İleri Evre Nonskuamoz KHDAK Sistemik Tedavisinde Güncel Yaklaşım Dr. Özden Altundağ Başkent Üniversitesi Medikal Onkoloji 14 Mayıs 2013

NSCLC-Evreye Göre Dağılım Scagliotti GV, JCO 2008

Akciğer Kanseri Subtipleri WHO klasifikasyonu: 4 majör histolojik tip *Adenoskuamöz Ca, Pleomorfik, Sarkomatoid Ca, Karsinoid, Salivary gland tipi adenoca, Klasifiye edilemeyen Ca Diğer* %24.0 AdenoCa %38.3 TTF1, cytokeratin 7 &Mucin…Adenoca P63 & cytokeratin 5/6…Squamous cell Ca Discontinue use the term of BAC, mainly because of the absence of standardised criteria across disciplines Micropapiller lepidic, papillary, aciner, solid…%95 (Predominant histologic patterns) COMMON GENE MUTATIONS AND GENE PROFILING… MUCINOUS ADENOCA…Typically KRAS Mut (+), EGFR Mut (-). Presenting with multicentric consolidation, perhaps reflecting aerogenous spread.. Clear ve signed ring kullanılmıyor. Ancak Signed ring morphology to the EML4-ALK gene fusion mutation.. Large-cell Ca % 5 Small-cell %13 Skuamoz cell %19.7 SEER Database, 2004 3

Evre IV NSCLC hastaları 39y, kadın never-smoker, adenoca NSCLC Heterojenitesi Evre IV NSCLC hastaları 39y, kadın never-smoker, adenoca EGFR Mt Yıl 2013: Çoğu onkolog NSCLC nin tek hastalık olmadığı konusunda hemfikir Çoğu onkolog bu hastaların farklı tedaviler alması konusunda hemfikir

Evre IV NSCLC hastaları NSCLC Heterogenitesi Evre IV NSCLC hastaları 65y, erkek smoker, skuamöz 39y, kadın never-smoker, adenoca KRAS Mt EGFR Mt Yıl 2013: Çoğu onkolog NSCLC nin tek hastalık olmadığı konusunda hemfikir Çoğu onkolog bu hastaların farklı tedaviler alması konusunda hemfikir

Evre IV NSCLC hastaları NSCLC Heterogenitesi Evre IV NSCLC hastaları 65y, erkek smoker, skuamöz 39y, kadın never-smoker, adenoca KRAS Mt EGFR Mt 54y, erkek never-smoker, adenoca ALK füzyon Yıl 2013: Çoğu onkolog NSCLC nin tek hastalık olmadığı konusunda hemfikir Çoğu onkolog bu hastaların farklı tedaviler alması konusunda hemfikir

1995 META-ANALİZİ P=0.0001 Destek tedavisi+Kemoterapi Destek tedavisi Randomizasyondan sonra geçen süre (aylar) 6 12 18 24 Sağkalım 10 20 30 40 50 60 70 80 90 100 11 çalışma, 1190 hasta Cisplatin-bazlı kemoterapi destek tedeviden üstün (HR:0.73) NSCLC Collaborative Group, BMJ 1995

ECOG 1594: 4 First-line Doublet Referans kolu Paclitaxel 135 mg/m2 Cisplatin 75 mg/m2 3-hft Gemcitabine 1000 mg/m2 1, 8, 15. günler Cisplatin 100 mg/m2 1. gün 4-hft İleri evre, 1. basamak NSCLC (N = 1207) Docetaxel 75 mg/m2 Cisplatin 75 mg/m2 3-hft Platinum based doublet is recommended for fit pts and single agents can be offered in elderly pts or poor PS… Stratifikasyon: ECOG PS (0/1 vs 2) Son 6 ayda kilo kaybı (< % 5 vs %≥ 5) Evre (IIIB vs IV ya da rekürren) Beyin metastazları (var/yok) Paclitaxel 225 mg/m2 Carboplatin AUC 6.0 mg/mL/min 3-hft Schiller JH, NEJM 2002 8

