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J Lung Cancer 2011;10(1):1-12 Personalized Therapy in Lung Cancer: Focused on Molecular Targeted Therapy Lung cancer is the leading cause of cancer death worldwide, with an overall 5 year survival rate of 15%. Most patients present with advanced disease that requires systemic chemotherapy, which merely confers several months of survival benefit. Recent advances in understanding the molecular mechanisms underlying lung cancer have led to molecular targeted therapy in this field. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first successful personalized therapy for non-small cell lung cancer (NSCLC), with about 30 months of median overall survival in patients with sensitive EGFR mutations. In addition, monoclonal antibodies against vascular endothelial growth factor (VEGF) or EGFR are also in current clinical use. Resistance to EGFR-TKIs has emerged as a major limitation of these agents and become challenge clinically. A number of novel targeted agents have been developed and investigated in clinical trials to overcome the limitation of agents currently available. Recently, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK), as a novel molecular target of NSCLC, has been identified, and its inhibitor is under rapid clinical development. We herein review the molecular targeted therapies currently available for NSCLC and discuss the clinical data of novel agents under clinical development. (J Lung Cancer 2011;10(1):1 12) Key Words: Individualized Medicine, Lung neoplasms, Molecular targeted therapy Shin Yup Lee, M.D. and Jae Yong Park, M.D. Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea Received: June 2, 2011 Revised: June 13, 2011 Accepted: June 14, 2011 Address for correspondence Jae Yong Park, M.D., Ph.D. Department of Internal Medicine, Kyungpook National University School of Medicine, 50, Samdeok-dong 2-ga, Jung-gu, Daegu 700-712, Korea Tel: 82-53-420-5536 Fax: 82-53-426-2046 E-mail: jaeyong@kyungpook.ac.kr 서론폐암은전세계적으로암사망율 1위를기록하고있는치명적인질환이다. 지난수십년간수술, 방사선요법, 세포독성약물의발전과이들을병합하여폐암의치료성적을높이고자했던노력들에도불구하고, 폐암환자의 5년생존율은 15% 에불과하다 (1). 이러한불량한예후의주요원인은약 70% 의환자가근치적수술이불가능한진행된병기로진단되기때문이다 (2). 병기가진행된폐암의주된치료는항암화학요법이다. 1980년대에 cisplatin이도입된이후 1990년대에는여러가지신세대항암제와 platinum의병합치료로기존의최선의지지치료 (best supportive care) 에비해생존기간이수개월정도향상되었다 (3,4). 그러나, 여러신세대항암제-platinum doublet간의치료성적에큰차이를내지못했고 non-platinum doublet의시도에서도더이상의이득을얻지못하여 (4,5), 진행병기비소세포폐암의항암화학요법의 성적은중간생존기간 8 11개월, 1년생존율 30% 로매우저조하다 (6). 이러한참담한결과는개별환자에있어폐암의생물학적특징을고려하지않은경험적인집단치료의결과일것으로생각된다. 과거부터폐암의치료에조직형 ( 비소세포폐암 vs. 소세포폐암 ), 병기, 수행상태, 나이등의임상적, 병리학적인지표들을이용해왔으며이들은일종의전통적인맞춤또는개별화된치료 (personalized or individualized therapy) 라고볼수있다. 최근폐암의분자유전학적지식을응용한개별화된치료의시도는폐암치료에일대혁신을가져왔다. 분자표적의발견과표적치료제의개발, 그리고표적치료의결과를예측할수있는생물학적표지자 (biological biomarker) 의도입으로경험적인집단치료에서벗어나개개인의특성에맞는맞춤치료가현실로다가오고있다. 분자표적치료는치료의효과를극대화하고동시에부작용을최소화하고자하는이상적인목표에부합하는치료이다. 본고에서는진행병기비소세포폐암의치료분야에서이루어진개별화된 1

