Received: 25 September 2019 | Revised: 19 November 2019 | Accepted: 20 November 2019 DOI: 10.1111/cas.14254 ORIGINAL ARTICLE Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts Yung-Jue Bang1 | Wu-Chou Su2 | Martin Schuler3 | Do-Hyun Nam4 | Wan Teck Lim5 | Todd M. Bauer6 | Analia Azaro7,8 | Ronnie Tung Ping Poon9 | David Hong10 | Chia-Chi Lin11 | Mikhail Akimov12 | Samson Ghebremariam13 | Sylvia Zhao14 | Monica Giovannini13 | Brigette Ma15 1 Seoul National University College of Medicine, Seoul, Korea Abstract 2 National Cheng Kung University Hospital, Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Tainan, Taiwan Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET- 3 Department of Medical Oncology, West German Cancer Center, University Duisburg- positive solid tumor patients and dose expansion in advanced non-lung tumors. Essen and German Cancer Consortium Capmatinib was well tolerated with a manageable safety profile across all explored (DKTK), Partner Site University Hospital Essen, Essen, Germany doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, 4 Samsung Medical Center, Seoul, Korea and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). 5 National Cancer Centre, Singapore Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 6 Sarah Cannon Research Institute/ 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase Tennessee Oncology, PLLC, Nashville, Tennessee, USA 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% 7 Department of Medical Oncology, inhibition of c-MET phosphorylation in animal models) is expected to be achieved Molecular Therapeutics Research Unit, Vall and maintained. Among the dose-expansion patients (N = 38), best overall response d’Hebron University Hospital, Barcelona, Spain across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 8 Pharmacology Department, The 46%, other indications 28%); two other indication patients with gene copy number Autonomous University of Barcelona, (UAB), Barcelona, Spain (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemi- 9 Queen Mary Hospital, Hong Kong, China cally determined phospho-MET inhibition (H-score = 2) was shown following cap- 10 University of Texas/MD Anderson Cancer matinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal Center, Houston, Texas, USA 11 cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing National Taiwan University Hospital, Taipei, Taiwan (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, re- 12 Novartis Pharma AG, Basel, Switzerland spectively; no MET mutations were observed. Thus, the recommended phase 2 dose 13 Novartis Pharmaceuticals Corporation, (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was East Hanover, New Jersey, USA 14 well tolerated and showed antitumor activity and acceptable safety profile at the China Novartis Institutes for BioMedical Research, Shanghai, China RP2D. Abbreviations: AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUCtau, area under plasma-concentration time curve over dosing interval; BIRC, blinded independent review committee; BLRM, Bayesian Logistic Regression Model; CI, confidence interval; Cmax, maximum plasma concentration; CNS, central nervous system; CT, computed tomography; CV, coefficient of variation; DCR, disease control rate; DLT, dose-limiting toxicities; EGFR, epidermal growth factor receptor; EGFRwt, epidermal growth factor receptor wild-type; EWOC, escalation with overdose control; GBM, glioblastoma multiforme; GCN, gene copy number; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; IHC, immunohistochemistry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; ORR, objective response rate; PD, pharmacodynamics; PFS, progression-free survival; PK, pharmacokinetics; p-MET, phospho-MET; pRCC, papillary renal cell carcinoma; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor; Tmax, time to peak plasma concentration. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 536 |  wileyonlinelibrary.com/journal/cas Cancer Science. 2020;111:536–547. BANG et al. | 537 15 State Key Laboratory of Translational Oncology, Phase 1 Clinical Trial Centre, The (ClinicalTrials.gov Identifier: NCT01324479). Chinese University of Hong Kong, Hong Kong, China KEYWORDS capmatinib, MET amplification, MET dysregulation, phase 1, solid tumors Correspondence Yung-Jue Bang, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. Email: bangyj@snu.ac.kr Funding information Novartis Pharmaceuticals Corporation 1 | I NTRO D U C TI O N G1163. Thus, type Ib inhibitors are highly specific for MET with fewer off-target effects compared with type Ia inhibitors. Type II Dysregulation of MET signaling leads to activation of downstream inhibitors are ATP-competitive, but bind to the ATP adenine bind- pathways that include the RAS/MAPK, PI3K/AKT, and Rac/Rho ing site extending to the hydrophobic back pocket. They distort pathways, promoting cell proliferation, survival, and metastasis.1 the apo-MET autoinhibitory conformation and bind to an induced MET dysregulation, through gene amplification, mutation, and/or conformation. They do not have interaction with G1163. Type III overexpression has been described in multiple tumor types, includ- inhibitors bind to allosteric sites different from the ATP binding ing lung, HCC, GBM, pRCC, breast, colon, and gastric cancers.1 site. 28 Capmatinib (INC280) is an oral, ATP-competitive and highly High-level MET gene amplification was originally described in potent type 1b MET inhibitor in biochemical (IC 50 0.13 nmol/L) 2 gastric cancer cell lines, resulting in increased mRNA and protein and cellular (IC 50 ~ 1 nmol/L) assays and has proven to be highly overexpression.3 In EGFRwt, NSCLC de novo MET amplification has selective versus other kinases in large panels of biochemical been reported in 1% to 4% of newly diagnosed cases.4-6 MET am- and binding assays. 