ECOG 1594-OS Schiller JH, NEJM 2002

ECOG 1594 P=0.001 Schiller JH, NEJM 2002

ECOG 1594 P=0.001 Schiller JH, NEJM 2002

ECOG 1594 P=0.001 Schiller JH, NEJM 2002

Randomizasyondan sonra geçen süre SWOG 9509 100 80 60 40 20 Cisplatin/paclitaxel Cisplatin/vinorelbine Sağkalım Oranı 0 12 24 36 48 Randomizasyondan sonra geçen süre Kelly, JCO 2001

NSCLCCG 2008 META-ANALİZİ 16 randomize kontrollü çalışma 2174 hasta (bireysel hasta datası) Yaş, cinsiyet, evre, histolojik subgrup ve PS ile değişmiyor 1995 metaanalizinden sonra ilk metaanaliz HR 0.78 Burdett S, JCO 2008

Prediktif biyomarkerlar İleri Evre NSCLC 2013 Histoloji İdame Prediktif biyomarkerlar Gandara DR Clin Lung Cancer. 2009 15

Carboplatin Cisplatinden Daha Az mı Etkili? CISCA Meta-analiz 2968 hasta (9 çalışma) Cis ya da Carbo randomize edilmiş. RR: Cis > carbo (% 30 cis; % 24 carbo) Overall survivalde anlamlı faklılık yok Subgrup analiz: Survival: Cis > Carbo (3. jenerasyon ajanlarla kombine edildiğinde ve non-skuamöz histolojide) Cisplatin-bazlı kemoterapi: Köşetaşı Ardizzoni et al, JNCI 2007

Hipotez: NSCLC Tedavisi Histoloji Bazlı Olmalıdır Pemetrexed ile skuamoz vs nonskuamoz histolojilerde farklı etkinlik JMDB: 1. basamak tedavide Pemetrexed/cisplatin vs Gemcitabine/cisplatin[1] JMEI: 2. basamak tedavide Pemetrexed vs docetaxel[2] JMEN: İİdame tedavide Pemetrexed vs plasebo[3] Cisplatin/Pemetrexed is superior to cisplatin/Gemcitabine, although o interaction by histological subtype was shown in trial that compared pemetrexed/carboplatin with gemcitabine/carboplatin…   This hypothesis that treatment of non-small-cell lung cancer should be histology based is related to the observation primarily that there is differential activity of pemetrexed in squamous vs nonsquamous subtypes of non-small-cell lung cancer, and that is from 3 studies as shown here. 1. Scagliotti GV. J Clin Oncol. 2008 2. Otani S. Gan To Kagaku Ryoho. 2012 3. Greenhalgh J. Health Technol Assess. 2010;14(suppl 2)

JMDB: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin PC Pemetrexed 500 mg/m2 Cisplatin 75 mg/m2 (n = 862) Evre IIIB / IV ECOG 0,1 Kemonaive GC Gemcitabine 1250 mg/m2 1, 8. Cisplatin 75 mg/m2 (n = 863) Scagliotti GV, JCO 2008

JMDB: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin Non-Skuamöz Skuamöz p = 0.011 p = 0.051 Scagliotti GV, JCO 2008

ECOG 4599: Faz III-Bevacizumab-Nonskuamöz NSCLC PC Paclitaxel 200 mg/m2 Carboplatin AUC = 6 mg/mL/min (n = 444) Evre IIIB / IV Nonskuamöz histoloji ECOG 0,1 Beyin metastazı yok (N = 878) PCB PC x 6 kür + Bevacizumab 15 mg/kg hastalık progresyonuna kadar (n = 434) Sandler A, NEJM 2006

ECOG 4599 6.2 vs 4.5 ay 12.3 vs 10.3 ay Sandler A, NEJM 2006 Interesting that subgrouping the genders revealed survival advantage only for men, not women. AVAIL çalışmasında da GC ile Bevacizumabla hem yanıt oranları hem de PFS daha iyi ancak OS farkı yok EKİM 2006 da FDA APPROVAL ALDI Sandler A, NEJM 2006

FLEX ÇALIŞMASI Pirker R, Lancet. 2009; Pirker R, WCLC 2011. AbsO-01.06.

