenocarcinoma of had a BOR of stable disease at each assessment (on days unknown primary with MET amplification (fluorescent 39, 84, 126, 168, 210, and 252). in situ hybridization–determined GCN 24.51) and experienced a partial response (as per assessments on DISCUSSION day 82 and 124); this patient was escalated to 400 In this study, capmatinib was well tolerated when given mg BID (starting on day 127) but later experienced with food in patients with MET-dysregulated advanced progressive disease (as per assessment on day 166) and solid tumors; no DLTs were observed at either the 300 was permanently discontinued from the study on day mg BID or 400 mg BID dose levels, and an increase in 168. capmatinib exposure was observed with a dose increase The investigator-determined ORR was 25% (95% from 300 mg BID to 400 mg BID. Accordingly, the 400 CI, 3.2–65.1) at the 300 mg BID dose level owing to mg BID dose was selected as the higher of the tolerated partial responses in 2 patients, and 0% at the 400 mg doses in this study. The 400 mg BID dose (tablet) was BID dose level. Accordingly, the ORR for all patients also used in the pivotal Phase II GEOMETRY mono- across both dose escalation and expansion phases was 1 study.32 The capmatinib tablet formulation currently 5.7% (95% CI, 0.7–19.2). The DCR was 37.5% (95% has a recommended dose of 400 mg BID with or CI, 8.5–75.5) at the 300 mg BID dose level, 22.2% without food.33 (95% CI, 8.6–42.3) at the 400 mg BID dose level, and The observed increase in capmatinib exposure from 25.7% (95% CI, 12.5–43.3) across all patients. 300 mg to 400 mg BID seems over dose-proportional Three patients in the 300 mg BID dose level cohort in this study (geometric mean Cmax , 1550 vs 3050 had their dose escalated from 300 mg BID to 400 mg ng/mL; geometric mean AUCtau , 9370 vs 16,800 ng 1102 Volume 43 Number 6 V. Moreno et al. × h/mL). However, we posit that this observation is occurrences of DLTs. Overall, safety observations were largely due to the small sample size of the 300 mg BID in line with the existing safety profile for capmatinib cohort (n = 7). Indeed, capmatinib (tablet formulation) administered under fasted conditions in patients with has previously shown a linear PK profile from 200 advanced solid malignancies,13 ,36 with no major or mg to 400 mg BID in a population PK analysis using new observations. Indeed, Bang et al13 observed no pooled data from several studies (data on file, Novartis DLTs among patients with advanced MET-positive Pharmaceuticals Corporation).33 Furthermore, dose solid tumors who were treated with the capmatinib proportionality has also been reported from 200 tablet at the 400 mg BID dose under fasted conditions. to 600 mg with the capmatinib tablet after single However, DLT (grade 3 depression) occurred in 1 administration in healthy subjects (data on file, patient receiving the 400 mg BID tablet in a Japanese Novartis Pharmaceuticals Corporation). Phase I dose escalation study in patients with advanced Compared with the median steady-state Tmax of solid tumors not stratified according to MET status.36 1.09 hours in GEOMETRY mono-1 cohorts 1 to When capmatinib was given with food in the present 5, in which capmatinib 400 mg BID (tablet) was study, the most frequent AEs (any grade) were fatigue given under fasted conditions,32 the median Tmax for (45.7%), nausea (40.0%), peripheral edema (28.6%), capmatinib 400 mg BID after administration with and dyspnea (20.0%); the most common TRAEs (any a high-fat meal in this study was delayed, with a grade) were fatigue (37.1%) and nausea (34.3%). value of 4.0 hours at steady-state (C1D7). At steady- These findings are generally consistent with the 400 state, accumulation of capmatinib 400 mg BID was mg BID tablet arms of other Phase I studies.13 ,36 low and numerically similar when administered with These findings are also concordant with those across food in the current study (Racc geometric mean, all cohorts of the Phase II GEOMETRY mono-1 1.29) and under fasted conditions in GEOMETRY study (n = 364), in which capmatinib (400 mg BID mono-1 cohorts 1 to 5 (Racc geometric mean 1.39).32 tablet) had a manageable safety profile, with the Compared with the steady-state exposure for the 400 most commonly reported AEs (any grade) as follows: mg BID capmatinib tablet under fasted conditions, peripheral edema (all cohorts, 51%; fasted cohorts, reported by Wolf et al32 (geometric mean Cmax , 51%; nonfasted cohorts, 53%), nausea (all cohorts, 4780 ng/mL; geometric mean AUC0–12h , 20,200 ng 45%; fasted cohorts, 46%; nonfasted cohorts, 37%), × h/mL), the geometric mean Cmax was ˜36% lower and vomiting (all cohorts, 28%; fasted cohorts, 29%; and the geometric mean AUC0–12h was ˜20% lower nonfasted cohorts, 21%). The most common TRAEs when administered with food in this study (geometric (any grade) across all cohorts were peripheral edema mean Cmax , 3050 ng/mL; geometric mean AUC0–12h , (42.9%), nausea (34.3%), vomiting (18.7%), and 16,800 ng × h/mL). Furthermore, at steady-state, increased blood creatinine levels (18.4%).32 accumulation of capmatinib 400 mg BID was low and Capmatinib was recently granted accelerated ap- numerically similar when administered with food in the proval by the FDA (May 2020) and subsequently current study (Racc geometric mean, 1.29) and under received approval by the Japanese Ministry of Health, fasted conditions in GEOMETRY mono-1 cohorts 1 Labor, and Welfare (June 2020) for the treatment of to 5 (Racc geometric mean, 1.39).32 Overall, these METex14-mutated metastatic NSCLC on the basis PK data indicate that capmatinib administration with of findings from GEOMETRY mono-1.33 In this food affects the absorption rate; however, based on trial, patients received capmatinib 400 mg BID orally the similar steady-state AUC0-12h when capmatinib until disease progression or unacceptable toxicity. was administered under fasted conditions or with Capmatinib (fasted conditions) led to a clinically food, it can be concluded that the extent of the meaningful ORR benefit in patients with treatment- absorption was similar. A key strength of this study naive (n = 28; ORR, 68%; 95% CI, 48–84) and was the collection of PK data for capmatinib when previously treated (n = 69; ORR, 41%; 95% CI, administered with a high-fat meal, which enabled 29–53) METex14-mutated advanced NSCLC.32 In assessment of the maximum impact of food on addition, in cohort 6, capmatinib (without fasting exposure. restrictions) exhibited efficacy as second-line therapy In the present study, capmatinib was well tolerated in patients with METex14-mutated advanced NSCLC when administered with food, and there were no (n = 31; ORR, 48.4%; 95% CI, 30.2–66.9).34 In  2021 1103 Clinical Therapeutics the present study, in which preliminary evidence of from AstraZeneca and Roche; and personal fees from capmatinib antitumor activity was an exploratory Kyowa Kirin and Pierre Fabre, all of which are objective and MET selection criteria were broader than outside of the current work. Dr. Wermke has received those in GEOMETRY mono-1,33 the ORR was 5.7% grant support (research funding) and personal fees (95% CI, 0.7–19.2) and the DCR was 25.7% (95% CI, (honoraria) from Novartis, outside of the current 12.5–43.3) across all patients. However, as this study work. Dr. Basque, Kapoor, and Giovannini and Mr. was not primarily designed or powered to evaluate Nidamarthy are full-time employees of Novartis. antitumor activity, no conclusions or comparisons Dr. Cui is a full-time employee and shareholder of regarding efficacy can be made. Moreover, only one Novartis. The authors have indicated that they have no patient with a METex14 mutation, which is now other conflicts of interest regarding the content of this recognized as an oncogenic driver, was enrolled in article. this study; the significance of MET amplification (with Data were collected and analyzed by the sponsor GCN ≥4) and MET overexpression (IHC score +3 in (Novartis Pharmaceuticals Corporation) in conjunc- ≥50% of tumor cells) remain poorly understood. tion with the authors. CONCLUSIONS ACKNOWLEDGMENTS Safety observations and capmatinib exposure data for This study was funded and designed by the sponsor the capmatinib tablet formulation (300 mg BID and (Novartis Pharmaceuticals Corporation) in accordance 400 mg BID) administered with food were consistent with Good Publication Practice (GPP3) guidelines with the published safety profile and PK data under (http://www.ismpp.org/gpp3). fasted conditions in patients with advanced MET- The authors thank Conor A. Bradley, PhD, of No- positive solid tumors, with no DLTs observed in this vartis Ireland Limited, for providing medical writing study. Thus, based on a review of all safety and support. The authors also thank Marta Torrente, PhD, PK data, we conclude that the capmatinib tablet of Novartis Pharma AG for her contributions during formulation at 400 mg BID was well tolerated with the conduct of the study. food in patients with MET-dysregulated advanced solid Drs. Cui, Basque, and Giovannini contributed to tumors. These findings support the current capmatinib designing the study. Drs. Moreno, Basque, Arkenau, dosing recommendation of 400 mg BID with or Majem, Giovannini, Yachnin, and Wermke contributed without