Capmatinib: First Approval

Sohita Dhillon1

© Springer Nature Switzerland AG 2020

Capmatinib (Tabrecta™) is an oral, small molecule mesenchymal-epithelial transition (MET) inhibitor being developed by Novartis Oncology, under a license from Incyte Corporation, for the treatment of lung cancer. Capmatinib targets and selectively binds to MET, including the mutant variant produced by exon 14 skipping, and inhibits cancer cell growth driven by the mutant MET variant. In May 2020, oral capmatinib received its first global approval in the USA for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumours have a mutation that leads to MET exon 14 skip- ping, as detected by an FDA-approved test. Clinical development for the treatment of glioblastoma, liver cancer, malignant melanoma, breast cancer, colorectal cancer, head and neck cancer and solid tumours is ongoing in several countries. This article summarizes the milestones in the development of capmatinib leading to its first approval.

Capmatinib (Tabrecta™): Key points

A kinase inhibitor is being developed by Novartis Oncol- ogy, under a license from Incyte Corporation, for the treatment of cancer.
Received its first approval on 6 May 2020 in the USA. Approved for the treatment of adults with metastatic
NSCLC whose tumours have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test.


Mesenchymal-epithelial transition (MET) receptor tyrosine kinase is expressed in epithelial cells of many organs, includ- ing the liver, pancreas, prostate, kidney, muscle and bone

Enhanced material for this AdisInsight Report can be found at .

This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- clinical and clinical studies to market launch and beyond.
marrow [1, 2]. MET binds to its ligand, hepatocyte growth factor, and activates a wide range of signalling pathways, including those involved in proliferation, motility, migration and invasion. Under normal conditions, MET mediates pro- cesses such as embryogenesis, tissue regeneration, wound healing and the formation of nerve and muscle. However, MET dysregulation through gene amplification, mutation and/or overexpression, can promote the development and progression of several cancers, including lung, liver, breast and ovarian cancers [1, 2]. Thus, MET is an attractive target for therapeutic blockade in cancer, particularly in advanced non-small cell lung cancer (NSCLC), where MET dysregu- lation is recognized as a negative prognostic factor [3–5].
Capmatinib (Tabrecta™) is an oral, small molecule, MET inhibitor being developed by Novartis Oncology, under a license from Incyte Corporation, for the treat- ment of cancer. Capmatinib targets and selectively binds to MET, including the mutant variant produced by exon 14 skipping, and inhibits cancer cell growth driven by the mutant MET variant [6]. On 6 May 2020 [7], oral cap- matinib received its first global approval in the USA for the treatment of adults with metastatic NSCLC whose tumours have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test [6]. The recommended dosage of capmatinib is 400 mg administered orally twice daily with or without food [6]. Dosage reduction and/or discontinuation of treatment may be required for the man-

[email protected]
agement of adverse reactions with capmatinib therapy [6]. Clinical development for the treatment of glioblastoma,

1.1Springer Nature, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
liver cancer, malignant melanoma, breast cancer, colorectal

Phase 1 studies initiated (Jan 2010)

Orphan Drug status granted in the USA (Mar) Orphan Drug status granted in the USA (Jun) Breakthrough Therapy status granted (2nd-line
therapy) in the USA (Jun)
Breakthrough Therapy status granted (1st-line therapy) in the USA (Sep)
NDA accepted and Priority Review granted in the USA (Feb)
Approved in the USA for metastatic NSCLC (May)

2013 2014 2015 2016 2017 2018 2019 2020 2021 2022


Advanced HCC

Advanced NSCLC
Advanced soft tissue sarcomas
Est Oct 2024

Key milestones in the development of capmatinib, focusing on its use in the treatment of non-small-cell lung cancer. HCC hepatocellular carci- noma, NDA New Drug Application, NSCLC non-small-cell lung cancer

cancer, head and neck cancer and solid tumours is ongoing in several countries.