FLEX ÇALIŞMASI Pirker , Lancet 2009

FLEX ÇALIŞMASI Pirker , Lancet 2009 Although all trials showed increased response rates with cetuximab, most failed to confirm either a significant or clinically meaningful survival benefit….For that reason, cetuximab has not been approved for treatment of NSCLC… Pirker , Lancet 2009

FLEX Sağkalım: Yüksek EGFR Ekspresyonu Skuamoz Cell Ca (N = 144) 100 Sağkalım Median, ay 1 Yıl, % 11.2 44 8.9 25 80 CT + cetuximab CT 60 HR: 0.62 (%95 CI: 0.43-0.88) OS (%) 40 For response rate, progression-free survival and overall survival, patients with high H-scores benefitted whereas patients with low scores did not by comparison with patients receiving chemotherapy alone. 20 6 12 18 24 30 Aylar Pirker R, Lancet. 2009; Pirker R, WCLC 2011. AbsO-01.06. 25

Prediktif biyomarkerlar İleri Evre NSCLC 2013 Histoloji İdame Prediktif biyomarkerlar Many predictive and prognostic markers have been assessed in NSCLC, but until recently no single molecular marker has been shown to be useful for either patient selection or selection of spesific drugs. Gandara DR Clin Lung Cancer. 2009 26

FLEX: IHC Skoruna göre Yanıt ve OS FLEX: EGFR ekspresyon düzeylerine göre RR (IHC skor) KT+Cetuximab: Yüksek EGFRnin sağkalım yanıtında prediktif değeri Düşük EGFR Ekspresyon (< 200), n = 776 (%69) Yüksek EGFR Ekspresyon (≥200), n = 345 (%31) Düşük EGFR Yüksek EGFR HR: 0.99 HR: 0.73 44.4 100 80 32.6 60 29.6 28.1 OS (%) 40 20 There was a modest survival benefit in this trial overall, which on recent analysis, was amplified in those patients who had a great deal of EGFR protein expression in their cancer by an immunohistochemistry H-score. 1/3 of patients had high EGFR IHC expression, demographics balanced on low vs high groups Marginal benefit nedeniyle FDA onayı yok… Aylar 6 12 18 24 30 P = .36 P = .002 Aylar Interaksiyon P = .044 Tedavi interaksiyon test P = .040 CT + cetuximab CT + cetuximab CT CT Pirker R, Lancet. 2009; Pirker R, WCLC 2011. AbsO-01.06.

Metastatik NSCLC-TKI (Gefitinib) IDEAL 1, 2: Mayıs 2003 Gefitinib hızlandırılmış onay No controlled gefitinib trials to date demonstrate a clinical benefit, such as improvement diasease related symptoms or greater survival. Accelerated approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit. Based on the data from two pivotal phase II trials, IDEAL (Iressa dose evaluation in advanced lung cancer) 1 and 2 (Fukuoka, Kris), gefitinib 250 mg dose daily was approved for use in patients with previously treated advanced NSCLC. Cohen MH, The Oncologist, 2003

ISEL-Sağkalım (#1129) Aralık 2004 te Gefitinib onayı geri çekildi Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never smokers and patients of Asian origin. Planlanmamış subgrup analizlerinde: Never smoker ve Asya orijinlilerde daha uzun sağkalım Thatcher N, Lancet 2005

Gefitinib+Kemoterapi Kemoterapi ile kombine kullanımda etkinlik ya da sağkalımda iyileşme yok. INTACT 1: Gemcitabine/Cisplatin+Gefitinib INTACT 2: Paclitaxel/Carboplatin+Gefitinib Giaccone G JCO 2004; Herbst R JCO 2004

EGFR Mutasyon ve Gefitinib Yanıtı Hasta No Cins Yaş Patoloji Önceki tedavi sayısı Sigara Tedavi süresi (ay) OS (ay) EGFR Mut Yanıt 1 K 70 BAC 3 Hiç 15.6 18.8 Evet Major 2 E 66 > 14.0 64 Adeno 9.6 12.9 Parsiyel 4 81 Önceden > 13.3 > 21.4 Minor 5 45 > 14.7 6 32 > 7.8 7 62 > 4.3 8 58 11.7 17.9 9 42 > 33.5 Hayır Adeno, adenocarcinoma; BAC, bronchioloalveolar carcinoma; NSCLC, non-small-cell lung cancer; OS, overall survival.   Here, we see the basis for this. This is one of the initial publications from the New England Journal of Medicine by Dr. Lynch and colleagues, in which they defined a group of patients who benefitted from gefitinib therapy. The same would be true for erlotinib. You can see in this small group of patients who were found to have EGFR mutation that they tended to be women, they tended to be younger, and they tended to have adenocarcinoma or what we call bronchioloalveolar carcinoma. They tended to be never-smokers. These were the clinical characteristics that were taken forward. Lynch TJ, NEJM 2004; Paez JG, Science 2004

