NSCLC-Targeted Therapy

Transcription

1 NSCLC-Targeted Therapy Sarayut L. Geater Division of Respiratory and Respiratory Critical Care Medicine Department of Internal Medicine Faculty of Medicine Prince of Songkla University

2 COI Honoraria AstraZeneca

3 NSCLC 85-90% of Lung Cancer 85-90% of NSCLC presented with advanced stage

4 NSCLC Sx in early stage Multimodality Rx in locally adv-nsclc Systemic treatment in adv-nsclc

5 Systemic Rx for Adv-NSCLC First, second and third line of treatment First-maintenance, second and third line of treatment

6 NSCLC: Advanced Stage Supportive vs Chemo+Supportive _ Supportive care + chemotherapy --- Supportive care Hazard ratio % reduction in the risk of death 10% improvement in survival at one year Stewart et al, Meta-analysis. BMJ 1995; 311:

7 BMJ1995 ECOG1594, SWOG9509

8 Chemotherapy? Chemotherapy in advanced NSCLC has reached a plateau Novel chemotherapy combinations are not likely to confer substantial improvements in survival 1 Delbaldo C, et al. JAMA 2004;292: National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Non-small cell lung cancer, version Available at:

9 (Thailand) Options Payment methods Availability of the treatment options Patient factors

10 Payment Methods Individual payment scheme Self-paid (out-of-pocket) Traditional medicine Clinical trials

11 Individual Payment Scheme CSMBS UCS SSS Other

12 CSMBS No or minimal limitation OCPA (pre-authorize) Self paid for the limitation

13 UCS and SSS Only NLED PAP: e.g. IPAP Self paid for non-nled

14 Targeted Rx for NSCLC EGFR-TKI ALK-I anti-vegf

15 EGFR TKIs: registration trials in unselected NSCLC <br />ISEL (gefitinib) and BR.21 (erlotinib) Presented By Daniel Costa at 2014 ASCO Annual Meeting

16 Gefitinib: IPASS Study Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light ex-smokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease design Gefitinib (250 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # Endpoints Primary Progression-free survival (noninferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression * Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor Mok et al NEJM 2009

17 Comparison of progression-free survival by mutation status within treatment arms Probability of PFS Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) Gefitinib, HR=0.19, 95% CI 0.13, 0.26, p< No. events M+ = 97 (73.5%) No. events M- = 88 (96.7%) Carboplatin / paclitaxel, HR=0.78, 95% CI 0.57, 1.06, p= No. events M+ = 111 (86.0%) No. events M- = 70 (82.4%) Time from randomisation (months) Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- group M+, mutation positive; M-, mutation negative Mok et al NEJM 2009

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19 Histological subtype? IPASS Study designs: selected adenocarcinoma (or BAC) never/light smoke Subset EGFR??? impact??? Front line TKI!!

20 NEJ002: Trial design Patients EGFR mutationpositive Stage IIIB/IV NSCLC or postoperative relapse Chemonaïve ECOG PS 0-1 Gefitinib (250 mg daily) N=115 1:1 randomisation Carboplatin (AUC 6) / paclitaxel (200 mg / m 2 ) 3-weekly N=115 Endpoints Primary Progression-free survival Secondary Overall survival Objective response rate Toxicity Quality of life Maemondo et al 2010

21 NEJ002: Progressionfree survival

22 NEJ002: Overall survival

23 WJTOG3405: Trial design Patients EGFR mutationpositive Stage IIIB/IV NSCLC or postoperative recurrence Chemonaïve WHO PS 0-1 Gefitinib (250 mg daily) N=86 1:1 randomisation Cisplatin/Docetaxel Every 21 days N=86 Endpoints Primary Progression-free survival Secondary Overall survival Objective response rate Mitsudomi et al 2010