30,31 Capmatinib caused regression of MET- plification is also implicated in the acquired resistance to EGFR TKI, dependent tumors at tolerable doses in animal models across a reported in 5% to 26% of cases, regardless of the presence of the range of tumor types, including NSCLC, HCC, and GBM. 30,31 MET 7-13 T790M mutation. dependency in such responsive tumor models was associated with In addition, MET mutations have been identified in primary tu- MET gene amplification (NSCLC, HCC), MET exon 14 skipping mu- mors as well as in metastatic lesions of several cancers, including tation (NSCLC), marked MET overexpression without amplifica- 14,15 head and neck, pRCC, liver, ovarian, and NSCLC. In NSCLC, tion (NSCLC), or coexpression of MET and its ligand HGF (GBM). splice site alterations at exon 14 that lead to reduced internalization The present phase 1 dose-escalation study (NCT01324479) as- and degradation and net overexpression occur in 2% to 3% of adeno- sessed the safety and tolerability of capmatinib in patients with ad- carcinomas16-19 and in up to 22% of sarcomatoid NSCLC. 20 vanced MET-positive solid tumors. We also report herein the safety Elevated levels of the receptor ligand HGF and/or overexpres- and efficacy observed in expansion cohorts of patients with MET- sion of MET is often associated with resistance to chemotherapy and dysregulated gastric cancer, HCC, and other tumors (including GBM radiotherapy. 21 Overall, MET dysregulation is recognized as a nega- and pRCC). Safety and efficacy results of the expansion cohort of tive prognostic factor, especially in advanced NSCLC22-24 and is also patients with advanced NSCLC is reported separately (Schuler M et associated with poor clinical outcomes in patients with glioblastoma al; manuscript submitted). and squamous cell carcinoma of the head and neck. 25,26 Several MET inhibitors, comprising small molecule TKI and mAb targeting MET or its ligand, HGF, have been developed. 27 2 | M ATE R I A L S A N D M E TH O DS TKI are mainly divided into three types (I, II, and III) depending on binding of ATP to the MET kinase domain. 28,29 The apo-MET ki- 2.1 | Study design and treatment nase adopts a distinctive autoinhibitory conformation (activation loop locks into the ATP binding site through a salt bridge between This was a phase 1, open-label, multicenter, nonrandomized, two- D1228 and K1110). Type I MET inhibitors are ATP-competitive, part study comprising dose-escalation and expansion parts in- and bind to MET unique autoinhibitory conformation (π-stacking cluding patients with gastric cancer, HCC, and other solid tumor with Y1230 in the MET activation loop). Type I inhibitors are fur- indications. In the first part of the study, molecularly prescreened ther divided into type Ia and type Ib. Potency of type Ia inhibi- patients with MET-dysregulated advanced solid tumors were en- tors is due to interaction with Y1230, the hinge, and the solvent rolled in the dose-escalation phase. In the expansion phase, pa- front glycine residue G1163 (analogous to the same position as tients with solid tumors, including NSCLC, were enrolled based on ALK G1202 and ROS1 G2032), whereas type Ib MET inhibitors MET dysregulation. Later, an additional expansion group was imple- have stronger interactions with Y1230 and the hinge, but not with mented to enrol patients with EGFRwt NSCLC preselected centrally 538 | BANG et al. based on a high MET expression (IHC score 3+); results for the origi- criteria were symptomatic CNS metastases that are neurologically nal NSCLC expansion group and additional expansion group are re- unstable or requiring increasing doses of steroids to control; prior ported separately (Schuler M et al; manuscript submitted). therapy with MET inhibitors or HGF-targeted therapy; or any CNS The primary objective of the present study was to determine the deficits (for GBM, CNS symptoms grade 2 or greater). MTD/RP2D of oral capmatinib based on the incidence, frequency, and category of DLT in cycle 1 and the AE. A two-parameter BLRM using the EWOC principle32,33 was used to guide the dose escalation for de- 2.3 | Clinical assessments termination of the MTD or RP2D. Dose escalation was based on the incidence of DLT during cycle 1, with additional analyses carried out Tumor lesions were assessed according to the RECIST v1.0 (inves- if significant toxicities were observed during later cycles (criteria for tigator confirmed) or MacDonald criteria for patients with GBM. DLT provided in Table S1). After completion of a given cohort, the deci- CT-based tumor assessments were carried out unless contraindi- sion to dose escalate and the actual dose chosen depended on risk as- cated or for GBM, in which case MRI with contrast was carried out. sessment calculations using the BLRM and medical review of available Assessments were carried out at screening, every 8 weeks beginning clinical and laboratory data, and the BLRM estimated the MTD by up- at the start of cycle 3 and as required to confirm response, and at dating estimates of the probability of observing a DLT in the first cycle. the end of treatment (if no scan within 30 days prior to end of treat- For a given schedule, the MTD was defined as the highest drug dosage ment). Safety assessments were carried out based on all AE, clinical not expected to lead to DLT in >33% of patients in the first 28 days. laboratory data, and physical examinations. The key secondary endpoint was ORR by investigator assessment, defined as the proportion of subjects with measurable disease whose best overall response is either complete response or partial response 2.4 | Pharmacokinetics analysis according to the RECIST v1.1 or MacDonald criteria (only for GBM). Other secondary objectives were to further characterize antitumor During the phase 1 dose-escalation part of the study, pre-dose and activity, safety and tolerability, PK and PD (paired biopsies; IHC of 0.5, 1, 2, 4, 6, and 8 h post-dose PK