2 J Lung Cancer 2011;10(1):1-12 치료, 특히분자표적치료 (molecular target therapy) 에초점을맞추어최근까지의연구와향후의연구방향에관해조망해보고자한다. Anti-epidermal Growth Factor Receptor (EGFR) Therapy 1) EGFR tyrosine kinase inhibitor (EGFR-TKI) Gefitinib (Iressa R ) 과 erlotinib (Tarceva R ) 는 1세대 EGFR- TKI로서 EGFR tyrosine kinase에 ATP가결합하는것을가역적으로방해하여 EGFR의활성화를억제함으로써수용체하부신호경로 (downstream signaling) 를차단한다. 1세대 EGFR-TKI를이용한대표적인임상연구들은 Table 1과같다. 진행병기비소세포폐암의 2nd/3rd line의치료로서 EGFR- TKI와최선의지지치료를비교한 3상임상연구로 BR.21 (erlotinib) 연구와 ISEL (gefitinib) 연구가대표적이다 (7,8). BR.21연구는위약군에비하여 erlotinib 치료군에서생존기간 (overall survival, OS) 이유의하게향상되었다 (Hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.58 0.85; p <0.001). 남성에비하여여성이 (p=0.006), 다른조직형에비하여선암이 (p<0.001), 흡연자에비하여비흡연자가 (p< 0.001), 다른인종에비하여아시아인이 (p=0.02) 좋은치료반응을보였다. 하지만생존기간의연장은남성, 흡연자, 선암이외의조직형, 아시아인이외의인종에서도관찰되었다. ISEL연구는 primary end point (PEP) 인 OS의향상은없었으나 (HR, 0.89; 95% CI, 0.77 1.02; p=0.087), 소그룹분석에서는아시아인종, 비흡연자에서위약군에비하여 gefitinib군의 OS가증가되었다. INTEREST연구는진행병기비소세포폐암의 2nd/3rd line 단일약제치료로서표준치료인 docetaxel과 gefitinib을비교한 3상임상연구로 PEP인 OS에서 gefitinib의비-열등성을입증하였다 (9). 또한 docetaxel군 Table 1. Main Clinical Trials of the First Generation EGFR-TKIs Study Phase Setting Treatment PFS (mo) OS (mo) RR (%) Primary end point IDEAL 1 II 2nd/3rd line G250 2.7 7.6 18.4 G500 2.7 8.0 19 IDEAL 2 II 3rd line G250 N/A 7.0 12 G500 6.0 9 ISEL III 2nd/3rd line G 3.0 5.6 8 OS (Unmet) Placebo 2.6 5.1 1 BR.21 III 2nd/3rd line E 2.2 6.7 9 OS (Met) Placebo 1.8 4.7 1 INTEREST III 2nd line, non-inferiority G 2.2 7.6 9.1 OS (Met) Docetaxel 2.7 8.0 7.6 IPASS III 1st line, non-inferiority G 5.7 18.6 43.0 PFS (Met) Asian, adenocarcinoma, Pac/Carb 5.8 17.3 32.2 never/light smokers SATURN III Maintenance after platinum E 12.3 wks 12.0 12 PFS (Met) doublet Placebo 11.1 wks 11.0 5 ATLAS III Maintenance after platinum Bev+E 4.8 14.4 N/A PFS (Met) doublet+bev Bev+placebo 3.7 13.3 N/A INTACT 1 III 1st line Gem/Cis+G250 (cont d) 5.8 9.9 50.3 OS (Unmet) Gem/Cis+G500 (cont d) 5.5 9.9 49.7 Gem/Cis+placebo 6.0 10.9 44.8 INTACT 2 III 1st line Pac/Carb+G250 (cont d) N/A 9.8 30.4 OS (Unmet) Pac/Carb+G500 (cont d) 8.7 30.0 Pac/Carb+placebo 9.9 28.7 TRIBUTE III 1st line Pac/Carb+E (cont d) N/A 10.6 21.5 OS (Unmet) Pac/Carb+placebo 10.5 19.3 TALENT III 1st line Gem/Cis+E (cont d) N/A 10.0 31.5 OS (Unmet) Gem/Cis+placebo 10.3 29.9 BeTA III 2nd line E+Bev 3.4 9.3 12.6 OS (Unmet) E+placebo 1.7 9.2 6.2 PFS: progression free survival, OS: overall survival, RR: response ratio, mo: months, G250: gefitinib 250 mg, G500: gefitinib 500 mg, G: gefitinib, E: erlotinib, Pac/Carb: paclitaxel/carboplatin, Bev: bevacizumab, Gem/Cis: gemcitabine/cisplatin, cont d: continued, N/A: not assessed.