food in patients with MET-dysregulated to patient accrual. Drs. Cui, Kapoor, Basque, and advanced solid tumors.33 Giovannini, and Mr. Nidamarthy, contributed to data analysis. All authors contributed to data interpretation, DISCLOSURES writing and critical revision of the manuscript, and Dr. Moreno has received personal fees (advisory board have read and approved the final version of this honoraria) from Bristol Myers Squibb, Bayer, Pieris, manuscript. Janssen, Roche and Basilea, outside of the current Novartis is committed to sharing with qualified work. Dr. Greil has received personal fees from external researchers, access to patient-level data and AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, supporting clinical documents from eligible studies. Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, These requests are reviewed and approved by an inde- Daiichi Sankyo, and Janssen, outside of the current pendent review panel on the basis of scientific merit. All work. Dr. Arkenau is employed by the Sarah Cannon data provided are anonymized to respect the privacy Research Institute, UK (part of HCA Healthcare of patients who have participated in the trial in line UK); and has received personal fees (advisory board with applicable laws and regulations. The availability honoraria) from Pierre Fabre, Servier, BeiGene, Bicycle, of this trial data is according to the criteria and process BioNTech, iOnctura, Roche, Guardant and Taiho, described on www.clinicalstudydatarequest.com. outside of the current work. Dr. Majem has received grant support and personal fees from Bristol Myers REFERENCES Squibb; personal fees and non-financial support from 1. Birchmeier C, Birchmeier W, Gherardi E, Vande Merck Sharp & Dohme and Boehringer Ingelheim; Woude GF. Met, metastasis, motility and more. Nat Rev personal fees, non-financial support, and other support Mol Cell Biol. 2003;4:915–925. 1104 Volume 43 Number 6 V. Moreno et al. 2. 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E-mail: Victor.Moreno@startmadrid.com. 1106 Volume 43 Number 6 V. Moreno et al. APPENDIX PK/PD data during a dose-escalation decision meeting. If the safety and PK data at the starting dose of 300 mg bid SUPPLEMENTARY METHODS were determined to be supportive by a dose-escalation Study Dose-escalation Rules committee (with consensus between Investigators and In this study, successive cohorts received increasing the Sponsor), then the dose of capmatinib was to be doses of capmatinib (300 and 400 mg twice daily escalated up to a maximum dose of 400 mg bid (a 33% [bid]; tablet formulation) with food. For dose-escalation dose increment) to identify the higher of the tolerated decisions, each cohort consisted of at least 6 newly dose level of capmatinib. This was to occur when the enrolled patients to be treated at the specified dose following conditions were met: at least 6 patients had level; the first cohort of 6 patients were treated with the been treated at this dose; the posterior probability of starting dose of 300 mg bid with food. To be considered targeted toxicity at this dose exceeded 50% and was evaluable for dose-escalation decisions, patients were the highest among potential doses; it was the dose required to complete a minimum of the first 28 days recommended for patients, either per the BLRM or of treatment (the minimum exposure criterion) with the by review of all clinical data by the Investigators and minimum safety evaluation and drug exposure, or have Sponsor. had a dose-limiting toxicity (DLT) within the first 28 To better understand the safety, tolerability and PK days of treatment. As patients could discontinue during of capmatinib, additional cohorts were to be enrolled the first 28 days of treatment without experiencing a at preceding dose levels before or while proceeding DLT (for example, due to early disease progression), with further dose escalation. If a decision was made to additional patients were to be enrolled, unless 3 patients escalate to a higher dose level, but one or more additional were already evaluable in that cohort. patient(s) treated at the preceding dose level experienced Dose-escalation decisions were guided by the adaptive a DLT during the first 28 days of treatment, then the Bayesian logistic regression model (BLRM) along with BLRM was to be updated with this new information escalation with overdose control (EWOC) criteria,37 , before any additional patients were enrolled at that 38 as well as by clinical judgement regarding safety, higher dose level. Patients ongoing were to continue tolerability, and pharmacokinetics (PK), in order to treatment at their assigned dose