Non-Small Cell Lung Cancer

Transcription

1 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

2 Is Chemotherapy Beneficial in NSCLC?

3 Survival Benefit for Chemotherapy vs. BSC Agent Hazard p value Median 1-year ratio survival survival (months) (%) Alkylating agents 1.26 ( ) 0.87 ( ) Vinca or etoposide Cisplatin 0.73 < ( ) BMJ 1995;311:

4 1990 s: Paclitaxel, Docetaxel, Gemcitabine, Vinorelbine New agents 1990 s

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6 Is there a best platinum regimen

7 First-Line Therapy Study n RR (%) OS (mo) ECOG Cisplatin Paclitaxel Cisplatin Gemcitabine Cisplatin Docetaxel Carboplatin Paclitaxel l SWOG Cisplatin Vinorelbine Carboplatin Paclitaxel Scagliotti Cisplatin Gemcitabine Cisplatin Pemetrexed

8 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%

9 Postel-Vinay S, et al. Nat Rev Clin Oncol 2012;9:144-55

10 ERCC1 mrna Customized Trial Cobo M, et al. J Clin Oncol 2007;25:

11 ERCC1 mrna Customized Trial Outcome Control Low High p value ERCC1 genotype ERCC1 genotype n 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:

12 ERCC1 mrna Customized Trial Outcome Control Genotype p value n 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:

13 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

14 Histology and anti-vegf therapy

15 Anti-VEGF: Bevacizumab

16 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:

17 Squamous Cell Carcinoma Shows Higher mrna and Protein Levels for Thymidylate Synthase Ceppi P, et al. Cancer 2006;107:

18 Second Line Therapy 1. Docetaxel 2. Pemetrexed 3. Erlotinib

19 Second-Line Therapy First author Therapy n RR (%) OS (m) PFS (m) 1-yr OS Shepherd Docetaxel 75 mg/m Best supportive care Hanna Pemetrexed 500 mg/m Docetaxel 75 mg/m Shepherd Erlotinib 150 mg Best supportive care Sh h d FA t l J Cli O l Shepherd FA, et al. J Clin Oncol 2000;18: Hanna N, et al. J Clin Oncol 2004;22: Shepherd FA, et al. N Engl J Med 2005;353:123-32

20 Targeted Therapy For Lung Cancer

21 EGFR and ALK

22 Gefitinib (ZD1839) Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)

23 EGFR: the early years

24 Thatcher N, et al. Lancet 2005;366:

25 Thatcher N, et al. Lancet 2005;366:

26 Who will respond to gefitinib? 1. Adenocarcinoma 2. Never smokers 3. Female gender 4. East Asians Thatcher N, et al. Lancet 2005;366:

27 The Discovery of EGFR Mutations in Lung Adenocarcinoma

28 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:

29 Lynch TJ, et al. N Engl J Med 2004;350:

30 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: Paez J, et al. Science 2004;304: Pao W, et al. Proc Natl Acad Sci 2004;101:

31 EGFR Sensitizing Mutations 18 G719X 4% P-loop GXGXXG motif Ligand Binding 19 E746 - A750 deletion 44% αc-helix insertion 5% αc-helix Ligand Binding Transmembrane 21 L858R 41% A-loop DFG motif L861Q Tyrosine Phosphorylation Autophosphorylation 24

32 IPASS: Study design

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35 EGFR Inhibitors Study Treatment n PFS (mo) OS (mo) Maemondo Gefitinib Car / pac Mitsudomi Gefitinib Cis / doc EURTAC Erlotinib OPTIMAL Erlotinib Car / gem LUX-Lung 3 Afatinib Cis / pem LUX-Lung 6 Afatinib Cis / gem

36 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.

37 EGFR TKI Acquired Resistance Clin Cancer Res 2011;17:5530-7

38 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

39 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

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42 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

43 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.

44 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.

45 EML4/ALK ceritinib ceritinib ib alecitinib ceritinib

46 ALK TKI Acquired Resistance Camidge DR, et al. Nat Rev Clin Oncol 2012;9:268-77

47 ALK TKI Acquired Resistance Shaw AT, et al. J Clin Oncol 2013;31:

48 Other Mutations

49 Further developments in other mutation subsets of adenocarcinoma

50 Other Targets HER2 mutations: trastuzumab, afatinib BRAF mutations: vemurafenib, dabrafenib ROS1 rearrangements: crizotinib RET rearrangements: vandetanib, cabozantinib a b

51 Squamous Carcinoma FGFR1 amplification DDR2 mutations PIK3CA mutations / PTEN loss

52 Immunotherapy: PD-1 and CTLA4

53 Immunotherapy in Advanced Disease: PDL-1 Antibodies

54 Anti-PD-1, PD-L1 Agents in Development

55 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?

56 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?

57 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?

58 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?