24 WJTOG3405: Progression-free survival HR=0.49, 95% CI ; p< Mitsudomi et al 2010

25 OPTIMAL study design! Chemonaїve! Stage IIIB/IV NSCLC Erlotinib 150mg/day! EGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) Randomization R 1:1! ECOG PS 0 2 (n=165) Carboplatin (AUC5 d1) gemcitabine (1000 mg/m 2 d1,8) q 3w, up to 4 cycles Primary endpoint! Progression-free survival (PFS) Secondary endpoints! Overall survival (OS), objective response rate (ORR), time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analyses Stratification factors! Mutation type! Histology! Smoking status Efficacy assessment! Every 6 weeks Act Mut+ = activating mutations; ECOG = Eastern Cooperative Oncology Group; PS = performance status HRQoL = health-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale

26 OPTIMAL PFS (ITT) PFS probability Erlotinib (n=82) Gem/carbo (n=72) HR=0.16 ( ) Log-rank p< Time (months) Patients at risk Erlotinib Gem/carbo Cut-off date 16 August 2010 Zhou, et al. ESMO 2010

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29 LUX Lung3 LUX-Lung 3: a randomized, open-label, Phase III study of afatinib vs cisplatin/pemetrexed as 1st-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations J.C.-H. Yang, M. Schuler, N. Yamamoto, K. O Byrne, V. Hirsh, T. Mok, S.L. Geater, S. Orlov, C.-M. Tsai, M. Boyer, W.-C. Su, J. Bennouna, T. Kato, V. Gorbunova, K.H. Lee, R. Shah, D. Massey, V. Zazulina, M. Shahidi, L. V. Sequist

30 Study design Stage IIIB (wet)/iv lung adenocarcinoma (AJCC version 6) EGFR mutation in tumor (central lab testing; Therascreen EGFR29* RGQ PCR) Randomization 2:1 stratified by EGFR mutation (Del19/L858R/ other) and race (Asian/non-Asian) Afatinib 40 mg/day Cisplatin + Pemetrexed 75 mg/m mg/m 2 i.v. q21days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO, safety, PK *EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE. Tumor assessments - 6 weekly until Week 48 and 12-weekly thereafter until progression/start of new therapy. Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and 3-weekly until progression or new anti-cancer therapy

31 Primary endpoint: PFS Progression-free survival (probability) % 22% Afatinib n=230 Cis/pem n=115 PFS event, n (%) 152 (66) 69 (60) Median PFS (months) Hazard ratio (95% confidence interval) 0.58 ( ) P= = Number at risk Progression-free survival (months) Afatinib Cis/Pem

32 Time to deterioration in lung cancer-related symptoms Cough

33 Time to deterioration in lung cancer-related symptoms Cough Dyspnea

34 Time to deterioration in lung cancer-related symptoms Cough Dyspnea Pain

35 LUX Lung6 LUX-Lung 6: A randomized, open-label, Phase III study of afatinib vs. gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced adenocarcinoma of the lung Yi-Long Wu 1, Caicun Zhou 2, Cheng-Ping Hu 3, Jifeng Feng 4, Shun Lu 5, Yunchao Huang 6, Wei Li 7, Mei Hou 8, Jian Hua Shi 9, Kye Young Lee 10, Dan Massey 11, Yang Shi 12, Jiongjie Chen 12, Victoria Zazulina 11, Sarayut L Geater 13 1 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2 Shanghai Pulmonary Hospital, Yangpu District, Shanghai, China; 3 Dept. of Pulmonary Medicine, Xiangya Hospital, Central South University, Changsha, China; 4 Department of Medical Oncology, Jiangsu Provincial Cancer Hospital, Nanjing, Jiangsu, China; 5 Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, China; 6 Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China; 7 Cancer Center, First Hospital of Jilin University, Changchun, China; 8 West China Hospital, Sichuan University, Chengdu, Sichuan, China; 9 Lin Yi Tumor Hospital, Linyi, Shandong Province, China; 10 Konkuk University Medical Center, Seoul, Korea; 11 Boehringer Ingelheim Limited, Bracknell, UK; 12 Boehringer Ingelheim Int'l Trading (Shanghai) Co., Ltd., Shanghai, China; 13 Division of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand

36 LUX-Lung 6 study design Asian patients (China, South Korea, Thailand) Stage IIIB (wet)/iv lung adenocarcinoma (based on AJCC 6th edition) EGFR mutation in the tumour* No prior treatment for advanced disease, no prior EGFR TKI ECOG PS 0 or 1 Randomization (2:1) Stratified by mutation (Del19/L858R/ other) Afatinib 40 mg/day Gemcitabine + cisplatin 1000 mg/m 2 Day 1, Day mg/m 2 i.v. q21 days, up to 6 cycles Primary endpoint: Progression-free survival (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO, safety *Central lab testing; Therascreen EGFR29 RGQ PCR detecting 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. Dose escalated to 50 mg if limited adverse events (AEs) observed in Cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AEs. Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy. Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy. AJCC = American Joint Committee on Cancer; EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; ECOG PS = Eastern Cooperative Oncology Group performance status; i.v. = intravenous; q = every; RECIST = Response Evaluation Criteria In Solid Tumors; ORR = overall response rate; DCR = disease control rate; DoR = duration of response; OS = overall survival; PRO = patient-reported outcome.

37 Primary endpoint: PFS by independent review (all randomized patients) PFS significantly prolonged with afatinib compared to chemotherapy 1.0 Afatinib (n=242) Gem/cis (n=122) Progression-free survival (probability) % Median PFS (months) Hazard ratio (95% CI) ( ) Afatinib Gem/cis p< % Number at risk Progression-free survival (months) Afatinib Gem/cis PFS = progression-free survival; CI = confidence interval; gem/cis = gemcitabine/cisplatin.

38 Primary endpoint: PFS by independent review (all randomized patients) in LUX-Lung 6 and LUX-Lung 3 PFS findings with afatinib were consistent between trials 1.0 LUX-Lung 6 LUX-Lung 3 Progression-free survival (probability) % 22% 47% Median PFS (months) Hazard ratio (95% CI) Afatinib (n=242) Gem/cis (n=122) Afatinib (n=230) Pem/cis (n=115) ( ) p< ( ) p= Afatinib LUX-Lung 6 Gem/cis LUX-Lung 6 Afatinib LUX-Lung 3 Pem/cis LUX-Lung 3 2% Number at risk Progression-free survival (months) Afatinib (LL6) Gem/cis (LL6) Afatinib (LL3) Pem/cis (LL3) Gem/cis = gemcitabine/cisplatin; pem/cis = pemetrexed/cisplatin; PFS = progression-free survival; CI = confidence interval.

39 Afatinib delayed time to deterioration for cough, dyspnoea and pain compared with chemotherapy Time to deterioration in lung cancer-related symptoms Estimated probability Cough Median time to deterioration (months) Hazard ratio (95% CI) Afatinib (n=242) Gem/cis (n=122) NE ( ) p= Estimated probability Dyspnoea Median time to deterioration (months) Hazard ratio (95% CI) Afatinib (n=242) Gem/cis (n=122) ( ) p< Number at risk Time to deterioration (months) Afatinib Gem/cis Number at risk Time to deterioration (months) Afatinib Gem/cis Afatinib Gem/cis Estimated probability Pain Median time to deterioration (months) Hazard ratio (95% CI) Afatinib (n=242) Gem/cis (n=122) ( ) p= Gem/cis = gemcitabine/cisplatin; CI = confidence interval.; NE = not evaluable Number at risk Time to deterioration (months) Afatinib Gem/cis