1.1.1Company Agreements

In November 2009, Novartis entered into an exclusive worldwide licensing agreement with Incyte Corporation to develop two oral targeted investigational therapies cap- matinib (INCB 28060) and ruxolitinib (INCB 18424) for myelofibrosis and other cancers [8]. Under the terms of the agreement, Novartis had responsibility for the worldwide development of capmatinib. Novartis was responsible for all costs and activities for capmatinib after the phase 1 clinical trial. Incyte was eligible for additional payments after the first milestone, based on achieving defined development and commercialisation milestones, and was to receive royalties on future sales of capmatinib. Incyte retained the option to co-develop and co-promote the agent [8].
nivolumab. Additional details of the collaboration were not disclosed [9].

2Scientific Summary


Capmatinib is an ATP-competitive, highly potent (half maximal inhibitory concentration of 0.13 nmol/L) and selective kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping [6, 10, 11]. MET exon 14 skipping produces a truncated MET receptor with a missing regulatory domain that reduces its negative regulation, resulting in decreased degradation of the MET

In October 2014, Novartis entered into a clinical col- laboration with Bristol-Myers Squibb to evaluate the safety, tolerability and preliminary efficacy of three molecularly targeted compounds in combination with BMS’s investi- gational PD-1 immune checkpoint inhibitor, nivolumab, in phase 1/2 trials of patients with NSCLC [9]. Under the terms of the agreement, the studies were to be conducted








*2HCl * H2O

by Novartis to evaluate capmatinib, ceritinib, and EGF816 in combination with BMS’s investigational immunotherapy

Chemical structure of capmatinib

protein, sustained MET activation and oncogenesis [12]. Capmatinib inhibits phosphorylation of MET and its major downstream effectors in MET-dependent tumour cell lines, thereby potently inhibiting tumour cell proliferation and migration, and inducing apoptosis [10]. Capmatinib dem- onstrated antitumour activity in MET-dependent mouse tumour xenograft models derived from a range of tumour types, including human lung cancer with MET exon 14 skip- ping mutation or MET amplification, and liver cancer with MET amplification [6, 11]. Additionally, capmatinib reverses the effects of MET activation on the epidermal growth factor receptor (EGFR) and human epidermal growth factor recep- tor (HER)-3 pathways [10] and restores sensitivity to EGFR inhibitors in EGFR-mutant NSCLC cell lines with acquired resistance to EGFR inhibitors [11, 13].
Capmatinib at the recommended dosage of 400 mg twice daily was not associated with a large mean increase in the corrected QT interval (i.e. > 20 ms) [6].


Oral capmatinib exhibited linear pharmacokinetics, with exposure (Cmax and area under the concentration–time curve from 0 to 12 h) increasing approximately dose pro- portionally over a dose range of 200–400 mg. Capmatinib is rapidly absorbed, with peak plasma concentration (Cmax)

reached in approximately 1–2 h after administration of a 400 mg dose. Drug absorption after oral administration is estimated to be > 70%. The steady state of capmatinib is reached by day 3 after twice daily dosing, with an accu- mulation ratio of 1.5. In cancer patients, the exposure to capmatinib was similar after administration of capmatinib 400 mg twice daily with food and under fasted condi- tions; therefore, capmatinib can be taken without regard to food. The plasma protein binding of capmatinib is 96% and independent of capmatinib concentration. The steady- state mean apparent volume of distribution of capmatinib is 164 L [6].
Capmatinib is largely metabolized by CYP3A4 and alde- hyde oxidase. After a single oral dose of radiolabelled cap- matinib in healthy subjects, 78% of total radioactivity was recovered in the faeces (42% as unchanged drug) and 22% was recovered in the urine (negligible unchanged drug). The effective elimination half-life of capmatinib is 6.5 h and the mean steady-state apparent clearance is 24 L/h [6].
Coadministration of capmatinib with a strong CYP3A inhibitor increased capmatinib exposure (potentially increasing the incidence and severity of adverse reac- tions with capmatinib) and coadministration with a strong CYP3A inducer decreased capmatinib exposure (which may decrease the antitumour activity of capmatinib). A moderate CYP3A inducer may also decrease exposure to capmatinib if administered concomitantly [6].

