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Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease

Rana Kanaan, Charlie Strange
European Respiratory Review 2017 26: 170061; DOI: 10.1183/16000617.0061-2017
Rana Kanaan
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Dept of Medicine, Medical University of South Carolina, Charleston, SC, USA
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Charlie Strange
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Dept of Medicine, Medical University of South Carolina, Charleston, SC, USA
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  • For correspondence: strangec@musc.edu
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  • FIGURE 1
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    FIGURE 1

    Platelet-derived growth factor receptors (PDGFRs) and ligand patterns. PDGFRs are transmembrane proteins. The extracellular domain consists of five immunoglobulin-like domains; binding occurs at domains 2 and 3. The intracellular domain is a tyrosine kinase. There are three dimeric forms of PDGFRs (-αα, -ββ and -αβ). Five different ligand isoforms are known to bind to PDGFRs (AA, AB, BB, CC and DD).

  • FIGURE 2
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    FIGURE 2

    Platelet-derived growth factor (PDGF) signalling pathway. Binding of distinct dimeric PDGF ligands to the respective receptor dimer leads to autophosphorylation of the tyrosine residues within their intracellular domains. Autophosphorylation then leads to transduction of signals via recruitment of surrounding proteins containing Src homology region 2. These include domains such as Grb2, Grb7, SHC, PI3K and GTPase-activating protein for Ras. Signal transduction occurs via two main pathways: 1) the PI3K pathway, which mediates Akt signalling for the promotion of cell survival and 2) the mitogen-activated protein kinase (MAPK) cascade. Hydrolytic conversion of RAS-guanosine diphosphate (GDP) to RAS-guanosine triphosphate (GTP) leads to activation of MAPK cascade members, such as extracellular signal-regulated kinase (ERK) or MAPK kinase (MEK) via RAF1, resulting in gene target transcription. This pathway is important for cell growth, proliferation, differentiation and migration. Son of sevenless (SOS) is a nucleotide exchange factor for Ras.

