Non-Small Cell Lung Cancer in East tasia Chia-Chi (Josh) Lin, MD, PhD 林 家 齊 Director of Phase I Center, e Department of Oncology, National Taiwan University Hospital Clinical Associate Professor, Department of Urology, National Taiwan University College of Medicine
Is Chemotherapy Beneficial in NSCLC?
Survival Benefit for Chemotherapy vs. BSC Agent Hazard p value Median 1-year ratio survival survival (months) (%) Alkylating agents 1.26 (0.96-1.66) 0.87 (0.64-1.20) 0.095-1.0-06 Vinca or etoposide 08 04 0.4 +0.5 +04 Cisplatin 0.73 <0.0001 0001 +1.5 +10 (0.63-0.85) BMJ 1995;311:899-909
1990 s: Paclitaxel, Docetaxel, Gemcitabine, Vinorelbine New agents 1990 s
Is there a best platinum regimen
First-Line Therapy Study n RR (%) OS (mo) ECOG Cisplatin Paclitaxel 288 21 7.8 Cisplatin Gemcitabine 288 22 81 8.1 Cisplatin Docetaxel 289 17 7.4 Carboplatin Paclitaxel l 290 17 81 8.1 SWOG Cisplatin Vinorelbine 202 28 80 8.0 Carboplatin Paclitaxel 206 25 8.0 Scagliotti Cisplatin Gemcitabine 863 28 10.3 Cisplatin Pemetrexed 862 31 10.3
First-Line Therapy Palliates symptoms Improves the quality of life Improves survival Particularly in patients with ECOG performance status 0-1 Response rate: 20-30% Median time-to-progression: 4-6 months Median overall survival: 8-10 months 1-year overall survival: 30-40% 2-year overall survival: 10-15%
Postel-Vinay S, et al. Nat Rev Clin Oncol 2012;9:144-55
ERCC1 mrna Customized Trial Cobo M, et al. J Clin Oncol 2007;25:2747-54
ERCC1 mrna Customized Trial Outcome Control Low High p value ERCC1 genotype ERCC1 genotype n 141 129 96 CR 4.3% 2.3% 4.2% PR 33.3% 48.1% 39.6% CR + PR 39.3% 53.2% 47.2%.03 SD 40.4% 28.7% 27.1% PD 17.7% 15.5% 21.9% Cobo M, et al. J Clin Oncol 2007;25:2747-54
ERCC1 mrna Customized Trial Outcome Control Genotype p value n 141 225 CR 4.3% 3.1% PR 33.3% 44.4% CR + PR 39.3% 51.2%.02 SD 40.4% 18.2% PD 17.7% 6.3% Cobo M, et al. J Clin Oncol 2007;25:2747-54
Complexities of lung cancer pathogenesis result in diverse histologic subtypes 1. Lepedic: favorable 2. Acinar: intermediate 3. Papillary: Intermediate 4. Solid: poor Invasive mucinous adenocarcinoma
Histology and anti-vegf therapy
Anti-VEGF: Bevacizumab
Pemetrexed / Cisplatin vs. Gemcitabine / Cisplatin (JMDB) Survival difference related to differential expression of thymidylate synthase (TS) Squamous cell carcinoma higher expression of TS Lower response rate to pemetrexed Scagliotti GV, et al. J Clin Oncol 2008;26:3543-51
Squamous Cell Carcinoma Shows Higher mrna and Protein Levels for Thymidylate Synthase Ceppi P, et al. Cancer 2006;107:1589-96
Second Line Therapy 1. Docetaxel 2. Pemetrexed 3. Erlotinib
Second-Line Therapy First author Therapy n RR (%) OS (m) PFS (m) 1-yr OS Shepherd Docetaxel 75 mg/m 2 55 6 75 7.5 26 2.6 37 Best supportive care 100 0 4.6 1.6 12 Hanna Pemetrexed 500 mg/m 2 283 9 7.9 3.4 30 Docetaxel 75 mg/m 2 288 9 8.3 3.5 30 Shepherd Erlotinib 150 mg 488 9 6.7 2.2 30 Best supportive care 243 0 4.7 1.8 21 Sh h d FA t l J Cli O l 2000 18 2095 103 Shepherd FA, et al. J Clin Oncol 2000;18:2095-103 Hanna N, et al. J Clin Oncol 2004;22:1589-97 Shepherd FA, et al. N Engl J Med 2005;353:123-32
Targeted Therapy For Lung Cancer
EGFR and ALK
Gefitinib (ZD1839) Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
EGFR: the early years
Thatcher N, et al. Lancet 2005;366:1527-37
Thatcher N, et al. Lancet 2005;366:1527-37
Who will respond to gefitinib? 1. Adenocarcinoma 2. Never smokers 3. Female gender 4. East Asians Thatcher N, et al. Lancet 2005;366:1527-37
The Discovery of EGFR Mutations in Lung Adenocarcinoma
9 patients with a response 8 had EGFR mutation 7 patients without a response 0 had EGFR mutation (p <0.001) 2 / 25 (8%) NSCLC were mutated in the same region of EGFR Lynch TJ, et al. N Engl J Med 2004;350:2129-39
Lynch TJ, et al. N Engl J Med 2004;350:2129-39
EGFR Inhibitors EGFR mutations ti and are more common in Lung adenocarcinoma Females Never smokers compared to former or current smokers East Asians compared to Western populations (40% vs. 10%) EGFR mutations Point mutations in exon 18 (G719X) 03% In-frame deletions in exon 19 45% Point mutations in exon 21 (L858R) 40% Point mutations in exon 21 (L861Q) 02% Lynch T, et al. N Engl J Med 2004;350:2129-39 Paez J, et al. Science 2004;304:1497-50 Pao W, et al. Proc Natl Acad Sci 2004;101:13306-11
EGFR Sensitizing Mutations 18 G719X 4% P-loop GXGXXG motif Ligand Binding 19 E746 - A750 deletion 44% αc-helix 20 766-768 insertion 5% αc-helix Ligand Binding Transmembrane 21 L858R 41% A-loop DFG motif L861Q Tyrosine Phosphorylation 22 23 Autophosphorylation 24
IPASS: Study design
EGFR Inhibitors Study Treatment n PFS (mo) OS (mo) Maemondo Gefitinib 114 10.8 27.7 Car / pac 114 54 5.4 26.66 Mitsudomi Gefitinib 88 9.2 36 Cis / doc 89 6.3 39 EURTAC Erlotinib 86 9.7 19.3 87 5.2 19.5 OPTIMAL Erlotinib 83 13.1 Car / gem 72 4.6 LUX-Lung 3 Afatinib 230 11.1 Cis / pem 115 6.9 LUX-Lung 6 Afatinib 242 11.0 Cis / gem 122 5.6
EGFR Inhibitors EGFR mutations ti are associated with very high h RRs (60-90%) to the specific tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib. Almost all patients with these dramatic responses develop acquired resistance. In about 50% of patients, resistance can be attributed to the emergence of clones harboring a second-site mutation in exon 20 (T790M), which alters binding of drug to the receptor. About 5-20% of EGFR mutant tumors from patients with acquired resistance display amplification of a gene encoding a different tyrosine kinase, MET.