levels. minimize the future risk of DLT. The adaptive BLRM In this study, intra-patient dose escalation was methodology provides an estimate of all dose levels that not permitted at any time within the first 4 cycles do not exceed the higher of the tolerated dose levels of treatment. After the fourth cycle was completed, assessed, incorporating all DLT information at all dose individual patients could be considered for treatment at levels. Accordingly, the next dose will have the highest a dose of INC280 higher than the dose to which they probability that the DLT rate will fall in the target were initially assigned, up to a maximum dose of 400 interval (16–33%; 0.16 ≤ DLT rate < 0.33) and will mg BID with food. always satisfy the EWOC principle of <25% posterior probability of excessive toxicity (<25% probability that Dose Modification, Treatment Interruption and the true DLT rate is ≥33%). If the first two patients Discontinuation in a cohort experienced a DLT, further enrollment to For patients who did not tolerate the protocol- that cohort was to stop, and the BLRM was to be specified dosing schedule of capmatinib, dose ad- updated with this new information; re-evaluation of the justments were permitted. All dose modifications, available safety, PK and pharmacodynamics (PD) data interruptions or discontinuations were based on the would occur. By incorporating information gained at worst preceding toxicity, as graded by the Common the preceding dose levels, additional patients were to be Terminology Criteria for Adverse Events (CTCAE) enrolled at this dose level or a lower dose level (as agreed version 4.03. by the Investigators and Sponsor) and if the BLRM In general, for grade 1 and tolerable grade 2 predicted that the risk that this dose exceeds the higher treatment-related toxicities, patients were continued of the tolerated dose levels assessed was <25%. on full doses. For intolerable grade 2 or 3 treatment- For implementation of dose-escalation decisions, related toxicities, dosing was interrupted until at least both the Investigators and Sponsor evaluated available resolution to grade 1 followed by either dose reduction toxicity information, BLRM recommendations and or re-initiation at the same dose level, depending on  2021 1106.e1 Clinical Therapeutics the type of toxicity. For any grade 4 toxicity, patients (dose level –2). For patients on a starting dose (dose level were to interrupt study treatment until resolution to –0) of 400 mg bid, dose reductions to 300 mg bid (dose grade 1, followed by either dose reduction or treatment level –1) and 200 mg bid (dose level –2) were allowed. discontinuation. No dose re-escalation was allowed. Patients were to discontinue treatment if, after If the administration of capmatinib was temporarily treatment was resumed at the lowest allowed dose (200 interrupted for reasons other than toxicity, then mg bid), the toxicity recurred with the same or worse treatment was to be resumed at the same dose. If severity despite use of maximal preventive measures (as the treatment was withheld due to toxicity, the dose per the study site guidelines). modification guidelines were to be followed. In either Dose reduction was based on the worst toxicity case, scheduled visits and all assessments (including demonstrated at the last dose. For each patient, a tumor assessments) were to continue. If the treatment maximum of 2 dose level modifications was allowed, was withheld for >21 consecutive days (from the first after which the patient was discontinued from treatment. day when a dose was interrupted), then treatment was For patients on a starting dose (dose level –0) of 300 mg permanently discontinued. Patients who discontinued bid, dose reduction to 200 mg bid (dose level –1) was due to a study drug-related adverse event or an abnormal allowed, but no subsequent dose reduction was allowed laboratory value underwent follow-up for toxicities. 1106.e2 Volume 43 Number 6 V. Moreno et al. Supplemental Table I. Study definition of dose-limiting toxicities. Toxicity Any of the following criteria Hematology Any hematologic toxicity = grade 3, lasting for > 7 consecutive days Any hematologic toxicity ≥ grade 4 (of any duration) Febrile neutropenia (absolute neutrophil count < 1.0 × 109 /L or 1000/mm3 ) and a single temperature of >38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than one hour Renal Serum creatinine ≥ grade 3 (≥ 3.0 × baseline or > 3.0 – 6.0 × ULN) Hepatic Total bilirubin ≥ grade 3 (> 3 × ULN) AST or ALT = grade 3 (> 5.0 – 20.0 × ULN) for > 7 consecutive days AST or ALT = grade 4 (> 20.0 × ULN) For patients with normal baseline AST and