Molecular Targeted Therapy in Lung Cancer 3 에비하여 gefitinib군은 grade 3, 4 독성의빈도가유의하게낮았다 (9% vs. 41%). 이연구에서는성별, 조직형, 인종, 흡연력에따라두치료군사이에 OS의차이가없었는데, 이는 docetaxel군에포함되었던환자가운데상당수의환자가연구기간이후 gefitinib을투여받았기때문으로분석되었다 (cross-over) (10). 이미 gefitinib의초기임상연구 (IDEAL 1, 2) 를포함한여러연구들에서아시아인, 여성, 선암, 비흡연자가특별히 EGFR-TKI에대한좋은반응과연관이있음이관찰되어이러한요소들은좋은반응을예측할수있는임상적예측지표 (clinical predictor) 로간주되었다 (11-14). 2004년에는 EGFR 유전자의체세포돌연변이 (somatic mutation) 가보고되어 EGFR-TKI에대한특히좋은반응을나타내는기전임이밝혀졌고, EGFR-TKI에대한좋은반응의임상적예측지표들을가지는환자들에서이돌연변이의빈도가특히높다는것이알려지게되었다 (15-17). 비소세포폐암에서 EGFR 돌연변이의빈도는유럽계백인에서는약 10%, 아시아인에서는약 25 50% 로보고되었으며, 특히아시아인선암에서는 21 67% 까지보고되고있다 (18,19). 대표적인활성화돌연변이 (activating mutation) 는 exon 19번의결손또는 exon 21 번의점-돌연변이 (L858R) 로이들은 EGFR 돌연변이의약 90% 를차지한다 (20). EGFR 돌연변이양성환자에서반응률 (response rate, RR) 은 55 82%, 무진행생존기간 (progression free survival, PFS) 은 9.4 13.3개월로보고되었으며, 돌연변이선별을하지않은환자에서의 RR은 10 20% 로보고되었다 (21,22). EGFR-TKI 치료의결과를예측할수있는분자생물학적표지자 (molecular biomarker) 로 EGFR 돌연변이이외에도 fluorescence in situ hybridization (FISH) 를이용한 EGFR copy number와 immunohistochemistry (IHC) 를이용한 EGFR expression 등이연구되었다 (23-26). 후향적표지자분석을시행한대규모임상연구를살펴보면, BR.21연구와 ISEL연구에서 high EGFR copy number (FISH 양성 ) 환자와 EGFR expression 양성인환자는위약군에비해서 EGFR-TKI군의생존결과가더좋았다 (Table 2). 그러나, 여러연구에서 EGFR expression은 EGFR copy number에비하여예측력 (predictive power) 이다소낮게평가되었다 (22-25). ISEL연구에서는 EGFR-TKI 치료가생존결과에미치는영향이 FISH 와 IHC의결과에따라통계적으로차이가있었으나 (p-inter <0.05), BR.21연구에서는유의한차이가없었다 (p-inter> 0.05). INTEREST연구는 FISH 양성환자에서 docetaxel에비하여 gefitinib의생존성적이우수함을증명하는것을 co-pep로정하였으나, FISH 양성환자에서 gefitinib과 docetaxel의효과는유사하였다 (9). KRAS 돌연변이는 EGFR- TKI치료의일차내성 (primary resistance) 의예측표지자 (predictive biomarker) 로서 (27), 또한나쁜예후를예측하는예후표지자 (prognostic biomarker) 로서주목을받았는데 (28), 여러연구에서일관되지않는결과를보이고있어논란의여지가있다. BR.21 연구에서는 KRAS 돌연변이양성인환자에서는지지치료군에비하여 erlotinib 치료군의생존율이낮았으나, KRAS 돌연변이음성환자에서는 erlotinib 치료군의생존율이더좋았다 (p-inter=0.09) (29). 