Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases
Table 2
IGF-1-targeted agents and their trials in lung diseases.
Category
Agents
Lung diseases in clinical trials
Major results or study design of representative trials
rhIGF-1
Mecasermin (Increlex), Myotrophin, CEP-151
Cystic fibrosis
NCT00566241: rhIGF-1 versus placebo on body weight and body composition in CF patients terminated for insufficient recruitment of participants.
rhIGF-1/rhIGFBP-3
Mecasermin rinfabate (Iplex)
BPD
NCT01096784: rhIGF-I/rhIGFBP-3 versus standard care in the occurrence of BPD in premature infants: 21.3% (10/47) versus 44.9% (22/49) (prevention of BPD is one of the secondary outcomes in this study).
IGF-1R TKI
Linsitinib (OSI-906, ASP7487)
Lung cancer
NCT01533181: linsitinib versus topotecan in relapsed or recurrent SCLC; PFS: 1.2 versus 3.0 m; OS: 3.4 versus 5.3 m. Leighl et al. [15]: linsitinib + erlotinib versus erlotinib in chemotherapy-naive patients with EGFR-mutation positive advanced NSCLC; PFS: 8.4 versus 12.4 m; ORR: 47.7% versus 75.0%; disease control rate: 77.3% versus 95.5%.
AXL1717
Lung cancer
NCT01561456: AXL1717 versus docetaxel in SCC or lung adenocarcinoma. NCT01466647: noncontrolled trial of AXL1717 + gemcitabine/carboplatin in SCC. Bergqvist et al. [14]: AXL1717 versus docetaxel in patients with previously treated, locally advanced, or metastatic NSCLC; PFS: 38.7 versus 37.4 weeks; rate of progression-free after 12 weeks: 25.9% versus 39.0%; ORR after 12 weeks: 0 versus 12.2%; disease control rate: 24.1% versus 36.6%.
XL228 against IGF-1R, Src, FGFR, and BCR-Abl
Lung cancer
NCT00526838: noncontrolled phase 1 trial of intravenous XL228 in subjects with advanced malignancies terminated by the sponsor.
IGF-1R mAb
Figitumumab (CP-751, 871)
Lung cancer
NCT00596380: figitumumab + paclitaxel/carboplatin versus paclitaxel/carboplatin as first-line treatment for advanced nonadenocarcinoma NSCLC; PFS: 4.7 versus 4.6 m; OS: 8.6 versus 9.8 m; ORR: 33% versus 35%. NCT00147537: figitumumab + paclitaxel/carboplatin versus paclitaxel/carboplatin as first-line treatment for advanced NSCLC; ORR: 37.4% versus 27.5%; PFS in groups of figitumumab 20 mg/kg, 10 mg/kg, or 0: 4.5 versus 4.4 versus 4.3 m. NCT00560573: figitumumab + gemcitabine/cisplatin versus figitumumab + pemetrexed/cisplatin as first-line treatment for advanced NSCLC; PFS: 6.5 versus 5.4 m; ORR: 56.5% versus 46.2%. NCT00673049: figitumumab + erlotinib versus erlotinib in advanced nonadenocarcinoma NSCLC; PFS: 2.1 versus 2.6 m; OS: 5.7 versus 6.2 m; ORR: 5.5% versus 3.8% terminated because combination therapy seemed to be unlikely to improve OS.
Cixutumumab (IMC-A12)
Lung cancer
NCT00887159: cixutumumab + etoposide/cisplatin versus etoposide/cisplatin versus vismodegib (a Hedgehog pathway inhibitor) + etoposide/cisplatin in extensive stage SCLC; PFS: 4.6 versus 4.4 versus 4.4 m; OS: 10.1 versus 8.8 versus 9.8 m; ORR: 50% versus 48% versus 56%. NCT00986674: cetuximab + paclitaxel/carboplatin versus cixutumumab + paclitaxel/carboplatin versus cetuximab + cixutumumab + paclitaxel/carboplatin in patients with advanced NSCLC who will not receive bevacizumab-based therapy; PFS: 3.4 versus 4.2 versus 4.0 m; OS: 9.8 versus 7.7 versus 8.8 m; ORR: 11.1% versus 22.0% versus 21.7%; deaths within 1 month: 6 versus 2 versus 5 terminated because of excessive grade 5 adverse events in patients receiving cetuximab therapy. NCT00955305: paclitaxel/carboplatin + bevacizumab versus paclitaxel/carboplatin + bevacizumab + cixutumumab in advanced nonsquamous NSCLC; PFS: 5.8 versus 7.0 m; OS: 16.2 versus 16.1 m; ORR: 46.2% versus 58.7% terminated for accrual with cixutumumab. Novello et al. [269]: pemetrexed/cisplatin + cixutumumab versus pemetrexed/cisplatin as first-line therapy in advanced nonsquamous NSCLC; PFS: 5.45 versus 5.22 m; OS: 11.33 versus 10.38 m; ORR: 37.9% versus 30.6%.