samples were collected on cycle p-MET, phospho-ERK, phospho-AKT, and phospho-S6, PK parame- 1 day 1 and on cycle 1 day 15; pre-dose PK samples were collected ters), and DCR (proportion of patients whose best overall response is on cycle 1 day 2, cycle 1 day 16, cycle 2 day 1, and cycle 3 day 1. either complete response or partial response or stable disease). During the phase 1 dose-expansion part of the study, pre-dose and In the dose-escalation part, separate cohorts of patients received 0.5, 1, 2, 4, 6, and 8 h post-dose PK samples were collected on cycle treatment with increasing doses of capmatinib, starting at 100 mg 1 day 15 in non-NSCLC patients; pre-dose PK samples were col- bid in capsule formulation. PK and safety data from a tablet safety lected on cycle 1 day 16 and cycle 2 day 1. Capmatinib concentra- cohort were also used to guide the calculation of a tablet dose that tions in plasma were measured using a validated LC-MS/MS method would achieve comparable exposure to that of the RP2D of capmati- with a lower limit of quantification of 1 ng/mL. Noncompartmental nib capsules and meet the EWOC criteria in the BLRM for tablet. In the PK analysis was done to generate PK parameters of capmatinib, and dose-expansion cohorts, patients were treated at a capmatinib dose of dose proportionality of capmatinib was assessed. 600 mg bid, which is the RP2D of capmatinib capsules as determined in the safety cohort. Patients were permitted to switch to the 400 mg bid tablet dose. Patients were treated in 28-day cycles provided there 2.5 | Statistical analysis was no evidence of disease progression or excessive toxicity and were continually reassessed for evidence of acute and cumulative toxicity. Data cutoff date for this report was July 17, 2017 when all pa- tients had discontinued. No formal statistical power calculations to determine sample size were carried out for this study. It was 2.2 | Patients estimated that a minimum of 15 subjects would be enrolled in the dose-escalation phase, including at least six subjects treated at the Adult patients (aged ≥18 years) with advanced solid tumors that are MTD/RP2D level. During the expansion phase, subjects with HCC, refractory to currently available therapies or for whom no effective NSCLC, or gastric cancer were enrolled into separate groups of treatment is available were eligible. Patients were required to have 10 subjects each. Each of these three groups could be expanded an ECOG Performance Status ≤2 and locally or centrally confirmed by 15 additional subjects for a maximum of 25 subjects per group MET dysregulation as follows: for NSCLC, nasopharyngeal cancer, if additional insight into the safety and/or efficacy was desired. triple-negative breast cancer, pRCC, gastric cancer, and any other Decision for such expansion of a group was to be made no later type of solid tumor, a MET H-score ≥150 or a ratio of MET/cen- than 16 weeks from initial treatment of the last subject for that tromere ≥2.0 or MET GCN ≥5, or ≥50% of tumor cells with IHC score group and by the Novartis Clinical Trial Team in consultation with 2+ or score 3+; for HCC and GBM, a MET H-score ≥50 or a ratio the study investigators after reviewing all available clinical data. A of MET/centromere ≥2.0 or MET GCN ≥5. Patients with pRCC and fourth group was expected to enrol up to 15 subjects with other germline MET mutation (in local report) were eligible. Key exclusion solid tumors (pRCC, GBM, and others). BANG et al. | 539 TA B L E 1 Patient demographics and disease characteristics in the dose-escalation and selected dose-expansion cohorts Expansion (RP2D) Gastric cancer HCC Other indications All expansion Dose escalation (N = 38) n=9 n = 11 n = 18 (N = 38) Age (median, y) 56.0 55.0 54.0 57.0 55.3 Age category (years), n (%) <65 32 (84) 9 (100) 8 (73) 13 (72) 30 (79) ≥65 6 (16) 0 3 (27) 5 (28) 8 (21) Gender (male, n [%]) 27 (71) 7 (78) 9 (82) 15 (83) 31 (82) Race Caucasian 6 (16) 9 (100) 6 (55) 13 (72) 28 (74) Asian 31 (82) 0 4 (36) 1 (6) 5 (13) Other 1 (3) 0 1 (9) 4 (22) 5 (13) ECOG PS, n (%) 0 21 (55) 3 (33) 7 (64) 10 (56) 20 (53) 1 16 (42) 6 (67) 4 (36) 6 (33) 16 (42) 2 1 (3) 0 0 1 (6) 1 (3) Missing 0 0 0 1 (6) 1 (3) Primary site of cancer Liver 15 (39) 0 11 (100) 0 11 (29) Colon 8 (21) 0 0 0 0 Stomach 2 (5) 9 (100) 0 0 9 (24) Lung 1 (3) 0 0 0 0 Other 12 (32) 0 0 18 (100) 18 (47) No. of prior lines of therapy, n (%) Missing 0 0 0 2 (11) 2 (5) 1 6 (16) 2 (22) 6 (55) 4 (22) 12 (32) 2 7 (18) 1 (11) 2 (18) 2 (11) 5 (13) ≥3 25 (66) 6 (67) 3 (27) 10 (56) 19 (50) Abbreviations: bid, twice daily; ECOG PS, ECOG performance status; HCC, hepatocellular carcinoma; RP2D, recommended phase 2 dose. The ORR was presented by treatment group with an exact 95% [0, 0.16) underdosing, [0.16, 0.33) targeted toxicity, and [0.33, 1.00] CI if response rate of 10% or higher was observed. Kaplan-Meier es- excessive toxicity. timate of median PFS and rate at 3, 6, and 12 months, along with 95% For secondary efficacy and safety endpoints, patients treated at CI, were summarized by treatment group according to the investiga- the RP2D for capmatinib during the escalation phase were pooled tor and BIRC. A waterfall plot of best percentage change from base- with those receiving the same dosing regimen and with same dis- line in sum of longest diameters according to the investigator was ease during the expansion phase. Safety data are summarized for all presented for each treatment group. AE were graded according to the patients who received at least one dose of capmatinib and had the Common Terminology Criteria for Adverse Events, version 4.0. at least one valid postbaseline safety assessment. The dose deter- For dose-escalation, a BLRM (with two parameters) guided by the mining set consisted of all subjects from the safety set who either EWOC principle was used to make dose recommendations and to met the minimum exposure criterion (capmatinib had been given at estimate the MTD. When the change from capsule to tablet formula- the full planned daily dose for ≥21 days out of 28 days [75%] and tion was implemented, a BLRM for the tablet formulation was set up the subject had sufficient safety evaluations, or had experienced a and used to monitor subject safety. Prior distributions for this model DLT during the first cycle). Efficacy data are summarized for all the incorporated the existing dose toxicity data for capmatinib as single patients with NSCLC who received at least one dose of capmatinib. agent in both capsule and tablet formulations. The posterior distri- PK analyses were based on data from patients in the dose-escalation butions for the risk of DLT were summarized to provide the posterior phase and expansion phase, with at least one evaluable capmatinib probability that the risk of DLT lies within the following intervals: PK profile. 540 | BANG et al. 2.6 | Study oversight All expansions This study was carried out in accordance with the Declaration of 22 (71.0) 6 (19.4) 5 (17.9) 5 (17.9) N = 38 N = 28 N = 31 3 (9.7) Helsinki and the principles of Good Clinical Practice. The protocol 9 (32) 9 (32) was approved by an Institutional Review Board at each hospital or site, and all patients provided written informed consent before any study procedures. The study was designed by the sponsor (Novartis Other indications Pharma AG). Data were collected and analyzed by the sponsor in conjunction with the authors. N = 11 1 4 5 1 N = 17 12 2 3 n = 18 3 | R E S U LT S Abbreviations: bid, twice daily; FISH, fluorescence in situ hybridization; GCN, gene copy number, HCC, hepatocellular carcinoma; IHC, immunohistochemistry. Assessment of MET overexpression by IHC and GCN by FISH for patients in the dose-escalation and selected dose-expansion cohorts A total of 38 patients (with HCC [n = 15], colon [n = 8], gastric n = 11 N=8 N=6 [n = 2], lung [n = 1], and other advanced solid tumor types [n = 12]) HCC were enrolled into the dose-escalation part of this phase 1 study 2 3 2 1 5 1 0 and 38 patients (with HCC [n = 11], gastric [n = 9], and other ad- vanced solid tumor types [non-NSCLC; n = 18]) were enrolled into Dose expansion Gastric cancer the expansion cohorts (Table 1). Fifty-five patients with NSCLC were also enrolled into an additional expansion cohort; results of these patients are reported separately (Schuler M et al; manu- N=9 N=7 n=9 script submitted). 2 2 2 3 5 2 0 In the dose-escalation cohort, 19 of 38 (50%) patients received All escalations N = 38 ≥3 prior lines of therapy. Of the 23 evaluable patients, 26.1% had tumors presenting with a high level of MET gene copy gain (GCN ≥6) and 16.7% of the 36 evaluable patients had MET-overexpressing 11 (30.6) 14 (38.9) 14 (60.9) tumors (IHC score 3+). 3 (13.0) 6 (16.7) 6 (26.1) 5 (13.9) N = 36 N = 23 In the dose-expansion part, the majority of patients were heav- ily pretreated, with 25 of 38 (66%) patients having received ≥3 prior lines of therapy. Of the patients enrolled in the selected expansion cohorts, where results were available (n = 31), 9.7% of patients had 400 (tablet) tumors presenting with high-level MET GCN and 13% of the 38 eval- uable patients had MET-overexpressing tumors (Table 2). None of the N=4 N=3 n=5 patients had tumors harboring MET exon 14 skipping mutations or *Denominator for calculating percentages equals number of known results. 1 2 1 0 3 0 0 other MET mutations known to confer sensitivity to MET inhibitors. In the escalation part, capmatinib capsules were evaluated at N=8 N=8 n=8 the following twice-daily (bid) doses: 100 mg (n = 4), 200 mg (n = 5), 600 1 2 5 0 4 3 1 250 mg (n = 4), 350 mg (n = 3), 450 mg (n = 9), and 600 mg (n = 8). In order to improve patient compliance in reducing pill burden, a tablet formulation was then introduced. Capmatinib in tablet formulation Dose escalation, mg bid N=9 N=6 n=9 450 was evaluated at the RP2D 400 mg bid (n = 5). In the dose-expan- 1 3 3 2 4 2 0 sion part, patients were enrolled at the RP2D of capmatinib, 600 mg bid, in capsule formulation. Seven patients treated with capmatinib in capsule formulation switched to the tablet formulation once it be- 100-350 N = 15 n = 16 N=6 came available. As of July 17, 2017, all patients in the dose-escalation and se- 2 7 2 4 3 1 2 lected cohorts of the dose-expansion part of the study had dis- continued treatment. Primary reason for end of treatment was IHC score, n (%)* disease progression (37 of 38 patients [97%] in the dose-escala- MET GCN n (%)* tion part and 29 of 38 patients [76%] in the dose-expansion part). TA B L E 2 One patient discontinued as a result of AE (AST increase) in the >4-<6 dose-escalation part and six of 38 patients (16%) in the dose-ex- 3+ <4 >6 2+ 1+ 0 pansion part (as a result of thrombocytopenia [n = 1], nausea [n = BANG et al. | 541 1], nausea/vomiting [n = 1], nausea/dizziness [n = 1], pneumonia 3.3 | Efficacy [n = 1], and peripheral edema [n = 1]). Reasons for discontinuation for the remaining patients in the selected cohorts of the dose-ex- Efficacy was reported according to the investigator’s assessment. pansion part were consent withdrawal (2 patients) and protocol In the dose-escalation part of the study, at the data cutoff date of deviation (1 patient). No patients discontinued as a result of death July 17, 2017, stable disease was reported in 10 of 38 (26%) patients in either part of the study. (Table 4). In the dose-escalation part, tumor shrinkage was observed in two patients (colon cancer and HCC) treated at 450 mg bid (cap- sule) dose level. 