그러나, KRAS Table 2. Summary of EGFR Biomarker Analyses from Randomised Trials Groups Treatment High expression, high copy number, or mutation positivity Low expression, low copy number, or mutation negativity p-inter HR* (95% CI) p-value HR* (95% CI) p-value EGFR copy number BR.21 E vs plac 0.43 (0.23 0.78) 0.004 0.80 (0.49 1.29) 0.35 0.12 ISEL G vs plac 0.61 (0.36 1.04) 0.07 1.16 (0.81 1.64) 0.42 0.05 INTEREST E vs Doc 1.09 (0.78~1.51) 0.62 NR EGFR protein expression BR.21 E vs plac 0.68 (0.49 0.95) 0.02 0.93 (0.63 1.36) 0.70 0.25 ISEL G vs plac 0.77 (0.56 1.08) 0.13 1.57 (0.86 2.87) 0.14 0.05 EGFR mutation BR.21 E vs plac 0.55 (0.25 1.19) 0.12 0.74 (0.52 1.05) 0.09 0.47 IPASS G vs PCa 0.48 (0.36 0.64) <0.0001 2.85 (2.05 3.98) <0.0001 <0.0001 KRAS mutation BR.21 E vs plac 1.67 (0.62 4.50) 0.30 0.69 (0.49 0.97) 0.03 0.09 *HR is for overall survival unless otherwise stated, p for interaction, HR is for progression free survival. E: erlotinib, G: gefitinib, plac: placebo, Doc: docetaxel, PCa: paclitaxel-carboplatin, HR: hazard ratio, CI: confidence interval, NR: not reported.

4 J Lung Cancer 2011;10(1):1-12 돌연변이는 EGFR 돌연변이와동시에발견되지않는데, EGFR-TKI에반응이없는것은 KRAS 돌연변이의존재가아니라 EGFR 돌연변이가없는것과관련이있을가능성이있다 (30,31). 위와같은대규모임상연구에서의 EGFR copy number와 expression 분석은대상환자중시료가가용한일부환자에서만시행된후향적분석으로제한점이있으며, EGFR-TKI 치료의결과에대한예측지표로서 EGFR copy number 검사의가치는전향적인연구에서추가적인검증이필요하다. IPASS연구는총 1,217명의환자에서 1st line 치료로 gefitinib과 paclitaxel-carboplatin을비교하였다. 앞선연구들과달리 EGFR 돌연변이의빈도가높은것으로알려진아시아인, 선암, 비흡연자 / 경량흡연자 (never/light smoker) 의선택적인환자군을대상으로연구를진행하였다 (32). 항암화학요법군에비하여 gefitinib군은 PFS, RR, 독성에서유의하게좋은결과를보였다. 전체환자중 EGFR 돌연변이결과가알려진 437명 (35.9%) 을대상으로분석하였을때, EGFR 돌연변이양성환자에서는항암화학요법군에비하여 gefitinib군이유의하게 PFS가연장되었으나 (HR, 0.48; p<0.0001), 돌연변이음성환자에서는 gefitinib이오히려열등하였다 (HR, 2.85; p<0.0001). Gefitinib과항암화학요법에대한 RR는 EGFR 돌연변이양성환자에서는각각 71% 와 47% 였고, 돌연변이음성군에서는각각 1.1%, 23.5% 였다. 전체환자에서두치료군간에 OS는차이가없었는데 ( 중간생존기간, 18.6 개월 vs. 17.3개월 ), 이러한결과는항암화학요법군의상당수에서병의진행시 gefitinib을사용하였기때문으로 (crossover) 생각된다. IPASS연구의결과는 EGFR 돌연변이가 EGFR-TKI 치료결과의강력한예측지표임을보여줌으로 써 EGFR 돌연변이를가지는비소세포폐암환자에서 1st line 치료로 EGFR-TKI를선택하는중요한근거가되었다. 