ALT and total bilirubin value: AST or ALT > 3.0 × ULN combineda with total bilirubin > 2.0 × ULN without evidence of cholestasisb OR For patients with abnormal baseline AST or ALT or total bilirubin value: (AST or ALT > 2 × baseline AND > 3.0 × ULN) OR (AST or ALT > 8.0 × ULN), whichever is lower, combined with (total bilirubin > 2 × baseline AND > 2.0 × ULN) Pancreas Asymptomatic ≥ CTCAE grade 3 serum amylase or lipase (> 2.0 × ULN) occurring for > 14 consecutive days Symptomatic serum amylase or lipase elevation, medical intervention required Diarrhea ≥ Grade 3, lasting for > 7 consecutive days, despite optimal treatment Neurologic Any neurological abnormality or toxicity ≥ grade 2 Cardiac ≥ CTCAE grade 3 Other adverse events Any adverse event ≥ grade 3 Single event or multiple occurrences of the same event that lead to a dosing interruption of > 7 days in cycle 1, may be considered as DLTs by the Investigators and Study Sponsor, even if not CTCAE grade 3 or higher a ‘Combined’ was defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold. b ‘Cholestasis’ was defined as ALP elevation (> 2 x ULN and R value [ALT/ALP in × ULN] < 2) in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis).CTCAE version 4.03 was used for all grading.Patients may have received supportive care (eg, transfusion of red blood cells) as per local institutional guidelines.ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicity; ULN, upper limit of normal.  2021 1106.e3 Clinical Therapeutics Supplemental Table II. Adverse events by preferred term (safety set). Capmatinib 300 mg bid Capmatinib 400 mg bid All patients (n = 8) (n = 27) (n = 35) Category All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3 AEsa – n (%) Fatigue 5 (62.5) 0 11 (40.7) 2 (7.4) 16 (45.7) 2 (5.7) Nausea 3 (37.5) 0 11 (40.7) 0 14 (40.0) 0 Peripheral edema 4 (50.0) 1 (12.5) 6 (22.2) 0 10 (28.6) 1 (2.9) Dyspnea 2 (25.0) 0 5 (18.5) 1 (3.7) 7 (20.0) 1 (2.9) Decreased appetite 1 (12.5) 0 5 (18.5) 0 6 (17.1) 0 Vomiting 1 (12.5) 0 5 (18.5) 1 (3.7) 6 (17.1) 1 (2.9) Rash 1 (12.5) 0 4 (14.8) 0 5 (14.3) 0 Diarrhea 0 0 5 (18.5) 0 5 (14.3) 0 Depression 1 (12.5) 0 3 (11.1) 1 (3.7) 4 (11.4) 1 (2.9) Headache 1 (12.5) 0 3 (11.1) 0 4 (11.4) 0 Constipation 0 0 4 (14.8) 0 4 (11.4) 0 a AEs with incidence of ≥ 10% of all grades are shown.AE, adverse event; bid, twice daily. 1106.e4 Volume 43 Number 6 V. Moreno et al. Supplemental Table III. Serious adverse events by preferred term (safety set). Capmatinib 300 mg Capmatinib 400 mg All patients bid (n = 8) bid (n = 27) (n = 35) Category All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3 SAEs – n (%) General physical health deterioration 1 (12.5) 1 (12.5) 1 (3.7) 1 (3.7) 2 (5.7) 2 (5.7) Abdominal pain 0 0 2 (7.4) 2 (7.4) 2 (5.7) 2 (5.7) Dyspnea 0 0 2 (7.4) 1 (3.7) 2 (5.7) 1 (2.9) Fracture pain 1 (12.5) 1 (12.5) 0 0 1 (2.9) 1 (2.9) Lung infection 1 (12.5) 1 (12.5) 0 0 1 (2.9) 1 (2.9) Lung infiltration 1 (12.5) 1 (12.5) 0 0 1 (2.9) 1 (2.9) Peripheral edema 1 (12.5) 1 (12.5) 0 0 1 (2.9) 1 (2.9) Pleural effusion 1 (12.5) 0 0 0 1 (2.9) 0 Depression 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Escherichia infection 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Hypersensitivity 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Hypocalcemia 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Hypokalemia 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Hypoproteinemia 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Infection 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Intracranial tumor hemorrhage 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Myocardial infarction 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Pericardial effusion 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Sepsis 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Upper gastrointestinal hemorrhage 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Vomiting 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) bid, twice daily; SAE, serious adverse event. Supplemental Table IV. Adverse events of special interest (safety set). Capmatinib 300 mg bid Capmatinib 400 mg bid All patients (n = 8) (n = 27) (n = 35) Category All grades Grade 3 All grades Grade 3 All grades Grade 3 AESIs – n (%) CNS toxicity 2 (25.0) 0 1 (3.7) 0 3 (8.6) 0 Liver toxicity 0 0 5 (18.5) 1 (3.7) 5 (14.3) 1 (2.9) Pancreatitis 0 0 2 (7.4) 2 (7.4) 2 (5.7) 2 (5.7) Pneumonitis 1 (12.5) 1 (12.5) 0 0 1 (2.9) 1 (2.9) QT prolongation 0 0 1 (3.7) 1 (3.7) 1 (2.9) 1 (2.9) Renal toxicity 1 (12.5) 0 2 (7.4) 0 3 (8.6) 0 AESI, adverse events of special interest; bid, twice daily; CNS, central nervous system.  2021 1106.e5