3.1 | Dose determination Efficacy results in the expansion cohorts of patients with gas- tric cancer, HCC, and other solid tumors (non-NSCLC including GBM Starting dose for dose escalation of this study was 100 mg bid as cap- and pRCC) are presented in Table 4. In these cohorts, stable disease sules. The bid regimen was selected based on the half-life of capmatinib was reported in two of nine (22%) patients with gastric cancer, five (3.5-6.3 h) and in order to maintain capmatinib concentrations above of 11 (46%) patients with HCC, and five of 18 (28%) patients with the EC90 (90% inhibition of c-MET phosphorylation in animal models) other advanced solid tumor types. Tumor reduction was reported in for p-MET inhibition in c-MET-dependent mouse tumor models (EC90 a number of patients; of note, two other solid tumor patients with ~71 nmol/L, total concentration).30 Across the six bid dose levels ex- GCN ≥6 achieved substantial tumor reduction (Figure 1). Duration plored in the capsule formulation, DLT occurred at 200 mg bid (grade of response for evaluable patients by disease cohorts is shown in 3 fatigue in 1 patient), 250 mg bid (grade 3 bilirubin increased in 1 Figure S1. patient), and 450 mg bid (grade 3 fatigue in 1 patient). No DLT were ob- served at the 600-mg bid capsule dose level. Based on the BLRM used to guide dose escalation, posterior probability of excessive toxicity was 3.4 | Pharmacokinetics analysis 20.1% for the 600 mg bid dose level in the dose-escalation phase (ie, <25% chance that the true DLT rate was ≥33%). No DLT was observed Capmatinib was rapidly absorbed after oral dose, with median time among patients treated with the tablet at the 400 mg bid dose. MTD to peak plasma concentration (Tmax) ranging from 1 to 4 h for cap- was not reached. Capmatinib tablets at 400 mg bid had comparable sules and approximately 2 h for tablets following single and multiple tolerability and exposure to that of 600 mg bid capsules. Capmatinib doses (Table 5). 400 mg bid tablets or 600 mg bid capsules were selected as the RP2D, Steady-state AUCtau and Cmax of capmatinib were generally dose a dose at which Ctrough >EC90 (90% inhibition of c-MET phosphoryla- proportional across the dose range from 100 to 600 mg bid for the tion in animal models) is expected to be achieved and maintained. capsules (Table 5). The drug accumulation ratio following multiple doses generally ranged from one- to twofold for the capsules, with more accumulation observed at 450 and 600 mg bid (ca. twofold). 3.2 | Safety Limited drug accumulation was observed with 400 mg bid tablets (Table 6). The most frequent AE (all grades, >30%) in the dose-escalation part re- Tablet formulation at 400 mg bid provided comparable mean ex- gardless of causality were decreased appetite (42%), peripheral edema posures to the capsules at 600 mg bid (Table 5). Mean (mean CV%) (40%), vomiting (40%), and nausea (37%) (Table S2). The most frequent steady-state exposure of capmatinib at the RP2D (tablet 400 mg bid) grade 3 or 4 AE (>5%) regardless of causality were increase in levels was 22 000 (35.5%) h*ng/mL for AUC0–12 h,ss and 4910 (51.0%) ng/ of blood bilirubin (11%), fatigue (8%), and AST increase (8%). The most mL for Cmax,ss (n = 8). common AE (all grades, >20%) suspected to be study drug-related were nausea (32%), decreased appetite (29%), vomiting (29%), fatigue (26%), and peripheral edema (21%) (Table 3). Study drug-related grade 3.5 | Pharmacodynamic data 3 or 4 AE were rare. The most commonly reported AE were fatigue (8%), ALT increase, and hypophagia (both 5%). Capmatinib PD activity in inhibiting the MET pathway was shown in In the selected cohorts of the dose-expansion part of the study, paired biopsies collected from a patient with advanced CRC. Near- the most frequent AE (all grades, >30%) regardless of causality were complete p-MET inhibition (as determined by IHC; H-score = 2) was nausea (42%), peripheral edema (39%), and fatigue (34%) (Table S2). shown following capmatinib at 450 mg bid in capsule formulation at The most frequent grade 3 or 4 AE regardless of causality were fa- cycle 1 day 15 (Figure S2). tigue (8%), nausea, AST increase, anemia, ascites, bilirubin increase, constipation, and ALT increase (all 5%). Nausea (29%), peripheral edema (26%), and fatigue (24%) were 4 | D I S CU S S I O N the most common AE suspected to be study drug-related (Table 3). ALT and lipase increases were the most commonly reported grade 3 Capmatinib was well tolerated with a manageable safety profile or 4 AE suspected to be study drug-related (both 5%). across all explored doses. Only three DLT were reported, one each TA B L E 3 Adverse events, suspected to be study drug related (any grade occurring in ≥5% of patients in either the dose-escalation or selected dose-expansion cohorts and grade 3 or 4) 542 | Dose escalation, mg bid Dose expansion (RP2D) 100-350 450 600 400 (tablet) All Gastric cancer HCC Other All expansions n = 16 n=9 n=8 n=5 N = 38 n=9 n = 11 n = 18 N = 38 All Grade All Grade All Grade All Grade Grade All Grade All Grade All Grade All Grade grades 3/4 grades 3/4 grades 3/4 grades 3/4 All grades 3/4 grades 3/4 grades 3/4 grades 3/4 grades 3/4 Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Nausea 3 (19) 0 4 (44) 0 3 (38) 0 2 (40) 0 12 (32) 0 0 0 5 (46) 1 (9) 6 (33) 0 11 (29) 1 (3) Decreased appetite 5 (31) 1 (6) 3 (33) 0 3 (38) 0 0 0 11 (29) 1 (2) 0 0 2 (18) 0 2 (11) 0 4 (11) 0 Vomiting 4 (25) 0 3 (33) 0 3 (38) 0 1 (20) 0 11 (29) 0 0 0 3 (27) 1 (9) 4 (22) 0 7 (18) 1 (3) Fatigue 3 (19) 2 (13) 3 (33) 1 (11) 3 (38) 0 1 (20) 0 10 (26) 3 (8) 3 (33) 1 (11) 3 (27) 0 3 (17) 0 9 (24) 1 (3) Peripheral edema 3 (19) 1 (6) 2 (22) 0 1 (13) 0 2 (40) 0 8 (21) 1 (3) 3 (33) 0 3 (27) 0 4 (22) 0 10 (26) 0 Asthenia 4 (25) 0 1 (11) 0 0 0 1 (20) 0 6 (16) 0 0 0 1 (9) 0 1 (6) 0 2 (5) 0 Hypoalbuminemia 3 (19) 1 (6) 0 0 1 (13) 0 2 (40) 0 6 (16) 1 (3) 0 0 0 0 1 (6) 0 1 (3) 0 AST increased 1 (6) 0 1 (11) 1 (11) 2 (25) 0 1 (20) 0 5 (13) 1 (3) 1 (11) 0 1 (9) 1 (9) 2 (11) 0 4 (11) 0 Diarrhea 2 (13) 0 0 0 2 (25) 0 1 (20) 0 5 (13) 0 0 0 4 (36) 0 3 (17) 0 7 (18) 0 Blood bilirubin 3 (19) 1 (6) 0 0 1 (13) 0 0 0 4 (11) 1 (3) 0 0 0 0 0 0 0 0 increased ALT increased 0 0 1 (11) 1 (11) 1 (13) 1 (13) 1 (20) 0 3 (8) 2 (5) 1 (11) 1 (11) 0 0 1 (6) 1 (6) 2 (5) 2 (5) Constipation 2 (13) 0 0 0 0 0 1 (20) 0 3 (8) 0 0 0 0 0 1 (6) 0 1 (3) 0 Upper abdominal 1 (6) 0 0 0 0 0 1 (20) 0 2 (5) 0 0 0 0 0 0 0 0 0 pain Amylase increased 2 (13) 1 (6) 0 0 0 0 0 0 2 (5) 1 (3) 0 0 0 0 0 0 0 0 Blood creatinine 2 (13) 0 0 0 0 0 0 0 2 (5) 0 0 0 1 (9) 1 (9) 1 (6) 0 2 (5) 1 (3) increased Headache 1 (6) 0 1 (11) 0 0 0 0 0 2 (5) 0 1 (11) 0 0 0 0 0 1 (3) 0 Hypophagia 2 (13) 2 (13) 0 0 0 0 0 0 2 (5) 2 (5) Myalgia 2 (13) 0 0 0 0 0 0 0 2 (5) 0 0 0 0 0 2 (11) 0 2 (5) 0 Odynophagia 1 (6) 0 0 0 0 0 1 (20) 0 2 (5) 0 0 0 0 0 0 0 0 0 Total protein 1 (6) 0 0 0 1 (13) 0 0 0 2 (5) 0 0 0 0 0 0 0 0 0 decreased Pyrexia 1 (6) 0 1 (11) 0 0 0 0 0 2 (5) 0 0 0 0 0 0 0 0 0 Stomatitis 0 0 0 0 1 (13) 0 1 (20) 0 2 (5) 0 0 0 0 0 1 (6) 0 1 (3) 0 Lipase increased 1 (6) 1 (6) 0 0 0 0 0 0 1 (3) 1 (3) 0 0 2 (18) 2 (18) 1 (6) 0 3 (8) 2 (5) Dyspepsia 0 0 0 0 1 (13) 0 0 0 1 (3) 0 0 0 0 0 2 (11) 0 2 (5) 0 Thrombocytopenia 1 (6) 0 0 0 0 0 0 0 1 (3) 0 1 (11) 1 (11) 1 (9) 0 0 0 2 (5) 1 (3) Dizziness 0 0 0 0 0 0 1 (20) 0 1 (3) 0 0 0 1 (9) 0 1 (6) 0 2 (5) 0 Maculo-papular rash 0 0 1 (11) 0 0 0 0 0 1 (3) 0 0 0 0 0 2 (11) 0 2 (5) 0 Localized edema 0 0 0 0 2 (11) 0 2 (5) 0 BANG et al. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice daily; HCC, hepatocellular carcinoma; RP2D, recommended phase 2 dose. BANG et al. | 543 at 200 mg bid, 250 mg bid, and 450 mg bid doses. No DLT were All expansions observed at the 600-mg bid capsule dose level. Based on the BLRM 13.4-43.1 used to guide dose escalation, the posterior probability of excessive 0.0-9.3 26 (68) 10 (26) 10 (26) N = 38 toxicity was 20.1% for the 600-mg bid dose level in the dose-escala- 2 (5) tion phase. Capmatinib exposure was found to increase by dose up 0 0 0 to 600 mg bid dose level. Other indications In the dose-escalation part, tumor shrinkage was observed for two patients (colon cancer and HCC) treated with the 450-mg bid 0.0-18.5 9.7-53.5 5 (27.8) (capsule) dose level. Near-complete PD effect (defined as p-MET in- n = 18 4 (22) 9 (50) 5 (28) hibition) was observed in this patient with colorectal cancer at 450- 0 0 0 mg bid capsule dose level. MTD was not reached. Thus, based on 16.7-76.6 considerations of the estimated MTD by the BLRM model along with 0.0-28.5 5 (45.5) n = 11 1 (9.1) 5 (46) 5 (46) Dose expansion (RP2D) overall assessment of safety, PK and PD results, and preliminary clin- HCC 0 0 0 ical efficacy data, the RP2D was determined initially to be 600 mg bid in capsule formulation. Best overall response by treatment group according to investigator in the dose-escalation and selected dose-expansion cohorts Gastric cancer In order to improve patient compliance reducing the pill burden, a 2.8-60.0 0.0-33.6 tablet formulation was introduced, as 12 capsules had to be taken bid as 2 (22.2) 4 (44) 2 (22) 3 (33) n=9 the 600 mg bid dose regimen. Relative bioavailability of INC280 tablet 0 0 0 with respect to capsule formulation was assessed in healthy subjects, and a tablet safety cohort at 400 mg bid was further evaluated in this All escalations study. The evaluated tablet formulation at a dose of 400 mg bid was well 13.4-43.1 0.0-9.3 25 (66) tolerated with no DLT reported, had a comparable favorable safety pro- 10 (26) 10 (26) N = 38 Abbreviations: bid, twice daily; CI, confidence interval; HCC, hepatocellular carcinoma; RP2D, recommended phase 2 dose. 3 (5) file, and comparable mean exposure to the capsule formulation at a dose 0 0 0 of 600 mg bid. Thus, the RP2D was determined to be 400 mg bid in tab- 400 (tablet) let formulation. A number of the expansion-part patients were switched 5.3-85.3 0.0-52.2 from the capsule formulation to the tablet as soon as it was available. 2 (40) 2 (40) 3 (60) n=5 Overall, capmatinib was well tolerated at the RP2D (600 mg bid 0 0 0 0 capsule and 400 mg bid tablet). The most common AE suspected to 0.0-36.9 0.3-52.7 be related to the study drug were mostly grade 1 or 2. 6 (75) 1 (13) 1 (13) 1 (13) n=8 600 Only a limited number of patients were determined to have tumors 0 0 0 harboring high-level MET gene copy gain or high MET overexpression or 2.8-60.0 0.0-36.9 MET mutations in both the escalation and selected expansion cohorts. 2 (22) 2 (22) 6 (67) 1 (11) n=9 Although the best overall response was limited with stable disease in 26% 450 0 0 0 of escalation patients and in 32% of the expansion patients (22% of pa- 0.8-90.6 tients in the gastric cancer cohort, 46% of patients in the HCC cohort, 0.0-70.8 1 (33) 1 (33) 2 (67) n=3 and 28% of patients with other advanced solid tumor types), a number of 350 0 0 0 0 these patients achieved substantial tumor reduction and durable stable disease; of note, two other solid tumor patients with GCN ≥6 achieved 0.0-60.2 0.6-80.6 1 (25) 1 (25) 1 (25) substantial tumor reduction (Figure 1). These results were similar to those 2 50) n=4 250 observed with capmatinib with Japanese patients with advanced solid 0 0 0 Dose escalation, mg bid tumors, where the best overall response was stable disease (reported in 0.0-52.2 0.5-71.6 18.2% of patients).34 BOI-9016M, a novel c-MET inhibitor, showed activ- 4 (80) 1 (20) 1 (20) n=5 200 ity in Chinese patients with advanced solid tumors, with partial response in 0 0 0 0 one (5%) of 20 patients and stable disease in 10 (50%) patients.35 Results 0.0-60.2 6.8-93.2 for other MET inhibitors have been reported in molecularly selected pa- 2 (50) 2 (50) 2 (50) n=4 100 tients with NSCLC. Crizotinib, a multikinase (ALK/ROS1/MET) inhibitor, Best overall response, n (%) 0 0 0 0 showed clinically meaningful antitumor activity in patients with MET exon Overall response rate, Progressive disease Complete response Disease control rate, 14-mutated NSCLC, with an ORR of 32% (21 of 65 patients; 95% CI: 21- Partial response 45)36 and in patients with high MET amplification (MET/CEP7 ≥4) status, Stable disease