Tables

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  • TABLE 1

    Summary of completed clinical trials

    Lung disease/documented PDGF-PDGFR involved in pathogenesisDrugCompleted clinical study, study phase, study design and number of patientsPatient populationInterventionPrimary outcomeResults
    IPAH
     PDGF-BB
     PDGFR-β
    Imatinib mesylateIMPRES [24]
    Phase 3, 24 weeks, multicentre, randomised, double blind, placebo controlled (n=202)
    PVR ≥800 dyn·s·cm−5 symptomatic on ≥2 PAH therapiesRandomised to receive imatinib 200 mg once daily or placeboChange in 6MWDMean treatment effect on 6MWD 32 m; p=0.002
    PVR decreased by 379 dyn·s·cm−5 p<0.001
    Serious AEs were more frequent with imatinib compared to placebo (44% versus 30%)
    SorafenibGomberg-Maitland et al. [25]
    Phase 1b, 16 weeks, single centre, open label (n=22)
    Advanced but stable PAH on parenteral prostanoids (with or without oral sildenafil)Received sorafenib started at 200 mg daily then escalated to 400 mg twice dailySafety and tolerabilitySorafenib was well tolerated at 200 mg twice daily
    AEs: moderate skin reactions on the hands and feet and alopecia
    NSCLC
     PDGF-A/B
     PDGFR-α/β
    Imatinib mesylate (in combination with paclitaxel)Bauman et al. [26]
    Phase 2, multicentre, single stage, open label (n=34)
    Age ≥70 years with untreated, stage IIIB/IV NSCLC and ECOG performance status 0–2Received up to six 28-day cycles of imatinib and paclitaxelRRMet primary end-point; however, no improvement in overall survival and PFS. Regimen not recommended for further study
    Linifanib (in combination with carboplatin and paclitaxel)Ramalingam et al. [27]
    Phase 2, multinational, open label (n=139)
    Stage IIIB/IV nonsquamous NSCLCReceived carboplatin and paclitaxel plus placebo, linifanib 7.5 mg or linifanib 12.5 mgPFSImproved PFS. Higher incidence of AEs known to be associated with VEGF/PDGF inhibition
    Nintedanib
    (BIBF 1120) with pemetrexed
    Ellis et al. [28]
    Phase 1, multicentre, open label (n=26)
    Metastatic, unresectable, or locally advanced NSCLC and had to have relapsed during or following one prior platinum-based chemotherapy regimenReceived BIBF 1120 starting dose of 100 mg twice daily (days 2–21) with pemetrexed 500 mg·m−2 (day 1) over a 21-day cycle
    BIBF 1120 dose was escalated until the MTD was determined
    Safety, tolerability and MTDThe MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg twice daily
    BIBF 1120 in this combination was tolerable, with promising signs of efficacy
    Nintedanib
    (in combination with docetaxel)
    LUME-Lung 1 [29]
    Phase 3, multicentre, double blind, randomised, placebo controlled (n=1314)
    Stage IIIb/IV recurrent NSCLC progressing after first-line chemotherapyRandomised to docetaxel 75 mg·m−2 by i.v. infusion on day 1 plus nintedanib 200 mg twice daily orally or placebo on days 2–21, every 3 weeks
    Treatment was continued until unacceptable AEs or disease progression
    PFSPFS was significantly improved after a median follow-up of 7.1 months
    Improved overall survival in all patients with adenocarcinoma (12.6 versus 10.3 months); more pronounced in the subgroup of patients who progressed within 9 months after start of first-line therapy (10.9 versus 7.9 months)
    AEs: diarrhoea, reversible increase in ALT and AST, gastrointestinal side-effects
    Nintedanib
    (in combination with premetrexed)
    LUME-Lung 2 [30]
    Phase 3, multicentre, double blind, randomised, placebo controlled (n=713)
    Stage IIIb/IV or recurrent NSCLC previously treated with chemotherapy. ECOG performance score of 0–1Randomised to pemetrexed 500 mg·m−2 i.v. on day 1, combined with either oral nintedanib 200 mg twice daily or placebo, given on days 2–21, every 3 weeksPFSStopped early. ITT analysis of PFS favoured the treatment arm (median 4.4 months versus 3.6 months; HR 0.83, 95% CI 0.70–0.99; p=0.0435)
    IPF
     PDGF-AA, -BB and -CC
    Imatinib mesylate (Gleevec)Daniels et al. [31]
    Phase 2, 96 weeks, multicentre, randomised, double blind, placebo controlled (n=119)
    Mild to moderate IPF diagnosed within 3–36 months of screening with clinical worsening in the past year (10% decline in FVC % pred or worsening chest radiograph or worsening dyspnoea)Randomised to receive imatinib mesylate 600 mg (six tablets) orally once daily or placeboCombined measure of disease progression (defined
    as 10% decline from baseline FVC) or death
    No effect on survival or lung function
    Nintedanib
    (BIBF 1120)
    TOMORROW [32]
    Phase 2, 12 months, multicentre, randomised, double blind, placebo controlled (n=432)
    Age ≥40 years with <5 years diagnosis of IPF, FVC ≥50% pred, DLCO 30–79% pred, PaO2 ≥55 mmHg at <1500 m altitude or ≥50 mmHg at >1500 m altitudeRandomisation to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day or 150 mg twice a day) or placeboAnnual rate of decline in FVCCompared to placebo, BIBF 1120 at a dose of 150 mg twice daily was associated with:
    a trend toward a reduction in the decline in lung function (0.06 versus 0.19 L·year-1);
    fewer acute exacerbations (2.4 versus 15.7 per 100 patient-years, p=0.02);
    preserved quality of life (−0.66 versus 5.46, p=0.007);
    gastrointestinal AEs, which led to more discontinuation in the 150 mg BIBF 1120 twice a day group;
    increase in liver aminotransferase levels
    INPULSIS-1 and 2 [33]
    Phase 3, 52 weeks, multicentre, randomised double blind, placebo controlled (n=1061)
    Age ≥40 years with <5 years diagnosis of IPF, FVC ≥50% pred, DLCO 30–79% pred,Randomised to receive 150 mg nintedanib twice daily or placeboAnnual rate of decline in FVCINPULSIS-1
    No difference in time to first acute exacerbation (HR 1.15, 95% CI 0.54–2.42)
    Comparable proportion of patients with at least one investigator-reported acute exacerbation (6.1% versus 5.4%, respectively, in the nintedanib and placebo groups)
    INPULSIS-2
    Significant increase in time to first acute exacerbation (HR 0.38, 95% CI 0.19–0.77)
    Lower proportion of patients with at least one investigator-reported acute exacerbation in the nintedanib group (3.6%) compared with placebo (9.6%)
    Most common AEs: diarrhoea followed by nausea
    PirfenidoneASCEND [34]
    Phase 3, 52 weeks, multicentre, double blind, placebo-controlled (n=555)
    Age 40–80 years, centrally confirmed diagnosis of IPFRandomised to receive pirfenidone 2403 mg per day or placeboChange in FVC or death at week 5247.9% relative reduction in the proportion of patients who had an absolute decline of ≥10% of FVC % pred or who died
    No significant difference in dyspnoea scores (p=0.16)
    No significant difference in rates of death from any cause (p=0.10) or from IPF (p=0.23)
    CAPACITY 004 [35]
    Phase 3, 72 weeks, multicentre, double blind, placebo randomised controlled trial (n=435)
    Age 40–80 years, diagnosis of IPF in the previous 48 months,
    FVC ≥50% and ≤90% pred, DLCO ≥35% and ≤90% pred 6MWT≥150 m
    Randomised to receive pirfenidone 2403 mg·day−1, or pirfenidone 1197 mg·day−1 or placeboChange in percentage of FVC % pred from baseline to week 72Significant reduction in decline of FVC (p=0.001). Mean FVC change at week 72 was –8·0±16.5% in the pirfenidone 2403 mg·day−1 group and –12.4±18.5% in the placebo group (difference 4.4%, 95% CI 0.7–9.1). Outcomes in the pirfenidone 1197 mg·day−1 group were intermediate to the pirfenidone 2403 mg·day−1 and placebo groups
    AEs: patients in the pirfenidone 2403 mg·day−1 group had higher incidences of nausea, dyspepsia, vomiting, anorexia, photosensitivity and dizziness
    CAPACITY 006 [35]
    Phase 3, 72 weeks, multicentre, double blind, randomised, placebo controlled (n=344)
    Age 40–80 years, diagnosis of IPF in the previous 48 months
    FVC ≥50% pred and ≤90% pred, DLCO ≥35% pred and ≤90% pred
    6MWT ≥150 m
    Randomised to receive pirfenidone 2403 mg·day−1
    or placebo
    Change in FVC % pred from baseline to week 72Significant reduction in decline of FVC. Mean change at week 72 was –9.0±19.6% in patients in the pirfenidone 2403 mg·day−1 group and –9.6±19.1% in patients in the placebo group
    AEs: same as CAPACITY 004
    HPSPirfenidoneGahl et al. [36]
    44 months, single centre, double blind, randomised controlled (n=21)
    Confirmed diagnosis of HPS and FVC 40–75% pred
    All 21 subjects were Puerto Rican; 20 were homozygous for the 16-bp duplication in exon 15 of HPS1; one was homozygous for a 3904-bp deletion in HPS3
    Randomised to receive pirfenidone 800 mg three times daily or placeboAverage rate of decline of FVC, FEV1, TLC and DLCO, measured as % pred, in the two treatment groups5% difference in the yearly rate of FVC decline (p=0.001)
    In patients with an initial FVC >50% pred, pirfenidone slowed lost pulmonary function (FVC, FEV1, TLC and DLCO) at a rate of 8% per year, compared to placebo
    O'Brien et al. [37]
    Single centre, double blind, randomised, placebo controlled (n=35)
    HPS-1 or -4 confirmed by molecular analysis and FVC 51–85% pred, regardless of radiographic evidence of fibrosis on HRCTRandomised to receive pirfenidone or placebo. A dosage escalation schedule was employed to reach 801 mg pirfenidone three times dailyRate of decline in FVCStopped early (after 12 months) due to futility
    No significant safety concerns
    Diffuse cutaneous systemic sclerosisNintedanibSpiera et al. [38]
    Phase 2a, 12 months, single centre, single arm, open label (n=30)
    Fulfilled the American College of Rheumatology classification criteria for systemic sclerosis and had the diffuse subtype. Stable MRSS of ≥16 points in the month between screening and baseline visits, and had disease duration of <10 years
    DLCO ≥30% pred
    Imatinib 400 mg dailyChange in the MRSS after 12 months of treatmentImproved MRSS 6.6 points or 22.4% (p=0.001)
    FVC improved by 6.4% pred (p=0.008)