EGFR Mutasyon ve Gefitinib Yanıtı Hasta No Cins Yaş Patoloji Önceki tedavi sayısı Sigara Tedavi süresi (ay) OS (ay) EGFR Mut Yanıt 1 K 70 BAC 3 Hiç 15.6 18.8 Evet Major 2 E 66 > 14.0 64 Adeno 9.6 12.9 Parsiyel 4 81 Önceden > 13.3 > 21.4 Minor 5 45 > 14.7 6 32 > 7.8 7 62 > 4.3 8 58 11.7 17.9 9 42 > 33.5 Hayır Adeno, adenocarcinoma; BAC, bronchioloalveolar carcinoma; NSCLC, non-small-cell lung cancer; OS, overall survival.   Here, we see the basis for this. This is one of the initial publications from the New England Journal of Medicine by Dr. Lynch and colleagues, in which they defined a group of patients who benefitted from gefitinib therapy. The same would be true for erlotinib. You can see in this small group of patients who were found to have EGFR mutation that they tended to be women, they tended to be younger, and they tended to have adenocarcinoma or what we call bronchioloalveolar carcinoma. They tended to be never-smokers. These were the clinical characteristics that were taken forward. Lynch TJ, NEJM 2004; Paez JG, Science 2004

EGFR Mutasyon ve Gefitinib Yanıtı Lynch TJ, NEJM 2004; Paez JG, Science 2004

BR.21 (Erlotinib vs Plasebo): OS CI, confidence interval; HR, hazard ratio; NSCLC, non-small-cell lung cancer; OS, overall survival; SD, stable disease.   This slide shows that survival curve for BR21. This difference between 4.7 and 6.7 months cannot be explained by EGFR mutation rate in this study. It has been checked and it does not account for this difference. It is not actually primarily a difference that is even explained by response. It is explained by the results of increased stable disease and increased disease control rate. In my opinion, this is the difference between cytotoxic and cytostatic effects. This primarily reflects a cytostatic effect of erlotinib in patients with wild-type EGFR cancers. I will show you this on the next slide. This same effect may be true for cetuximab, and that is being tested right now. Shepherd FA, NEJM 2005 TARCEVA® (erlotinib) PI. 2005. Data on file, OSI Pharmaceuticals, Inc.

BR.21 (Erlotinib vs Plasebo): OS CI, confidence interval; HR, hazard ratio; NSCLC, non-small-cell lung cancer; OS, overall survival; SD, stable disease.   This slide shows that survival curve for BR21. This difference between 4.7 and 6.7 months cannot be explained by EGFR mutation rate in this study. It has been checked and it does not account for this difference. It is not actually primarily a difference that is even explained by response. It is explained by the results of increased stable disease and increased disease control rate. In my opinion, this is the difference between cytotoxic and cytostatic effects. This primarily reflects a cytostatic effect of erlotinib in patients with wild-type EGFR cancers. I will show you this on the next slide. This same effect may be true for cetuximab, and that is being tested right now. Shepherd FA, NEJM 2005 TARCEVA® (erlotinib) PI. 2005. Data on file, OSI Pharmaceuticals, Inc.

BR.21: Erlotinib Genel Sağkalımı Uzatıyor-2./3. basamak Sonuç Erlotinib Plasebo HR P Değeri 1 yıl survival, % 31 21 -- Median OS, aylar 6.7 4.7 0.70 .001 Tek değişkenli analizde uzun sağkalımı etkileyen faktörler: Erlotinib tedavisi (P = .002) Asya kökenli (P = .01) Adenokarsinom (P = .004) Sigara içmemiş (P = .048) Kasım 2004 yılında Erlotinib 2. ve 3. basmak tedavşde FDA onayı aldıç Shepherd FA, NEJM 2005