n (%) 95% CI with an ORR of 40% (eight of 20 patients; 95% CI: 19.1-63.9).37 Tepotinib, n (%) 95% CI Unknown TA B L E 4 a selective MET inhibitor, showed activity with an ORR of 57.5% (23 of 40 patients; 95% CI: 40.9-73.0) by the investigator in patients with advanced NSCLC harboring MET exon 14 skipping mutations.38 544 | BANG et al. 100 80 Gastric Cancer (N = 3) HCC (N = 6) Other Indications (N = 9) IHC: 2+; GCN: unk IHC: unk; GCN: 12 IHC: 1+; GCN: unk IHC: 0; GCN: 4.13 60 IHC: unk; GCN: 6 IHC: 0; GCN: 4.8 IHC: 1+; GCN:3 40 20 0 IHC: 0; GCN: 5.43 IHC: unk; GCN: 2.00 IHC: 3+; GCN: unk IHC: unk; GCN: unk IHC: unk; GCN: 2.2 IHC: 3+; GCN: 2.95 IHC: 1+; GCN: 2.38 IHC: unk; GCN: 9.18 IHC: 2+; GCN: 5.42 IHC: 2+; GCN: 1.88 IHC: 1+; GCN: 2.62 –20 –40 –60 –80 –100 F I G U R E 1 Best percentage change from baseline in sum of tumor diameters according to investigator assessment in dose-expansion cohorts (N = 18)*. *Patients with measurable baseline disease and at least one valid postbaseline (BIRC) assessment (best percentage change from baseline <0 [n = 7] and >0 [n = 11]). BIRC, blinded independent review committee; GCN, gene copy number; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; unk, unknown. TA B L E 5 Summary of steady-state PK parameters for capmatinib PK analysis set: dose group, mg bid PK parameter 100 200 250 350 450 600 400 (tablet) (Cycle 1, Day 15) n=4 n=5 n=3 n=3 n=7 n = 45 n=8 AUC0–12 h (h*ng/mL) Mean (SD) 3820 (2420) 13 500 (6530) 7070 (3990) 19 400 (5360) 18 800 (6870) 25 600 (14 900) 22 000 (7790) CV% mean 63.5 48.5 56.4 27.7 36.6 58.3 35.5 Cmax (ng/mL) Mean (SD) 660 (550) 2500 (856) 1580 (1010) 4410 (3800) 3200 (1280) 4890 (3580) 4910 (2510) CV% mean 83.3 34.2 63.8 86.3 39.8 73.2 51.0 Tmax (h) Median 2.86 1.92 1.00 3.93 2.00 2.00 2.02 (Min; Max) (1.88; 4.00) (1.85; 8.00) (0.45; 2.02) (1.00; 4.02) (1.83; 7.87) (0.517; 8.42) (0.50; 4.33) Abbreviations: AUC0–12 h, area under concentration-time curve from time 0 to 12 h; bid, twice daily; Cmax, maximum observed plasma concentration; CV%, percent coefficient of variation; Tmax, median time to peak plasma concentration; PK, pharmacokinetics. TA B L E 6 Summary of accumulation ratio for capmatinib following repeated dosage PK analysis set: dose group, mg bid PK parameter 100 200 250 350 450 600 400 (tablet) (Cycle 1, Day 15) n=3 n=5 n=3 n=3 n=5 n = 15 n=5 Racc Mean (SD) 1.54 (0.786) 1.36 (0.869) 1.08 (0.443) 1.38 (0.614) 2.36 (1.75) 2.07 (0.848) 1.09 (0.408) CV% mean 50.9 63.9 40.8 44.5 74.0 40.9 37.6 Abbreviations: bid, twice daily; CV%, percent coefficient of variation; PK, pharmacokinetics; Racc, mean accumulation ratio; ss, at steady state. BANG et al. | 545 Overall, in the present study, suboptimal molecular selection for (research grants), MedImmune (research grants), Mirati (research MET status might have contributed to the limited efficacy observed grants), MiRNA (research grants), Molecular Templates (research in both the escalation and the expansion cohorts of patients with grants), Mologen (research grants), NCI-CTEP (research grants), gastric cancer, HCC, and other solid tumors. Novartis (research grants), Pfizer (research grants, and consulting Results of the expansion part of the study conducted with cap- or advisory role), Seattle Genetics (research grants, and consult- matinib at the RP2D in patients with advanced MET-dependent ing or advisory role), Takeda (research grants, and consulting or NSCLC, including a subset of patients enrolled with more stringently advisory role), Alpha Insights (consulting or advisory role), Axiom specified MET dysregulation biomarker criteria, are reported sepa- (consulting or advisory role), Baxter (consulting or advisory role), rately (Schuler M et al; manuscript submitted). Further, the predic- GLG (consulting or advisory role), Group H (consulting or advi- tive value of different mechanisms of MET dysregulation (including sory role), Guidepoint Global (consulting or advisory role), Infinity MET amplification and METΔex14 mutation) in advanced NSCLC is (consulting or advisory role), Janssen (consulting or advisory role), prospectively being explored in another ongoing phase 2 study of Merrimack (consulting or advisory role), Medscape (consulting capmatinib (NCT02414139). or advisory role), Numab (consulting or advisory role), and Trieza In summary, the RP2D of capmatinib was 600 mg bid capsule or Therapeutics (consulting or advisory role). 400 mg bid tablet. The tablet formulation is now used in all capma- tinib studies. Capmatinib was well tolerated and showed antitumor Total annual value of manuscript fees received: activity and acceptable safety profile at the R2PD. • Todd M. Bauer from Pfizer (paid to third part vendor for medical AC K N OW L E D G M E N T S writing/editorial support). We would like to take this opportunity to thank the participating patients, their families, all of the study co-investigators, and research Total annual value of research funds, endowments, endowed contributors. Medical writing support was provided by Pushkar chairs, and researcher-employment costs received: Narvilkar, Novartis Healthcare Pvt Ltd (Hyderabad, India) and Helen Garside (ex-Articulate Science employee). This study was funded by • Yung-Jue Bang (for clinical trials to the institution) from Novartis Pharmaceuticals Corporation. AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boehringer-Ingelheim, C O N FL I C T S O F I N T E R E S T MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Annual value of remuneration received: Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, Genexine. Martin Schuler (research grants provided to academic • Mikhail Akimov from Novartis (employment). institution from AstraZeneca, Bristol-Myers Squibb, Novartis. Wan • Samson Ghebremariam from Novartis (employment). Teck Lim from Novartis (personal fees). Todd M. Bauer (to the in- • Monica Giovannini (self) from