Dalotuzumab (MK-0646, h7C10)
Lung cancer
NCT00654420: erlotinib versus erlotinib + dalotuzumab in recurrent NSCLC; PFS: 1.6 versus 2.5 m; OS: 14.5 versus 6.9 m; ORR: 5.6% versus 2.8%. NCT00799240: pemetrexed/cisplatin versus pemetrexed/cisplatin + dalotuzumab in stage IV metastatic nonsquamous NSCLC; 14 versus 12 participants; partial response: 2 versus 3; stable disease: 7 versus 4; progressive disease: 3 versus 4; not evaluable: 2 versus 1; median time to progression: 173 versus 199 d; median survival: 262 versus 276.5 d terminated by the sponsors.
Teprotumumab (R1507, RV-001)
Lung cancer
NCT00760929: teprotumumab (weekly) + erlotinib versus teprotumumab (per 3 week) + erlotinib versus placebo + erlotinib in advanced NSCLC with progression following one or two prior regimes; PFS: 1.87 versus 2.7 versus 1.5 m; OS: 8.1 versus 12.1 versus 8.1 m; ORR: 8.8% versus 7% versus 8.8%. NCT00773383: teprotumumab + erlotinib in stage IIIB/IV NSCLC with progressive disease after clinical benefit to second- or third-line erlotinib monotherapy; rate of progression-free and alive in 3 weeks: 32.4%.
Robatumumab (SCH 717454, MK-7454)
Solid tumors (including lung cancer)
NCT00954512: noncontrolled trial of robatumumab + paclitaxel/carboplatin in advanced NSCLC; 3 participants: 2 with stable disease and 1 with progressive disease; terminated for business reasons.
Ganitumab (AMG-479)
Lung cancer, ARMS
NCT00819169: noncontrolled trial of ganitumab + conatumumab (a death receptor 5 agonist) in advanced solid tumors: nonsquamous NSCLC: stable disease 40%, progressive disease 60%, PFS 1.6 m; SCC: stable disease 71%, progressive disease 29%, PFS 3.3 m. NCT00791154: etoposide + platinum (carboplatin or cisplatin) ± ganitumab for extensive stage SCLC. NCT03041701: ganitumab + dasatinib (a Src family kinase inhibitor) in embryonal and alveolar rhabdomyosarcoma.
BIIB022
Lung cancer
NCT00970580: BIIB022 + paclitaxel/carboplatin in treatment-naive advanced NSCLC.
IGF-1/IGF-2 mAb
BI 836845
Lung cancer
NCT02191891: BI 836845 + afatinib in patients with EGFR mutant NSCLC with progression following prior EGFR-TKI treatment; recruiting participants.
NCT01563354: pasireotide versus everolimus versus pasireotide + everolimus in patients with neuroendocrine carcinoma of the lung and thymus. NCT01417806: pasireotide + topotecan in relapsed or refractory SCLC.
Other agents to be tested in lung disease trials
PL225B, AG-1024, AEW541, BVP51004 (kinase inhibitors of IGF-1R); BMS-754807, A-928605 (kinase inhibitors of IGF-1R and IR); KW-2450 (a pan-kinase inhibitor of IGF-1R, IR, Aurora A/B kinases); INSM-18 (a kinase inhibitor of IGF-1R and ErbB2); AVE1642 (an IGF-1R mAb); MM-141 (a mAb against IGF-1R and ErbB3); IGF-1 antisense oligodeoxynucleotide; IGF-methotrexate conjugate (765IGF-MTX); fusion protein of IGF-1 and vitronectin (VF001-DP); pUMVC3-IGFBP2-HER2-IGF1R plasmid DNA vaccine.
BPD: bronchopulmonary dysplasia. SCLC: small cell lung cancer. NSCLC: non-small cell lung cancer. SCC: squamous cell carcinoma. EGFR-TKI: epidermal growth factor receptor-tyrosine kinase inhibitor. PFS: progression-free survival. OS: overall survival. ORR: objective response rate. ARMS: alveolar rhabdomyosarcoma. GH: growth hormone. ACTH: adrenocorticotropic hormone. .. All the clinical trial data were accessed from PubMed or from the website ClinicalTrials.gov, which are services held by the U.S. National Institutes of Health. The authors declare no conflict of interests.