Features and properties of capmatinib
Alternative names INC-280; INCB-028060; TABRECTA™

Antineoplastics, benzamides, fluorobenzenes, heterocyclic bicyclo compounds, imidazoles, quinolines, small mol-
ecules, triazines

Mechanism of action Inhibits phosphorylation of MET and its major downstream effectors in MET-dependent tumour cells
Route of Administration Oral
Pharmacodynamics Demonstrated antitumour activity in MET-dependent mouse tumour xenograft models
Pharmacokinetics Time to peak plasma concentration ≈ 1–2 h
Plasma protein binding 96%; steady-state mean apparent volume of distribution 164 L Effective elimination half-life 6.5 h; mean steady-state apparent clearance 24 L/h
Most frequent adverse reactions
Any grade Peripheral oedema, nausea, fatigue, vomiting, dyspnoea, decreased appetite
Grade 3 or 4 Peripheral oedema, fatigue, dyspnoea ATC codes
WHO ATC code L01X-E (protein kinase inhibitors)
EphMRA ATC code L1H (protein kinase inhibitor antineoplastics)
Chemical name 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2b][1,2,4] triazin-2-yl]benzamide—hydrogen chloride—
water (1/2/1)

2.3Therapeutic Trials

2.3.1Phase 2 Studies

Capmatinib demonstrated clinically meaningful efficacy in NSCLC patients harbouring a mutation that leads to MET exon 14 skipping, who were participating in the ongoing, non-randomized, open-label, multicentre, multi-cohort phase 2 GEOMETRY mono-1 study (n = 334) [NCT02414139] [6, 14]. Eligible patients (aged ≥ 18 years) had stage IIIB/IV NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, were epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative and had ≥ 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [6, 14]. Patients with centrally con- firmed MET exon 14 skipping were assigned (regardless of MET amplification status/gene copy number) to cohorts 4 and 5b, and received capmatinib 400 mg twice daily. As of 15 April 2019, the efficacy evaluable population included 69 previously treated patients (in second- or third-line therapy) in cohort 4, and 28 treatment-naïve patients in cohort 5. The overall response rate (ORR) as determined by a Blinded Independent Review Committee (BIRC) was 41% (95% CI 29–53) [all partial responses (PRs)] in previously treated patients and 68% (95% CI 48–84) [64% PRs and 4% complete responses (CRs)] in treatment-naïve patients (primary end- point). Although data were immature at the time of analysis, the BIRC-assessed median duration of response (DOR) was 9.7 months (95% CI 5.5–13.0) in previously treated patients and 12.6 months (95% CI 5.5–25.3) in treatment-naïve patients, and the median progression-free survival (PFS) was 5.42 and 9.69, respectively [6, 14].
A retrospective analysis of GEOMETRY mono-1 showed that detection of MET exon 14 skipping mutations can be achieved by sequencing deoxyribonucleic acid (DNA) or by reverse transcription-polymerase chain reaction (RT-PCR) [15]. Of the 97 patients enrolled in GEOMETRY mono-1 with MET exon 14 skipping mutations (69 in cohort 4 and 28 in cohort 5b), 73 patients (53 in cohort 4 and 20 in cohort 5b) had base- line formalin-fixed, paraffin-embedded (FFPE) tumour biopsy samples that met the requirement for the FoundationOne® next- generation sequencing assay. The assay identified 72 of 73 MET exon 14 skipping mutation-positive patients, with a concord- ance of 99% to the qualitative RT-PCR used previously for test- ing. None of the RT-PCR negative patients were reported as positive by next-generation sequencing [15].
Capmatinib monotherapy also demonstrated objective response in Chinese patients with advanced NSCLC par- ticipating in an open-label, multiple-arm, phase 2 umbrella trial (NCT02276027) [16]. The study enrolled 66 patients (aged ≥ 18 years) with ECOG PS ≤ 2 who had failed prior treatment or were unsuitable for chemotherapy. After