IPASS ÇALIŞMASI 1:1 Primer endpoint: RFS From March 2006 through October 2007, a total of 1217 patients from 87 centers in Hong Kong,elsewhere in China, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand were randomly assigned to a study group Primer endpoint: RFS Sekonder endpointler: ORR, OS, QOL Diğer: EGFR mutasyonları, gen amplifikasyonu, ekspresyon Mok TS, NEJM 2009

IPASS: EGFR Mut (+) ve (-) Hastalarda PFS EGFR Mutasyon Pozitif EGFR Mutasyon Negatif Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) 1.0 1.0 HR: 0.48 (P < .0001) HR: 2.85 (P < .0001) 0.8 0.8 0.6 0.6 PFS PFS CI, confidence interval; C/P, carboplatin/paclitaxel; HR, hazard ratio; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.   On the next slide, we see that the results of this study were dictated by whether the patient had an underlying EGFR mutation. The overall progression-free survival actually showed a crossover and that was explained by what is seen here. In those patients who had tissue available, it was tested for EGFR mutation. If it was positive, the patients did better with gefitinib. If it was wild type, meaning no mutation, the patient actually benefitted more from chemotherapy. So, as shown, clinical characteristics are insufficient for selection of first line EGFR TKI therapy. Frontline EGFR TKI therapy outside of a clinical trial should, by and large, be restricted to patients who have an activating mutation. 0.4 0.4 0.2 0.2 4 8 12 16 20 24 4 8 12 16 20 24 Aylar Aylar Mok TS, N EJM 2009 38

EURTAC: Erlotinib vs KT EGFR Mutasyon (+) Mutasyon tipine göre stratifikasyon*, ECOG PS (0 vs 1 vs 2) Erlotinib 150 mg/gün PD Daha önceden KT almamış, stage IIIB/IV, mutated EGFR* (N = 174) Platinum Doublet† q3w x 4 kür PD Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled 42 hospitals in France, Italy, and Spain *Exon 19 delesyon ya da exon 21 L858R mutasyon. †Cisplatin /docetaxel; cisplatin/gemcitabine; carboplatin/docetaxel; carboplatin/gemcitabine Rosell R, Lancet Oncology 2012

EURTAC: PFS Erlotinible belirgin PFS avantajı 1.0 Erlotinib (n = 86) Kemoterapi (n = 87) 0.8 0.6 HR: 0.37 (log-rank P < .0001) 5.2 9.7 PFS Olasılığı 0.4 For patients who are EGFR-mutation positive, there was a significant advantage to treating with erlotinib first-line compared with chemotherapy first-line in terms of progression-free survival. The median progression-free survivals were 9.7 months vs 5.2 months. 0.2 3 6 9 12 15 18 21 24 27 30 33 Aylar Rosell R, Lancet Oncology 2012

LUX-Lung 3: First-line Afatinib vs Cisplatin/Pemetrexed EGFR+ NSCLC Afatinib: ERB ailesi reseptörlerini irreversibl bloke eder Faz II LUX-Lung 2: EGFR mutant AC Ca da aktif (del(19) and L858R mutasyonları) Stratifikasyon:EGFR mutasyon (del[19], L858R, diğer) ve Asyalı Afatinib 40* mg/day Progresyona kadar EGFR, epidermal growth factor receptor; IV, intravenous; NSCLC, non-small-cell lung cancer. Önceden tedavi almamış EGFR mutasyon (+) stage IIIB (wet)/IV Akciğer AdenoCa (N = 345) Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV 21 günde bir 6 kür (n = 115) Yang JC, ASCO 2012

Cisplatin/Pemetrexed (n = 115) LUX-Lung 3: Sonuçlar Sonuçlar Afatinib (n = 230) Cisplatin/Pemetrexed (n = 115) P Değeri PFS, tüm hastalar Median PFS, ay 12-mo PFS, % 11.1 47 6.9 22 .0004 (HR: 0.58) PFS, del(19) or L858R (n = 204) 13.6 51 (n = 104) 21 < .0001 (HR: 0.37) ORR, tüm hastalar, % 69.1 44.3 < .001 Median yanıt süresi, ay 5.5 -- ORR, del(19) or L858R, % 75 43.3 < .0001 Yang JC, ASCO 2012