40 Summary: EGFR mutation NSCLC Study IPASS WJTOG3405 NEJ002 EURTAC OPTIMAL LUXLung 3 LUXLung 6 Treatments Gefitinib vs Carboplatin/Paclitaxel (up to 6 cycles) Gefitinib vs Cisplatin/ Docetaxel (up to 6 cycles) Gefitinib vs Carboplatin/ Paclitaxel (at least 3 cycles) Erlotinib vs Cisplatin (or Carboplatin) plus Docetaxel or Gemcitabine (up to 4 cycles) Erlotinib vs Carboplatin/ Gemcitabine (up to 4 cycles) Afatinib vs Cisplatin/ Pemetrexed up to 6 cycles Afatinib vs Cisplatin/ Gemcitabine up to 6 cycles N ORR TKI vs CMT EGFR-mt Median PFS TKI vs CMT PFS HR [95% C.I.] % vs 47% 9.5 mo vs 6.3 mo 0.48 [ ] % vs 32% 9.2 mo vs 6.3 mo 0.49 [ ] % vs 31% 10.8 mo vs. 5.4 mo 0.30 [ ] % vs 15% 9.7 mo vs 5.2 mo 0.37 [ ] % vs 36% 13.1 mo vs 4.6 mo 0.16 [ ] % vs 23% 11.1 mo vs 6.9 mo 0.58 [ ] % vs 23% 11.0 mo vs 5.6 mo 0.28 [ ] ORR=overall response rate. HR=hazard ratio. C.I.=confidence interval. TKI=tyrosine kinase inhibitor. CMT=chemotherapy. PFS=progression free survival. mo=month

41 EGFR mutations in NSCLC Presented By Daniel Costa at 2014 ASCO Annual Meeting

42 EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR (2) Presented By Daniel Costa at 2014 ASCO Annual Meeting

43 ErbB receptor signal transduction

44 How do EGFR kinase mutations cause lung cancer? After a decade of research... our understanding is greatly improved but not complete Mutations lower the energy requirement for transition from inactive to Super-acceptor active concept conformation for EGFR mutations Mutations promote formation of asymmetric dimers with high catalytic activity ( super-acceptor concept) Dimers of mutant and wild-type kinases are essential for signaling Gajiwala KD et al Structure 2013; 21: Littlefield P, Jura N. Proc Natl Acad Sci USA 2013;110:

45 EGFR TKIs and EGFR mutated NSCLC:<br />Understanding the concepts of:<br />A. oncogene addiction<br />B. therapeutic window in relation to EGFR wild-type [WT] Presented By Daniel Costa at 2014 ASCO Annual Meeting

46 Different EGFR mutated NSCLCs and EGFR TKIs<br />(different therapeutic windows in relation to EGFR WT) Presented By Daniel Costa at 2014 ASCO Annual Meeting

47 Angiogenesis in primary tumour growth and metastasis Tumour is dormant Angiogenic switch Neovascularisation Hypoxia Facilitates rapid tumour growth by supplying oxygen and nutrients Facilitates metastasis Somatic mutation Small avascular tumour Tumour secretes pro-angiogenic factors Rapid tumour growth and metastasis Initiation Proliferation Maturation Bergers G, Benjamin LE. Nat Rev Cancer 2003;3:401 10

48 Anti-VEGF therapy: therapeutic implications Effect of anti-vegf therapy Regression of existing microvasculature Normalisation of surviving mature vasculature Clinical implications Increase in tumour response across treatment regimens Potential to combine effectively with other anticancer agents and enhance effects Early effects Inhibition of new and recurrent vessel growth Extended survival and delay of disease progression Maintenance of response through sustained inhibition of tumour growth Continued effects Poon RT et al. J Clin Oncol 2001;19(4):

