The Evolution of Therapies in Non-Small Cell Lung Cancer
Abstract
:1. Introduction
2. Current Therapies Available
2.1. Chemotherapy
2.2. Vascular Endothelial Growth Factor (VEGF) Inhibition
2.3. Proven Targeted Therapies
2.3.1. Epidermal Growth Factor Receptor (EGFR)
First-Generation EGFR Tyrosine Kinase Inhibitors (TKIs)
Second-Generation EGFR TKIs
First Generation EGFR TKI (Erlotinib, Gefitinib)-First-Line Studies | ||||||
---|---|---|---|---|---|---|
Trial | Population | Number | Agent (A) | Comparator (C) | Median PFS A vs. C (Months) | HR |
Mok et al. (2009) [40] Phase III | Adenocarcinoma, Asian, never or light smokers | 1217 | Gefitinib | Carboplatin, pacltaxel | 9.8 vs. 6.4 | 0.48 |
Maemondo et al. (2010) [41] Phase III | EGFR mutant | 230 | Gefitinib | Carboplatin, paclitaxel | 10.8 vs. 5.4 | 0.30 |
Mitsudomi et al. (2010) [42] Phase III | EGFR mutant | 172 | Gefitinib | Cisplatin, docetaxel | 9.2 vs. 6.3 | 0.489 |
Han et al. (2012) [43] Phase III | Adenocarcinoma, Asian, never or light smokers | 309 | Gefitinib | Cisplatin, gemcitabine | 5.8 vs. 6.4 | 1.198 |
42 EGFR +ve | 8.0 vs. 6.3 | 0.544 | ||||
Zhou et al. (2011) [44] Phase III | EGFR mutant | 154 | Erlotinib | Carboplatin, gemcitabine | 13.1 vs. 4.6 | 0.16 |
Rosell et al. (2012) [45] Phase III | EGFR mutant | 173 | Erlotinib | Platinum doublet | 9.7 vs. 5.2 | 0.37 |
Second Generation EGFR TKI (Afatinib, Dacomitinib, Neratinib) | ||||||
Sequist et al. (2013) [52] Phase III | EGFR mutant- 1st line setting | 345 | Afatinib | Cisplatin, pemetrexed | 11.1 vs. 6.9 | 0.58 |
Wu et al. (2014) [60] Phase III | EGFR mutant- 1st line setting | 364 | Afatinib | Cisplatin, gemcitabine | 11.0 vs. 5.6 | 0.28 |
Yang et al. (2012) [53] Phase II | EGFR mutant- 2nd line with no prior EGFR TKI | 129 | Afatinib | Single arm | 14.0 | NA |
Miller et al. (2012) [54] Phase IIb/III | EGFR mutant- after treatment with EGFR TKI | 585 | Afatinib | Placebo | 3.3 vs. 1.1 | 0.38 |
Katakami et al. (2013) [55] Phase II | Clinical post 1st line EGFR TKI, 72.6% mutant | 62 | Afatinib | Single arm | 4.4 | NA |
Ramalingam et al. (2014) [57] Phase III | All NSCLC post progression with chemotherapy | 878 | Dacomitinib | Erlotinib | 2.6 vs. 2.6 | 1.022 |
Ellist et al. (2014) [58] Phase III | All NSCLC post progression with chemotherapy and EGFR TKI | 720 | Dacomitinib | Placebo | 2.7 vs. 1.4 | 0.66 |
Sequist et al. (2010) [59] Phase II | All NSCLC | 167 | Neratinib | Single arm | 3.7 (Severe diarrhoea) | NA |
Third Generation EGFR TKI (Rociletinib, AZD9291) | ||||||
Sequist et al. (2015) [61] Phase I/II | EGFR mutant post progression on EGFR TKI | 130 | Rociletinib | Single arm | 13.1 | NA |
Janne et al. (2015) [62] Phase I/II | EGFR mutant post progression on EGFR TKI | 253 | AZD9291 | Single arm | 8.2 | NA |
Third-Generation EGFR TKIs
Dual Inhibition
Treatment Paradigm Following First-Line EGFR TKI
EGFR Inhibition in SCC
2.3.2. Anaplastic Lymphoma Kinase (ALK)
Second-Generation ALK Inhibitors
Other Targets
First Generation ALK TKI-Crizotinib | ||||||
---|---|---|---|---|---|---|
Trial | Population | Number | Agent (A) | Comparator (C) | Median PFS A vs. C (Months) | HR |
Kim et al. (2012) [77] Phase II | ALK positive post 1st line chemotherapy | 439 | Crizotinib | Single arm | 8.5 | NA |
Shaw et al. (2013) [78] Phase III | ALK positive post 1st line chemotherapy | 347 | Crizotinib | Pemetrexed or docetaxel | 7.7 vs. 3.0 | 0.49 |
Solomon et al. (2014) [79] Phase III | ALK positive- 1st line | 343 | Crizotinib | Platinum, pemetrexed | 10.9 vs. 7.0 | 0.45 |
Second Generation ALK TKI (Ceritinib, Alectinib) | ||||||
Shaw et al. (2014) [83] Phase I | ALK positive (68% progressed on Crizotinib) | 130 | Ceritinib | Single arm | 7.0 overall, 10.4 for ALK inhibitor naïve, 6.9 in prev. treated | NA |
Seto et al. (2013) [85,86] Phase I/II | ALK positive- 1st line setting | 58 | Alectinib | Single arm | Not yet reached >10.3 | NA |
2.4. Potential Targets under Study
2.4.1. ROS1
2.4.2. Mesenchymal-Epithelial Transition (MET)
2.4.3. Rearranged during Transfection (RET)
2.4.4. BRAF Mutation
2.5. Targets with No Currently Effective Therapy
2.5.1. Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (K-RAS) Mutation
2.5.2. Insulin-Like Growth Factor 1 Receptor (IGFR1)
2.5.3. Fibroblast Growth Factor Receptor 1 (FGFR1)
2.5.4. Discoidin Domain Receptors (DDR)
2.6. Immunotherapy in NSCLC
2.6.1. CTLA-4 Inhibition
2.6.2. PD-1 Pathway Inhibition
2.7. Stem Cell Inhibitors
2.8. Other Potential Biomarker Based Clinical Trials
2.9. Special Considerations for Elderly Patients
3. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Boolell, V.; Alamgeer, M.; Watkins, D.N.; Ganju, V. The Evolution of Therapies in Non-Small Cell Lung Cancer. Cancers 2015, 7, 1815-1846. https://doi.org/10.3390/cancers7030864
Boolell V, Alamgeer M, Watkins DN, Ganju V. The Evolution of Therapies in Non-Small Cell Lung Cancer. Cancers. 2015; 7(3):1815-1846. https://doi.org/10.3390/cancers7030864
Chicago/Turabian StyleBoolell, Vishal, Muhammad Alamgeer, David N. Watkins, and Vinod Ganju. 2015. "The Evolution of Therapies in Non-Small Cell Lung Cancer" Cancers 7, no. 3: 1815-1846. https://doi.org/10.3390/cancers7030864