2. Basamak Tedavi

Docetaxel :TAX 317 ve TAX 320 TAX 317 (N = 103) TAX 320 (N = 103) Stage IIIB/IV NSCLC Daha önceden platin bazlı tedavi almış Docetaxel vs BSC TAX 320 (N = 103) Lokal ileri evre/Metastatik NSCLC Docetaxel vs vinorelbine ya da ifosfamide BSC, best supportive care; NSCLC, non-small-cell lung cancer Shepherd F, JCO 2000 Fossella FV, JCO 2000

TAX 317 Shepherd F, JCO 2000

TAX 320 Çalışması Fossella FV, JCO 2000

Faz III-Pemetrexed vs Docetaxel Hanna N, JCO 2004

BR.21 (Erlotinib vs Placebo): OS CI, confidence interval; HR, hazard ratio; NSCLC, non-small-cell lung cancer; OS, overall survival; SD, stable disease.   This slide shows that survival curve for BR21. This difference between 4.7 and 6.7 months cannot be explained by EGFR mutation rate in this study. It has been checked and it does not account for this difference. It is not actually primarily a difference that is even explained by response. It is explained by the results of increased stable disease and increased disease control rate. In my opinion, this is the difference between cytotoxic and cytostatic effects. This primarily reflects a cytostatic effect of erlotinib in patients with wild-type EGFR cancers. I will show you this on the next slide. This same effect may be true for cetuximab, and that is being tested right now. Shepherd FA, NEJM 2005 TARCEVA® (erlotinib) PI. 2005. Data on file, OSI Pharmaceuticals, Inc.

Faz III INTEREST: Gefitinib vs Docetaxel Gefitinib 250 mg/gün PO (n = 733) Daha önceden 1-2 basamak tedavi almış (≥ 1 platin), PS 0-2 (N = 1466) Docetaxel 75 mg/m2 q3w (n = 733) Kim ES, Lancet. 2008

Faz III INTEREST: OS Kim ES, Lancet. 2008

INTEREST: Gefitinib vs Docetaxel Biomarkerlar İtalyan TAILOR çalışması: 2012 ASCO: Erlotinib Worse Than Docetaxel for Wild-Type EGFR NSCLC Douillard JY, JCO 2010

ALK-Pozitif NSCLC ALK (Anaplastic Lymphoma Kinase) Kromozomal rearrangement sonrasında onkojenik füzyon kinaz=EML4-ALK Hastaların klinik özellikleri: Genç yaş Hiç ya da çok az sigara içmiş AdenoCa 26/8/2011 de FDA approval Kwak EL, NEJM, 2010 52

Crizotinib-ALK (+) NSCLC Crizotinib (PF-02341066) Dual selektif inhibitor (ALK ve c-MET) ATP-kompetitif inhibitor Oral küçük molekül NSCLC hücre serilerinde hücre büyüme inhibisyonu ve apoptozisin indüksiyonu Doz-eskalasyon çalışmasında güvenilir 26/8/2011 de FDA approval (Accrelerated approval) The approval of crizotinib wasbased on reaponse rates, not survival data Kwak EL, NEJM, 2010 53

ALK-(+) NSCLC’de Crizotinib Yanıtı Crizotinib etkinlik ve güvenilirlik çalışması (ALK (+) 82 hasta) 60 PD SD PR CR 40 20 Percent Change From Baseline -20 -40 -30% NSCLC, non-small-cell lung cancer. -60 -80 -100 10 20 30 40 50 60 70 79 Patient No Kwak EL, NEJM, 2010 54

Crizotinib-OS 1 yıl OS:%74 2 yıl OS:%54 Shaw AT, Lancet Oncol 2011

Genel Sağkalım ALK (+) (Crizotinib alan) vs EGFR Mutant (TKI alan) Shaw AT, Lancet Oncol 2011

FAZ I Crizotinib: Update Sonuçlar 133 hastanın Update sonuçları 4 Eylül 2012 de yayınlandı... 2008-2011 87 of 143 pts had ORR..3 CR... 84 PR... Median PFS 9.7 mos... Median OS: Data not mature yet.. Median duration of response 49 week... Camidge DR, Lancet, 2012 57

PROFILE 1001: Crizotinib ROS1 Rearrangement ROS1 kromozomal rearrangement: Onkojenik füzyon sonrası aberran tirozin kinaz aktivitesi Faz I dose-eskalasyon çalışması ROS1-positif NSCLC’ de Crizotinib 250 mg BID etkinlik ve güvenilirlik (n = 15) ORR 8. haftada hastalık kontrol oranı ALK-negatif adenoca In the cell lınes ROS1 rearrangemenr çead to expression of oncogenic ROS1 fusion kinases and sensitivity to ROS kinase inhiibition… ROS1 encodes a reseptor kinase…Normal function is ınknown.. Lung, epididim ve muscle da var NSCLClerin %1 inde mevcut. Ayrıca GBM ve kolnajiyoselluler de de (+)… Shaw AT, eASCO 2012. Abstract 7508.