allocating patients to treatment arms based on molecular aberrations patients received capmatinib (400 mg twice daily tablets; patients selected based on MET IHC over- expression/amplification based on FISH, n = 16), ceritinib (750 mg once daily; ALK or ROS1 rearrangement, n = 26), binimetinib (45 mg twice daily; KRAS, NRAS or BRAF mutation, n = 22) or alpelisib (300 mg once daily; PIK3CA mutation/amplification, n = 2) monotherapy. Of these, 24 (36.4%) patients had confirmed PRs, which included three (18.8%) patients in capmatinib, 19 (73.1%) patients in ceri- tinib, two (9.1%) patients in binimetinib and no patient in alpelisib recipients. Patients receiving ceritinib had the longest PFS of 4.4 months [16].
An ongoing, open-label, multicentre, phase 2, dose- determining and expansion study (NCT01737827) demon- strated the antitumour activity of capmatinib monotherapy in a subset of patients with MET-dysregulated advanced hepatocellular carcinoma [17]. MET dysregulation was ini- tially defined as MET H-score ≥ 50 or ratio of MET gene copy number (GCN)/centromeres ≥ 2.0 or MET GCN ≥ 5; a protocol amendment was implemented after 33 patients had enrolled specifying tumours must have MET-high status; defined as MET IHC intensity score 3 + in ≥ 50% tumour cells, or 2 + in ≥ 50% of tumour cells plus MET GCN ≥ 5 by FISH, or MET GCN ≥ 5 by FISH alone if IHC unavailable). In the dose-determining phase, patients received capmatinib 300 mg twice daily capsules (n = 8) and in the expansion phase, patients received 600 mg twice daily capsules (n = 28) or 400 mg twice daily tablets (n = 2); the median duration of exposure to capmatinib was 55.5 days. In the dose- determining phase of the study, stable disease was reported as the best overall response in two (25%) patients. In the expansion phase (n = 30), the ORR (signal-seeking efficacy endpoint) was 10% and the disease control rate (DCR) was 33%, regardless of MET status (all responders had MET- high status). In the MET-high expansion group, the ORR and DCR was 30% and 50%, respectively, and six of the 10 MET-high patients achieved tumour shrinkage [17].

2.3.2Phase 1b Studies

Capmatinib in combination with gefitinib demon- strated promising clinical activity in a phase 1b/2 study (NCT01610336) in patients with EGFR-mutated, MET- dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR- tyrosine kinase inhibitor treatment [18]. In phase 1, 61 patients received capmatinib 100–800 once daily capsules or 200–600 mg twice daily capsules or tablets, plus gefitinib 250 mg once daily for a median duration of 21 weeks. The ORR across all doses was 23%; the recommended phase 2 dose (RP2D) was determined to be 400 mg twice daily (primary endpoint). In phase 2, 100 patients received the

RP2D plus gefitinib 250 once daily. At a median follow-up 12.2 months, the investigator-assessed ORR was 29% (pri- mary endpoint), DCR was 73% and the median DOR was 5.6 months [18].
No clear clinical activity of capmatinib plus buparlisib was observed in adults with recurrent glioblastoma with MET amplification who were participating in an open-label, multicentre phase 1b/2 study (NCT01870726). This may be explained in part by the combination of capmatinib plus buparlisib resulting in reduced exposure of both drugs; the trial was terminated after a pre-planned futility analysis [19].

2.3.3Phase 1 Studies

An open-label, multicentre, phase 1, dose-escalation (n = 38) and expansion (n = 38) study (NCT01324479) in patients with advanced MET-positive solid tumours determined the RP2D of capmatinib monotherapy to be 400 mg twice daily tablets or 600 mg twice daily capsules [20]. The maximum tolerated dose (MTD) of capmatinib was not reached (pri- mary objective) [20]. Among 55 pretreated patients with advanced MET-dysregulated NSCLC in this phase 1 study (NCT01324479; n = 26 patients in the original expansion

Key clinical trials of capmatinib
Drug(s) Indication Phase Status Location(s) Identifier Sponsor

Capmatinib and other targeted therapies
Soft tissue
3 Recruiting France NCT03784014; MULTI- SARC; C16-40; 2017- 002851-27
Institut National de la Santé Et
de la Recherche Médicale

