Journal List > J Lung Cancer > v.10(1) > 1050622

Lee and Park: Personalized Therapy in Lung Cancer: Focused on Molecular Targeted Therapy

Abstract

Lung cancer is the leading cause of cancer death worldwide, with an overall 5 year survival rate of 15%. Most patients present with advanced disease that requires systemic chemotherapy, which merely confers several months of survival benefit. Recent advances in understanding the molecular mechanisms underlying lung cancer have led to molecular targeted therapy in this field. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first successful personalized therapy for non-small cell lung cancer (NSCLC), with about 30 months of median overall survival in patients with sensitive EGFR mutations. In addition, monoclonal antibodies against vascular endothelial growth factor (VEGF) or EGFR are also in current clinical use. Resistance to EGFR-TKIs has emerged as a major limitation of these agents and become challenge clinically. A number of novel targeted agents have been developed and investigated in clinical trials to overcome the limitation of agents currently available. Recently, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK), as a novel molecular target of NSCLC, has been identified, and its inhibitor is under rapid clinical development. We herein review the molecular targeted therapies currently available for NSCLC and discuss the clinical data of novel agents under clinical development. (J Lung Cancer 2011;10(1):1 ? 12)

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Table 1.
Main Clinical Trials of the First Generation EGFR-TKIs
Study Phase Setting Treatment PFS (mo) OS (mo) RR (%) Primary end point
IDEAL 1 II 2nd/3rd line G250 2.7 7.6 18.4  
      G500 2.7 8.0 19  
IDEAL 2 II 3rd line G250 N/A 7.0 12  
      G500   6.0 9  
ISEL III 2nd/3rd line G 3.0 5.6 8 OS (Unmet)
      Placebo 2.6 5.1 1  
BR.21 III 2nd/3rd line E 2.2 6.7 9 OS (Met)
      Placebo 1.8 4.7 1  
INTEREST III 2nd line, non-inferiority G 2.2 7.6 9.1 OS (Met)
      Docetaxel 2.7 8.0 7.6  
IPASS III 1st line, non-inferiority G 5.7 18.6 43.0 PFS (Met)
    Asian, adenocarcinoma, never/light smokers Pac/Carb 5.8 17.3 32.2  
SATURN III Maintenance after platinum E 12.3 wks 12.0 12 PFS (Met)
    doublet Placebo 11.1 wks 11.0 5  
ATLAS III Maintenance after platinum Bev+ E 4.8 14.4 N/A PFS (Met)
    doublet+ Bev Bev+ placebo 3.7 13.3 N/A  
INTACT 1 III 1st line Gem/Cis+ G250 (cont’ d) 5.8 9.9 50.3 OS (Unmet)
      Gem/Cis+ G500 (cont’ d) 5.5 9.9 49.7  
      Gem/Cis+ placebo 6.0 10.9 44.8  
INTACT 2 III 1st line Pac/Carb+ G250 (cont’ d) N/A 9.8 30.4 OS (Unmet)
      Pac/Carb+ G500 (cont’ d)   8.7 30.0  
      Pac/Carb+ placebo   9.9 28.7  
TRIBUTE III 1st line Pac/Carb+ E (cont’ d) N/A 10.6 21.5 OS (Unmet)
      Pac/Carb+ placebo   10.5 19.3  
TALENT III 1st line Gem/Cis+ E (cont’ d) N/A 10.0 31.5 OS (Unmet)
      Gem/Cis+ placebo   10.3 29.9  
BeTA III 2nd line E+ Bev 3.4 9.3 12.6 OS (Unmet)
      E+ placebo 1.7 9.2 6.2  

PFS: progression free survival, OS: overall survival, RR: response ratio, mo: months, G250: gefitinib 250 mg, G500: gefitinib 500 mg, G: gefitinib, E: erlotinib, Pac/Carb: paclitaxel/carboplatin, Bev: bevacizumab, Gem/Cis: gemcitabine/cisplatin, cont’ d: continued, N/A: not assessed.