49 Historical development of anti-angiogenic agents 1990s First generation 2000s Second generation 2010s Third generation Thalidomide Interferon-α Tecogalan Minocycline Suramin TNP-470 MMPIs Bevacizumab (now integrated in standard care) Endogenous anti-angiogenics: endostatin, angiostatin TKIs (VEGFR ± PDGFR) Angiokinase inhibitors that target multiple pathways e.g. VEGFR, FGFR, PDGFR New targets e.g. Ang1/2 inhibitors VEGFR2 mab: ramucirumab Ang, angiopoietin; FGFR, fibroblast growth factor receptor; mab, monoclonal antibody MMPIs, matrix metalloproteinase inhibitors PDGFR, platelet-derived growth factor receptor Shepherd FA. Lung Cancer 2001;34(suppl 3):81 89; Horn L, Sandler AB. Clin Lung Cancer 2009;10(suppl 1):S7 16; Perol M, et al. J Clin Oncol 2014;32s (abstract LBA8006)

50 Two landmark phase III trials with bevacizumab E Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP x 6 (n=444) BEV (15 mg/kg) every 3 weeks + CP x 6 (n=434) BEV PD* PD *No crossover permitted; CP, carboplatin/paclitaxel; CG, cisplatin/gemcitabine 1 Sandler, et al. N Engl J Med 2006;355: ;

51 Two landmark phase III trials with bevacizumab E Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP x 6 (n=444) BEV (15 mg/kg) every 3 weeks + CP x 6 (n=434) BEV PD* PD AVAiL 2 Placebo + CG x 6 (n=347) PD* Previously untreated, stage IIIB, IV or recurrent nonsquamous NSCLC (n=1,043) BEV (15 mg/kg) every 3 weeks + CG x 6 (n=351) BEV PD BEV (7.5mg/kg) every 3 weeks + CG x 6 (n=345) BEV PD *No crossover permitted; 2 Reck M et al J Clin Oncol 2009;27: CP, carboplatin/paclitaxel; CG, cisplatin/gemcitabine 1 Sandler, et al. N Engl J Med 2006;355: ;

52 Experience with bevacizumab: meta-analysis of efficacy Meta-analysis confirmed that both OS and PFS in patients with NSCLC primarily of nonsquamous histology are significantly improved by bevacizumab treatment OS Trial HR HR (95% CI) AVF-0757g ( )* AVF-0757g ( )* ECOG ( ) AVAiL ( ) AVAiL ( ) JO ( ) PFS HR HR (95% CI) 0.76 ( ) 0.52 ( ) 0.66 ( ) 0.75 ( ) 0.85 ( ) 0.55 ( ) Total 0.90 ( ) p= ( ) p< Favours bevacizumab 1.0 Favours control 1.5 Test for heterogeneity, 2.0 p= Favours bevacizumab 1.0 Favours 1.5 control Test for heterogeneity, p=0.17 *The direction of the OS HR for the AVF-0757g trial was unknown; worst scenario has been chosen CI, confidence interval; ECOG, Eastern Cooperative Oncology Group HR, hazard ratio; PFS, progression-free survival Soria JC, et al. Ann Oncol 2013;24:20 30

53 Bevacizumab also shows promise in a maintenance setting Results from 4 independent clinical trials and details of an ongoing trial ATLAS 1 Maintenance BEV + erlotinib (n=370) vs BEV + placebo (n=373) PFS (primary endpoint): 4.8 vs 3.7 months (P<0.001) OS: 14.4 vs 13.3 months (P=0.5341) AVAPERL 2,3 Maintenance BEV (n=125) vs PEM./BEV (n=128) PFS (primary endpoint): 3.7 vs 7.4 months (P<0.001) OS: 15.9 vs 19.8 months (P=NS) POINTBREAK 4 Maintenance PEM/BEV (n=292) vs BEV (n=298) PFS: 6.0 vs 5.6 months (P=0.012) OS (primary endpoint): 12.6 vs 13.4 months (P=0.949) PRONOUNCE 5 Maintenance PEM (n=98) vs BEV (n=95) G4PFS (primary endpoint): 3.9 vs 2.9 months (P=NS) OS: 10.5 vs 11.7 months (P=NS) ECOG 6 Trial ongoing Assessing BEV vs PEM vs PEM/BEV Primary endpoint: OS BEV, bevacizumab; G4PFS, PFS without Grade 4 toxicity; NA, not available; PEM, pemetrexed Results are from independent clinical trials with different methodologies and therefore cannot be directly compared 1. Johnson BE et al. J Clin Oncol 2013;31: , 2. Barlesi F et al J Clin Oncol 31: ; 3. Barlesi F, et al. Ann Oncol 2014;25: ; 4. Patel JD, et al J Clin Oncol 2013;31: , 5. Zinner R, et al ASCO 2013, abstract LBA 8003; 6. NCT