Capmatinib, pembroli- zumab
Recruiting Multinational NCT04139317;
Novartis Pharmaceuticals

Recruiting Republic of
NCT03693339; STARTER_
Asan Medical Center

Capmatinib NSCLC 2 Recruiting USA NCT02750215; 16-019 Massachusetts General Hospital

Recruiting Multinational NCT02414139; CINC280A2201; 2014- 003850-15
Novartis Pharmaceuticals

Capmatinib, nivolumab, EGF816
Ongoing Multinational NCT02323126; CEG- F816X2201C; EGF816; 2014-003731-20
Novartis Pharmaceuticals

Capmatinib, docetaxel, spartalizumab
Ongoing Multinational NCT03647488; CINC280D2201; 2018- 001420-19
Novartis Pharmaceuticals

Capmatinib, BYL719, LDK378, MEK162
Completed China
Novartis Pharmaceuticals

Capmatinib, EGF816
1/2 Ongoing Multinational NCT02335944; CINC280X2105C; 2014- 000726-37
Novartis Pharmaceuticals

Capmatinib, gefitinib
1b/2 Completed Multinational NCT01610336; CINC280X2202; 2011- 002569-39
Novartis Pharmaceuticals

Recruiting USA
NCT02019693; 140037;
National Cancer Institute

Ongoing Asian coun-
Novartis Pharmaceuticals

Capmatinib, PDR001
1/2 Ongoing Multinational NCT02795429; CINC280X2108; 2015- 005417-76
Novartis Pharmaceuticals

Capmatinib, LGX818; MEK162, LEE011, BGJ398, BKM120
Melanoma 2
Ongoing Multinational NCT02159066; LOGIC-2;
Array BioPharma

Capmatinib, gefitinib, nazartinib
Recruiting Multinational NCT03040973; CIN-
Novartis Pharmaceuticals

HCC hepatocellular carcinoma, NSCLC non-small cell carcinoma, RCC papillary renal cell carcinoma

group and 29 patients enrolled in an additional expansion cohort), clinically meaningful antitumour activity was seen with capmatinib monotherapy (400 mg twice daily tablets or 600 mg twice daily capsules) in patients with either MET gene copy number (GCN) ≥ 6 and/or MET exon 14 muta- tion [21]. In the overall population, the investigator-assessed ORR was 20% (one CR and 10 PRs). In patients with MET- high status the investigator-assessed ORR was 24% (one CR and 8 PRs) and median PFS was 7.3 months. In patients with MET GCN ≥ 6 the investigator-assessed ORR was 47% (one CR and six PRs) and PFS was 9.3 months [21].
In another open-label, multicentre, phase 1 dose-escala- tion and expansion study (NCT01546428; n = 44) in Japa- nese patients with advanced solid tumours (regardless of MET status), the highest studied dose determined to be safe as a tablet formulation was 400 mg twice daily (primary endpoint); the highest safe dose for the capsule formulation was not determined [22]. The MTD of capmatinib was not reached. Of the 37 evaluable patients, eight had a best over- all response of stable disease [22].

2.4Adverse Events

Capmatinib monotherapy (400 mg twice daily tablets) had an acceptable tolerability profile in NSCLC patients harbouring a mutation that leads to MET exon 14 skipping, who were participating in the phase 2 GEOMETRY mono-1 study (NCT02414139) [6]. Among 334 patients who received cap- matinib, 31% were exposed to capmatinib for ≥ 6 months and 16% for ≥ 1 year. The most common (incidence ≥ 20%) any grade adverse reactions with capmatinib were periph- eral oedema (52%), nausea (44%), fatigue (32%), vomiting (28%), dyspnoea (24%) and decreased appetite (21%). The most common (incidence > 5%) grade 3 or 4 adverse reac- tions with capmatinib were peripheral oedema (9%), fatigue (8%) and dyspnoea (7%). Serious adverse reactions were reported in 51% of patients receiving capmatinib, with dysp- noea (7%), pneumonia (4.8%), pleural effusion (3.6%), gen- eral physical health deterioration (3%), vomiting (2.4%) and nausea (2.1%) occurring most commonly (incidence > 2%). One fatal adverse reaction (pneumonitis) occurred in one patient receiving capmatinib [6].
Adverse reactions resulted in permanent discontinua- tion of therapy in 16% of capmatinib recipients, with the most frequent (incidence ≥ 1%) reasons for discontinuation being peripheral oedema (1.8%), pneumonitis (1.8%) and fatigue (1.5%) [6]. Dose interruptions of capmatinib due to adverse reactions were required in 54% of patients, with peripheral oedema, increased blood creatinine, nausea and vomiting among the most common reasons (incidence > 2%) for dose interruption. Dose reductions due to adverse reac- tions occurred in 23% of capmatinib recipients, with the