Table 2.
Summary of EGFR Biomarker Analyses from Randomised Trials
Groups Treatment High expression, high copy number, or mutation positivity Low expression, low copy number, or mutation negativity p-inter
HR (95% CI) p-value HR (95% CI) p-value
EGFR copy number            
BR.21 E vs plac 0.43 (0.23∼0.78) 0.004 0.80 (0.49∼1.29) 0.35 0.12
ISEL G vs plac 0.61 (0.36∼1.04) 0.07 1.16 (0.81∼1.64) 0.42 0.05
INTEREST E vs Doc 1.09 (0.78~1.51) 0.62 NR    
EGFR protein expression            
BR.21 E vs plac 0.68 (0.49∼0.95) 0.02 0.93 (0.63∼1.36) 0.70 0.25
ISEL G vs plac 0.77 (0.56∼1.08) 0.13 1.57 (0.86∼2.87) 0.14 0.05
EGFR mutation            
BR.21 E vs plac 0.55 (0.25∼1.19) 0.12 0.74 (0.52∼1.05) 0.09 0.47
IPASS G vs PCa 0.48 (0.36∼0.64) <0.0001 2.85 (2.05∼3.98) <0.0001 <0.0001
KRAS mutation            
BR.21 E vs plac 1.67 (0.62∼4.50) 0.30 0.69 (0.49∼0.97) 0.03 0.09

HR is for overall survival unless otherwise stated

p for interaction

HR is for progression free survival.

E: erlotinib, G: gefitinib, plac: placebo, Doc: docetaxel, PCa: paclitaxel-carboplatin, HR: hazard ratio, CI: confidence interval, NR: not reported.

Table 3.
Mechanisms of Resistance to EGFR-TKI
Intrinsic resistance Acquired resistance
Drug-resistant EGFR mutations Second-site EGFR mutations
- T790M - T790M, D761Y, T854A
- Exon 20 insertion Pathways bypassing EGFR signaling
Genomic alterations co-occuring with EGFR mutations - MET activation
- HER2 TK domain mutations ㆍ MET gene amplification
- PTEN loss ㆍ HGF overexpression
- PIK3CA mutation - IGF 1R overexpression
- IGF 1R overexpression - Epithelial to mesenchymal transition (EMT)
Resistance in EGFR wild type tumors  
- KRAS mutation  
- BRAF mutation  
- EML4-ALK  
- MET activation  
ㆍ MET amplification  
ㆍ HGF overexpression  
Table 4.
Targeted Agents for Lung Cancer in Clinical Development
Class of target Drug Target Phase
ErbB family BIBW2992 (Afatinib) EGFR, HER2 (irreversible) III
  HKI-272 (Neratinib) EGFR, HER2 (irreversible) II
  Lapatinib EGFR, HER2 (reversible) II
  AV-412/MP-412 EGFR, HER2 (reversible) I
  AZD8931 EGFR, HER2/3 (reversible) I
  PF-00299804 EGFR, HER2/4 (irreversible) III
  EKB-569 (Pelitinib) EGFR, HER2/4 (irreversible) II
  IMC-11F8 (Necitumumab) EGFR (monoclonal antibody) III
  Pertuzumab HER2 (monoclonal antibody) II
EGFR/VEGF ZD-6474 (Vandetanib) EGFR, VEGFR2, RET III
  BMS-690514 EGFR, HER2/4, VEGFR1/2/3 II
  XL647 EGFR, HER2, VEGFR2/3, EPHB4 II
MET PF-02341066 (Crizotinib) MET, ALK III
  ARQ197 MET III
  XL184 MET, VEGFR1/2/3, RET, c-Kit, Flt3 II
  GSK1363089 (Foretinib) MET, VEGFR1/2/3, PDGFR, c-Kit, Flt3 I/II
  MetMAb MET (monoclonal antibody) II
IGF1R CP-751,871 (Figitumumab) IGF1R III
PI3K/AKT/mTOR pathway Temsirolimus mTOR II
  Everolimus FKBP-12, mTOR II
  AP23573 mTOR II
  MK2206 AKT II
  XL147 PI3K I
  Enzastaurin PKC II
  ISIS3521 PKC III
RAS/RAF/MAPK/MEK pathway AZD6244 MEK II
  PD-0325901 MEK II
STAT signaling Dasatinib Src, PDGFR, c-Kit II
HSP90 IPI-504 (Retaspimycin) Hsp90 II
  17-AAG (Tanespimycin) Hsp90 I
VEGFR Sorafenib VEGFR2/3, PDGFR, RAF, c-Kit III
  Sunitinib VEGFR1/2/3, PDGFR, c-Kit, RET, Flt3 III
  BIBF-1120 VEGFR, PDGFR, FGFR III
  Cediranib VEGFR1/2/3, PDGFR, c-Kit III
  Motesanib VEGFR1/2/3 III

Based on ClinicalTrials.gov.

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