    PDGF: platelet-derived growth factor; PDGFR: PDGF receptor; IPAH: idiopathic pulmonary arterial hypertension; NSCLC: nonsmall cell lung cancer; IPF: idiopathic pulmonary fibrosis; HPS: Hermansky–Pudlak syndrome; PVR: pulmonary vascular resistance; PAH: pulmonary arterial hypertension; 6MWD: 6-min walking distance; AEs: adverse events; ECOG: Eastern Cooperative Oncology Group; RR: response rate; PFS: progression-free survival; VEGF: vascular endothelial growth factor; MTD: maximum tolerated dose; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ITT: intention to treat; FVC: forced vital capacity; % pred: % predicted; DLCO: diffusing capacity of the lung for carbon monoxide; PaO2: arterial oxygen tension; 6MWT: 6-min walk test; FEV1: forced expiratory volume in 1 s; TLC: total lung capacity; HRCT: high-resolution computed tomography; MRSS: modified Rodnan skin score.

    • TABLE 2

      Summary of drug targets and median inhibitory concentration (IC50)

      Drug targetIC50 nM
      Imatinib [39, 40]PDGFR
      V-Abl
      C-Kit
      100
      600
      100
      Linifanib [41]PDGFR-β
      KDR
      CSF-1R
      Flt-1/3
      66
      4
      3
      3/4
      Nintedanib [42, 43]PDGFR-α/β
      VEGFR1/2/3
      FGFR1/2/3
      59/65
      34/13/13
      69/37/108
      PK10453 [44]PDGFR-α/β10.1/35
      Sorafenib [43, 45]PDGFR-β
      Raf-1
      B-Raf
      VEGFR-2
      57
      6
      22
      90
      Sunitinib [46]PDGFR-β
      VEGFR2 (Flk-1)
      2
      80
      PirfenidoneTGF-β
      PDGF-A and -B
      NA
      NA

      PDGFR: platelet-derived growth factor receptor; VEGFR: vascular endothelial growth factor receptor; FGFR: fibroblast growth factor receptor; TGF: transforming growth factor; NA: not available.

      Supplementary Materials

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      • Supplementary Material

        C. Strange ERR-0061-2017_Strange

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      Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease
      Rana Kanaan, Charlie Strange
      European Respiratory Review Dec 2017, 26 (146) 170061; DOI: 10.1183/16000617.0061-2017

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      Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease
      Rana Kanaan, Charlie Strange
      European Respiratory Review Dec 2017, 26 (146) 170061; DOI: 10.1183/16000617.0061-2017
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        • Abstract
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        • Introduction
        • PDGF signalling pathways
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