most common (incidence > 2%) reasons for dose reductions being peripheral oedema, increased alanine transferase, increased blood creatinine and nausea. Other clinically rel- evant adverse reactions reported in < 10% of patients receiv- ing capmatinib included pruritus (allergic and generalized), interstitial lung disease/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria and acute pancrea- titis [6].

2.5Companion Diagnostic

The US FDA has approved the Foundation®OneCDx (F1CDx) next-generation, sequencing-based in vitro diag- nostic device for the detection of MET single nucleotide variants (SNVs) and indels that lead to MET exon 14 skip- ping in patients with NSCLC who may benefit from treat- ment with capmatinib [6, 23]. The F1CDx assay, developed by Foundation Medicine in collaboration with Novartis, is performed at Foundation Medicine, Inc. sites using DNA isolated from FFPE tumor tissue specimens [23].

2.6Ongoing Clinical Trials

In addition to the ongoing phase 2 studies discussed in Sect. 2.3.1 (NCT02414139 and NCT01737827), a ran- domized phase 3 study (NCT03784014) is recruiting an estimated 960 patients with advanced soft-tissue sarcomas in France to assess if next-generation sequencing can be conducted for a large proportion of patients. In parallel, the study aims to assess the efficacy of an innovative treatment strategy guided by high-throughput molecular analysis. Several treatments will be assessed including capmatinib, nilotinib, ceritinib, and trametinib plus dabrafenib.
Several phase 2 studies are ongoing in patients with NSCLC, including a randomized, open-label, multina- tional phase 2 study (NCT04139317) that is recruiting ≈ 96 patients to evaluate the efficacy and safety of com- bination therapy with capmatinib and pembrolizumab ver- sus pembrolizumab alone as first-line therapy for patients with locally advanced or metastatic NSCLC who have PD-L1 expression ≥ 50% and have no EGFR mutation or ALK rearrangement. Patients are also being recruited in South Korea for an open-label, phase 2 umbrella trial (NCT03693339) that will assess the safety and efficacy of capmatinib monotherapy in ≈ 27 patients with NSCLC har- bouring MET exon 14 skipping mutation. Another phase 2 study (NCT02750215) is recruiting ≈ 20 patients in the USA to assess the efficacy and safety of capmatinib in patients with advanced NSCLC with MET exon 14 alterations who have received prior treatment with a MET inhibitor. An open-label, multinational phase 2 study (NCT02323126) is underway to assess the efficacy and safety of capmatinib plus nivolumab, or nazartinib (EGF816) plus nivolumab in

≈ 68 previously treated NSCLC patients. In addition, a ran- domized, multinational phase 2 study (NCT03647488) is assessing the safety and efficacy of capmatinib plus spartali- zumab combination therapy versus docetaxel in pretreated adults with EGFR wildtype, ALK rearrangement negative advanced/metastatic NSCLC.
Other phase 2 studies are assessing the efficacy and safety of capmatinib monotherapy/combination therapy in patients with papillary renal cell carcinoma (NCT02019693), mela- noma (NCT02159066) and solid tumours (NCT03040973).

3Current Status

On 6 May 2020 [7], capmatinib received its first approval in the USA for the treatment of adults with metastatic NSCLC whose tumours have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test [6].

Compliance with Ethical Standards

Funding The preparation of this review was not supported by any external funding.

Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a contracted employee of Adis International Ltd/
Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.


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