54 Bevacizumab also shows promise in a maintenance setting AVAPERL achieved its primary endpoint Barlesi F, et al. J Clin Oncol 2013;31:

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58 PROFILE 1007 The new england journal of medicine original article Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer Alice T. Shaw, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Ph.D., Takashi Seto, M.D., Lucio Crinó, M.D., Myung-Ju Ahn, M.D., Tommaso De Pas, M.D., Benjamin Besse, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Fiona Blackhall, M.D., Ph.D., Yi-Long Wu, M.D., Michael Thomas, M.D., Kenneth J. O Byrne, M.D., Denis Moro-Sibilot, M.D., D. Ross Camidge, M.D., Ph.D., Tony Mok, M.D., Vera Hirsh, M.D., Gregory J. Riely, M.D., Ph.D., Shrividya Iyer, Ph.D., Vanessa Tassell, B.S., Anna Polli, B.S., Keith D. Wilner, Ph.D., and Pasi A. Jänne, M.D., Ph.D.

59 PROFILE 1007 A Progression-free Survival Probability of Progression-free Survival (%) No. at Risk Crizotinib Chemotherapy Hazard ratio for progression or death in the crizotinib group, 0.49 (95% CI, ) P< Chemotherapy Crizotinib Months B Progression-free Survival with Crizotinib vs. Pemetrexed or Docetaxel Probability of Progression-free Survival (%) No. at Risk Crizotinib Pemetrexed Docetaxel Hazard ratio for progression or death, 0.59 (95% CI, ) P<0.001 (vs. pemetrexed) Hazard ratio for progression or death, 0.30 (95% CI, ) P<0.001 (vs. docetaxel) Crizotinib Doxcetaxel Months Pemetrexed

60 PROFILE 1007 A Overall Change from Baseline in Symptoms and Global QOL Reduction in Symptom Score Mean Change from Baseline P<0.001 for all comparisons Alopecia Cough Dyspnea Crizotinib Fatigue Pain in Chest Chemotherapy Pain in Arm or Shoulder Pain in Other Parts Global QOL Mean Change from Baseline Improvement in Global QOL B Time to Deterioration with Respect to a Composite Lung-Cancer-Symptom End Point Probability of No Deterioration (%) No. at Risk Crizotinib Chemotherapy Hazard ratio, 0.54 (95% CI, ) P< Chemotherapy 25 8 Months Crizotinib

61 Targeted in Thailand Gefitinib, erlotinib, (afatinib soon) Bevacizumab Crizotinib

62 Limitation for EGFR-TKI CSMBS OCPA: Gefitinib / erlotinib only 2nd-3rd line UCS and SSS: self-paid only (or PAP)

63 Clinical Impact of Applying Iressa Patient Access Program (IPAP) to non-civil Services Medical Benefit Scheme (non-csmbs) in Advanced Stage, non-small Cell Lung Cancer (adv-nsclc) in Songklanagarind Hospital Pathamaporn Siriratsattayagul M.D. Sarayut L. Geater. M.D.

64 Non-CSMBS First_line CMT Second_line CMT First_line CMT IPAP Second_line CMT IPAP First_line CMT Second_line CMT First_line CMT Second_line CMT IPAP

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66 Limitation for Bevacizumab Only self-paid for all payment scheme

67 Limitation for ALK-inhibitor CSMBS: 2nd line ALK +ve (FISH) NSCLC with good explanation UCS and SSS: self-paid only

68 Any Question? Thank you for attention