EGFR TKI Acquired Resistance Clin Cancer Res 2011;17:5530-7
1 st Generation Gefitinib ib Erlotinib EGFR Tyrosine Kinase Inhibitors EGFR wild type EGFR activating EGFR T790M mutation mutation Yes Yes No 2 nd Generation Yes Yes Yes Afatinib Dacomitinib 3 rd Generation No Yes Yes Osimertinib Rociletinib
First generation (anilino-quinazolines) Gefitinib Erlotinib Lapatinib Second generation (anilino-quinazolines) Neratinib (anilino-cyanoquinoline) Dacomitinib Afatinib Third generation (anilino-pyrimidines) WZ4002 CO-1686 Alex Waterson
EML4-ALK Translocation ALK translocation in ~4% (64 / 1709) of lung adenocarcinoma Younger age, more advanced stage Soda M, et al. Nature 2007;448:561-6
ALK Inhibitors EML4-ALK fusion proteins: These translocations arise from a small inversion within chromosome 2p that t leads to the formation of a fusion-gene comprising the N terminal of the echinoderm microtubule associated protein-like 4 (EML4) gene and the intracellular tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) gene. The ALK fusion protein is relatively rare, occurring in 3-7% of NSCLCs.
ALK Inhibitors Clinical i l characteristics ti associated with EML4- ALK-positive lung cancer appears to be a younger age at diagnosis, minimal smoking history, male gender, and adenocarcinoma histology with signet-ring features. Patients with lung cancers harboring an ALK fusion protein have demonstrated dramatic responses to small-molecule l l ALK inhibitors in early clinical trials.
EML4/ALK ceritinib ceritinib ib alecitinib ceritinib
ALK TKI Acquired Resistance Camidge DR, et al. Nat Rev Clin Oncol 2012;9:268-77
ALK TKI Acquired Resistance Shaw AT, et al. J Clin Oncol 2013;31:1105-11
Other Mutations
Further developments in other mutation subsets of adenocarcinoma
Other Targets HER2 mutations: trastuzumab, afatinib BRAF mutations: vemurafenib, dabrafenib ROS1 rearrangements: crizotinib RET rearrangements: vandetanib, cabozantinib a b
Squamous Carcinoma FGFR1 amplification DDR2 mutations PIK3CA mutations / PTEN loss
Immunotherapy: PD-1 and CTLA4
Immunotherapy in Advanced Disease: PDL-1 Antibodies
Anti-PD-1, PD-L1 Agents in Development
Conclusion Chemotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: histology Adenocarcinoma: pemetrexed / cisplatin Squamous cell carcinoma: gemcitabine / cisplatin Targeted therapy is active in advanced lung adenocarcinoma. Predictive biomarker: driver genetic alterations EGFR mutation: geftinib, erlotinib, afatinib ALK fusion: crizotinib, ceritinib, alectinib Immunotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: tumor cells or immune cells? PD-L1?
Conclusion Chemotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: histology Adenocarcinoma: pemetrexed / cisplatin Squamous cell carcinoma: gemcitabine / cisplatin Targeted therapy is active in advanced lung adenocarcinoma. Predictive biomarker: driver genetic alterations EGFR mutation: geftinib, erlotinib, afatinib ALK fusion: crizotinib, ceritinib, alectinib Immunotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: tumor cells or immune cells? PD-L1?
Conclusion Chemotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: histology Adenocarcinoma: pemetrexed / cisplatin Squamous cell carcinoma: gemcitabine / cisplatin Targeted therapy is active in advanced lung adenocarcinoma. Predictive biomarker: driver genetic alterations EGFR mutation: geftinib, erlotinib, afatinib ALK fusion: crizotinib, ceritinib, alectinib Immunotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: tumor cells or immune cells? PD-L1?
Conclusion Chemotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: histology Adenocarcinoma: pemetrexed / cisplatin Squamous cell carcinoma: gemcitabine / cisplatin Targeted therapy is active in advanced lung adenocarcinoma. Predictive biomarker: driver genetic alterations EGFR mutation: geftinib, erlotinib, afatinib ALK fusion: crizotinib, ceritinib, alectinib Immunotherapy is active in advanced non-small cell lung cancer. Predictive biomarker: tumor cells or immune cells? PD-L1?