PROFILE 1001: Klinik Aktivite ve Güvenirlik ROS1-pozitif hastalarda Crizotinib antitümor aktivitesi ALK (+) hastalarda daha önceden rapor edilen yanıtlarla aynı Outcome ROS1 Pozitif[1] (n = 14) ALK Pozitif[2] (n = 19) ORR, % 57.1 52.6 Yanıt, n CR PR SD PD Other 1 7 4 2 10 5 3 DCR AT 8 hft, % 79 ALK, anaplastic lymphoma kinase; CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progression of disease; PR, partial response; SD, stable disease. Kabul edilebilir toksisite; Çoğu düşük dereceli, >4 toksisite yok 1.Shaw AT, ASCO 2012. Abstract 7508. 2.Kwak EL, ASCO 2009 Abstract 3509.

Faz II: Afatinib+Cetuximab Most patients in the study (>90%) derived clinical benefit from the combination and objective responses were observed in both T790M-positive and T790M-negative tumors (Figure 3), with a confirmed objective response rate of 40%. These data support the hypothesis that EGFR mutation-positive NSCLC, with acquired resistance to erlotinib and gefitinib, continues to depend on EGFR signaling. Data on progression-free and overall survival are eagerly awaited and efforts are ongoing to elucidate the mechanisms underlying the observed tumor regressions and possible mechanisms of progression on the combination. Janjigian YY, JCO 2011

Akciğer Kanserinde Moleküler Konsorsiyum-Akciğer Adenokanserlerinin Analizi Mutasyon yok KRAS %22 AKT1 EGFR % 17 NRAS MEK1 EML4-ALK % 7 MET AMP HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Mutasyon: Rezekte edilen hastaların %54’ünde (280/516) Johnson BE, IASLC WCLC 2011 61

MetMAb + Erlotinib vs Erlotinib SCA-14 SABCS V6 02-13-07.pptSCA-10 breast cancer slides_8-21-06.ppt 8/2/2018 MetMAb + Erlotinib vs Erlotinib MetMAb (Onartuzumab): Met reseptör targeting Ab Met diagnostik pozitif (n = 66); Met diagnostik negatif (n = 62)-IHC MetMAb + erlotinib: Met (+) populasyonda sağkalım avantajı Spigel DR, ASCO 2011 62

MetMAb + Erlotinib vs Erlotinib PFS OS Placebo + Erlotinib 1.5 MetMAb + Erlotinib 2.9 0.53 0.04 Placebo + Erlotinib 3.8 MetMAb + Erlotinib 12.6 0.37 0.002 Median, ay HR Log-rank P Median, ay HR Log-rank P 0.2 0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.8 1.0 PFS HR: 0.53 OS HR: 0.37 PFS OS 3 6 9 12 15 18 3 6 9 12 15 18 21 TTP (Aylar) OS (Aylar) Progresyon riskinde 2 kat azalma ve ölüm riskinde 3 kat azalma Spigel DR, ASCO 2011

Akciğer Kanserinde Moleküler Konsorsiyum-Akciğer Adenokanserlerinin Analizi Mutasyon yok KRAS %22 AKT1 EGFR % 17 NRAS MEK1 EML4-ALK % 7 MET AMP HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Mutasyon: Rezekte edilen hastaların %54’ünde (280/516) Johnson BE, IASLC WCLC 2011 64