Novartis (employment). stitution) from Daiichi Sankyo, Medpacto (grants), Incyte (grants), • Monica Giovannini (family member) from Bluebirdbio Mirati Therapeutics (grants), MedImmune (grants), Abbvie (grants), (employment). AstraZeneca (grants), MabVax (grants), Stemline Therapeutics (grants), Merck (grants), Lilly (grants), GlaxoSmithKline (grants), Annual profit from shares received: Novartis (grants), Genentech (grants), Deciphera (grants), Merrimack (grants), Immunogen (grants), Millennium (grants), • Mikhail Akimov has Novartis Stock. Phosplatin Therapeutics (grants), Calithera Biosciences (grants), • Samson Ghebremariam has Novartis Stock. Kolltan Pharmaceuticals (grants), Principia Biopharma (grants), • Monica Giovannini (self) has Novartis Stock. Peloton (grants), Immunocore (grants), Roche (grants), Aileron • Monica Giovannini (family member) has Bluebirdbio Stock. Therapeutics (grants), Bristol-Myers Squibb (grants), Amgen (grants), Onyx (grants), Sanofi (grants), Boehringer-Ingelheim Total annual value of daily allowances/honoraria received: (grants), Astellas Pharma (grants), Five Prime Therapeutics (grants), Jacobio (grants), Top Alliance BioScience (grants), Janssen • David Hong from AbbVie (research grants), Adaptimmune (re- (grants), Clovis Oncology (grants), Takeda (grants), Karyopharm search grants, and consulting or advisory role), Amgen (research Therapeutics (grants), Foundation Medicine (grants), ARMO grants), AstraZeneca (research grants), Bayer (research grants, and Biosciences (grants), Leap Therapeutics (grants and other), Ignyta consulting or advisory role), BMS (research grants), Daiichi Sankyo (grants, non-financial support and other), Moderna Therapeutics (research grants), Eisai (research grants), Fate Therapeutics (re- (grants, non-financial support and other), Pfizer (grants, personal search grants), Genentech (research grants, consulting or ad- fees and other), Loxo (grants, personal fees and non-financial visory role), Genmab (research grants), Ignyta (research grants), support), Bayer (grants, personal fees and non-financial support), Infinity (research grants), Kite (research grants), Kyowa (research Guardant Health (personal fees and non-financial support from) grants), Lilly (research grants), LOXO (research grants), Merck outside the submitted work. David Hong from Molecular Match 546 | BANG et al. (Advisor), OncoResponse (founder), and Presagia Inc. (Advisor). acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932-20937. Brigette Ma from Novartis (personal fees [advisory role] and re- 9. Chen HJ, Mok TS, Chen ZH, et al. Clinicopathologic and molecular search grant), BI (personal fees [advisory role]), BMS (personal features of epidermal growth factor receptor T790M mutation and fees [advisory role]), and MSD (personal fees [advisory role]), and c-MET amplification in tyrosine kinase inhibitor-resistant Chinese Roche (personal fees [speaker]). non-small cell lung cancer. Pathol Oncol Res. 2009;15:651-658. 10. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 sig- Other annual remuneration received: naling. Science. 2007;316:1039-1043. 11. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and • David Hong from LOXO, MiRNA, ASCO, AACR, SITC, and histological evolution of lung cancers acquiring resistance to EGFR Genmab. inhibitors. Sci Transl Med. 2011;3:75ra26. 12. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor spec- • Mikhail Akimov from Novartis. imens at the time of acquired resistance to EGFR-TKI therapy in • Samson Ghebremariam from Novartis. 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. • Monica Giovannini (self) from Novartis (employment). 2013;19:2240-2247. • Monica Giovannini (family member) from Bluebirdbio 13. Minari R, Bordi P, Tiseo M. Third-generation epidermal growth fac- tor receptor-tyrosine kinase inhibitors in T790M-positive non-small (employment). cell lung cancer: review on emerged mechanisms of resistance. Transl Lung Cancer Res. 2016;5:695-708. DATA AVA I L A B I L I T Y S TAT E M E N T 14. Lorenzato A, Olivero M, Patane S, et al. Novel somatic mutations of Novartis will not provide access to patient-level data if there is a the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res. 2002;62:7025-7030. reasonable likelihood that individual patients could be re-identified. 15. Lee JH, Han SU, Cho H, et al. A novel germ line juxtamembrane Met Phase 1 studies, by their nature, present a high risk of patient re- mutation in human gastric cancer. Oncogene. 2000;19:4947-4953. identification; therefore, patient individual results for phase 1 stud- 16. Drilon AE, Camidge DR, Ou S-HI, et al. Efficacy and safety of crizo- ies cannot be shared. In addition, clinical data, in some cases, have tinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15_suppl): 108. been collected subject to contractual or consent provisions that 17. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via prohibit transfer to third parties. Such restrictions may preclude diverse exon 14 splicing alterations occurs in multiple tumor types granting access under these provisions. Where co-development and confers clinical sensitivity to MET inhibitors. Cancer Discov. agreements or other legal restrictions prevent companies from shar- 2015;5:850-859. 18. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 pa- ing particular data, companies will work with qualified requestors to tients with lung cancer harboring MET exon 14 skipping alterations. provide summary information where possible. J Thorac Oncol. 2016;11:1493-1502. 19. Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations ORCID in non-small-cell lung cancer are associated with advanced age and Yung-Jue Bang https://orcid.org/0000-0001-6000-4597 stage-dependent MET genomic amplification and c-Met overex- pression. J Clin Oncol. 2016;34:721-730. 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