Potansiyel “Druggable” Moleküler Hedefler? Gene Event Type Frequency, % FGFR1 Amplification 20-25 FGFR2 Mutation 5 PIK3CA 9 PTEN Mutation-deletion 18 CCND1 8 CDKN2A Deletion/mutation 45 PDGFRA Amplification-mutation EGFR 10 MCL1 BRAF 3 DDR2 4 ERBB2 2 K-ras EGFR B-raf HER2 PIK3CA ALK MET Other Other (Undefined) This slide shows some data regarding adenocarcinoma on the left, and then on the right are brand new data that were presented by Hammerman et al at our 2011 World Conference on Lung Cancer. And it displays what we call potential druggable molecular targets. Now, for adenocarcinoma we have already talked about some of these, such as EGFR or ALK. But what I want to draw your attention to is that squamous cell carcinoma, which was a black box, in other words molecularly they looked pretty much the same. We are now realizing that they are also very different from case to case. For example, for genes such as fibroblast growth factor receptor or a number of other abnormalities here, there are mutations or amplifications or deletions which could dictate therapy. There are a number of fibroblast growth factor inhibitors now in development, for example, that we know in animal models are very effective in treating squamous cell carcinomas with amplification of this gene.   So we will find out within the next few years the clinical applicability, but the point here is that I think more and more we will be individualizing therapy, even for squamous cell subtypes. Hammerman P, IASLC WCLC 2011 65

KRAS-mutated NSCLCde 2.line Selumetinib+Docetaxel Faz II randomize, plasebo-kontrollü Selumetinib: Potent MEK1 ve MEK2 nin potent, selektif inhibitörü, downstream KRAS üzerinde etki Selumetinib 75 mg BID + Docetaxel 75 mg/m2 21 günde bir (n = 44) KRAS-mutant, lokal ileri veya metastatik stage IIIB/IV NSCLC (1. basamak tedavi sonrası progressif) (N = 87) BID, twice daily; NSCLC, non-small-cell lung cancer. Placebo BID + Docetaxel 75 mg/m2 21 günde bir Janne PA, ASCO 2012. Abstract 7503.

2. line Selumetinib+Docetaxel: Klinik Sonuçlar Selumetinib + Docetaxel (n = 43) Placebo + Docetaxel (n = 40) HR (P değeri) Median OS, ay 9.4 5.2 0.80 (.2069) Median PFS, ay 5.3 2.1 0.58 (.0138) 6-mo PFS, % 37.1 15.8 (.0158) En iyi ORR, % CR PR SD ≥ 6 hft PD NE 37.2 44.2 18.6 50.0 45.0 5.0 (< .0001) Median yanıt süresi, gün 182 -- Relatif tumor değişimi -26% (.004) Janne PA, ASCO 2012. Abstract 7503.

‘Take Home’ Mesajlar Birinci Basamak Tedavi: PC, nonskuamözde GC’den üstün Kemoterapi ile hedefe yönelik ajanlarin kombinasyonu Bevacizumab (nonskuamöz, hemoptizisi olmayan) Cetuximabla sağkalımda orta dereceli iyileşme (skuamözde de etkili) Frontline EGFR TKI, EGFR mutasyonu (+) hastalarda seçenek olabilir (özellikle exon 19 del) IPASS de ve EURTAC PFS de olumlu etki (OS Ø) EML4-ALK: Crizotinib (Prospektif çalışma yok)

‘Take Home’ Mesajlar İkinci Basamak: Üçüncü basamak: Docetaxel Pemetrexed Erlotinib Crizotinib Üçüncü basamak:

Paclitaxel Gemcitabine 1998 Histoloji-directed therapy İleri Evre NSCLC Crizotinib 2011 Docetaxel 2002 Gefitinib 2003 1. basamak 2. basamak 3. basamak İdame Erlotinib Pemetrexed 2004 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Bevacizumab 2006 Pemetrexed 2008/2009 Vinorelbine 1994 Carboplatin* 1989 12+ Median OS (aylar) Cisplatin* 1978 ~ 8-10 ~ 6 ~ 2-4 1970 1980 1990 2000 Bevacizumab + PC BSC Tek ajan platinum Doublets Histoloji-directed therapy NCCN. Clinical practice guidelines in oncology. v.3.2012 70

Bireyselleştirilmiş vs Ampirik Tedavi As clinicians striving to personalised therapy where we match the right drug to the right patient Pharma industry reluctance to select small subpopulations but with increasing cost of new targeted agents, patient selection paramount We have made progress with increasing choices - antiangiogenic avastin, EGFR targeted therapy in NSCLC Not yet in a position where we have a right drug for every patient Doğru hasta-Doğru ilaç

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