임상적으로좋은반응이예상되는선택적인환자군 (First- SIGNAL) (33) 또는 EGFR 돌연변이양성환자만을대상으로 1st line gefitinib의성적을조사한다른연구들 (34,35) 에서도 IPASS연구와유사한결과를확인하였고, EGFR 돌연변이양성환자만을대상으로한 1st line erlotinib에대한연구 (EURTAC, OPTIMAL) 가현재유럽과중국에서각각진행중이다. 2) EGFR-TKI 내성 EGFR-TKI 치료초기에좋은반응을보이던환자들도결국에는거의예외없이 TKI에대한내성을획득하여병의진행을경험하게되는데대개치료시작 6 12개월무렵으로알려져있다 (20). EGFR-TKI에대한 2차내성 (secondary resistance) 의기전으로는 T790M을비롯하여 D761Y, T854A 등의 EGFR의 2차돌연변이 (secondary mutation) 와 EGFR 신호경로를우회 (bypass) 하는기전으로크게나누어볼수있다 (Table 3). 후자에는 c-met 유전자증폭 (amplification) 을비롯하여 IGF1R등의중복경로 (overlapping pathway) 의변이에의한 EGFR 하부신호경로의활성화가가능하다 (36-39). Epithelial-mesenchymal transition (EMT) 은원격전이와병의진행에중요한역할을하며, EGFR을우회하는기전으로 TKI에대한내성을나타낼수있다 (40). T790M 돌연변이는획득내성의약 50% 를차지하며, 내성의기전으로는 TK 부위의구조적변형을일으키거나 (41), ATP 결합부위의 ATP 결합력을증가시킴으로써 (42) gefitinib이나 erlotinib의결합을방해하여 EGFR-TKI 내성에 Table 3. Mechanisms of Resistance to EGFR-TKI Intrinsic resistance Acquired resistance Drug-resistant EGFR mutations Second-site EGFR mutations - T790M - T790M, D761Y, T854A - Exon 20 insertion Pathways bypassing EGFR signaling Genomic alterations co-occuring with EGFR mutations - MET activation - HER2 TK domain mutations ㆍMET gene amplification - PTEN loss ㆍHGF overexpression - PIK3CA mutation - IGF 1R overexpression - IGF 1R overexpression - Epithelial to mesenchymal transition (EMT) Resistance in EGFR wild type tumors - KRAS mutation - BRAF mutation - EML4-ALK - MET activation ㆍMET amplification ㆍHGF overexpression

Molecular Targeted Therapy in Lung Cancer 5 Table 4. Targeted Agents for Lung Cancer in Clinical Development Class of target Drug Target Phase* ErbB family BIBW2992 (Afatinib) EGFR, HER2 (irreversible) III HKI-272 (Neratinib) EGFR, HER2 (irreversible) II Lapatinib EGFR, HER2 (reversible) II AV-412/MP-412 EGFR, HER2 (reversible) I AZD8931 EGFR, HER2/3 (reversible) I PF-00299804 EGFR, HER2/4 (irreversible) III EKB-569 (Pelitinib) EGFR, HER2/4 (irreversible) II IMC-11F8 (Necitumumab) EGFR (monoclonal antibody) III Pertuzumab HER2 (monoclonal antibody) II EGFR/VEGF ZD-6474 (Vandetanib) EGFR, VEGFR2, RET III BMS-690514 EGFR, HER2/4, VEGFR1/2/3 II XL647 EGFR, HER2, VEGFR2/3, EPHB4 II MET PF-02341066 (Crizotinib) MET, ALK III ARQ197 MET III XL184 MET, VEGFR1/2/3, RET, c-kit, Flt3 II GSK1363089 (Foretinib) MET, VEGFR1/2/3, PDGFR, c-kit, Flt3 I/II MetMAb MET (monoclonal antibody) II IGF1R CP-751,871 (Figitumumab) IGF1R III PI3K/AKT/mTOR pathway Temsirolimus mtor II Everolimus FKBP-12, mtor II AP23573 mtor II MK2206 AKT II XL147 PI3K I Enzastaurin PKC II ISIS3521 PKC III RAS/RAF/MAPK/MEK pathway AZD6244 MEK II PD-0325901 MEK II STAT signaling Dasatinib Src, PDGFR, c-kit II HSP90 IPI-504 (Retaspimycin) Hsp90 II 17-AAG (Tanespimycin) Hsp90 I VEGFR Sorafenib VEGFR2/3, PDGFR, RAF, c-kit III Sunitinib VEGFR1/2/3, PDGFR, c-kit, RET, Flt3 III BIBF-1120 VEGFR, PDGFR, FGFR III Cediranib VEGFR1/2/3, PDGFR, c-kit III Motesanib VEGFR1/2/3 III *Based on ClinicalTrials.gov. 관여한다고알려져있다. T790M 돌연변이에의한획득내성을극복하기위하여여러가지비가역적 EGFR-TKI가연구되고있으며 (Table 4), EGFR, HER2 이중억제제인 BIBW2992 (afatinib) 에대한연구가가장많이진행되어, 최근 3상임상연구 (LUX-Lung 1) 의결과가보고되었다 (43). 2nd/3rd line 치료로 EGFR-TKI ( 최소 12주간 ) 를투여받은후진행한진행병기폐암환자를대상으로 afatinib군과위약군을비교하였으며, PEP인 OS (HR, 1.08; 95% CI, 0.86 1.35) 는유의한향상이없었으나, 위약군에비하여 PFS가유의하게연장 (3.3개월 vs. 1.1개월 ; HR, 0.38; p<0.0001) 되었다. 현재 EGFR 돌연변이양성환자들을대상으로 1st line 으로 BIBW2992와 platinum doublet을비교하는 3상임상연 구가진행중이다 (LUX-Lung 3, 6). PF0299804는 EGFR, HER2/4의비가역적인억제제로이전에항암화학요법을받은진행병기폐암환자를대상으로시행한 2상연구에서 erlotinib치료와비교하여 PFS의연장 (HR=0.67; p=0.017) 과 RR (17% vs 4%; p=0.008) 의향상을보였다 (44). c-met 유전자증폭은 EGFR-TKI에대한획득내성의 20% 정도를차지하며 ERBB3을통한 PI3K/AKT 신호경로를활성화시킴으로써 EGFR-TKI의저항성을초래한다 (45). 최근비소세포폐암에서 EGFR-TKI에대한획득내성의기전으로 EGFR 돌연변이 (T790M) 와 c-met 유전자증폭이동시에존재할수있는것으로보고되어 (46), c-met 억제제 (ARQ197, XL184, MetMAb) 와 EGFR-TKI의병합치료에대한임상연구가진

6 J Lung Cancer 2011;10(1):1-12 행되고있다 (Table 4) (47-49). 과거항암화학요법을받았던진행병기비소세포폐암환자에서 erlotinib+arq197과 erlotinib+위약군을비교한 2상임상연구에서 erlotinib+arq197 병용군에서 PFS가연장되었는데 (16.1주 vs. 9.7주 ; adjusted HR, 0.68; p<0.05), 이러한효과는비편평상피세포형, EGFR 돌연변이음성, KRAS 돌연변이양성환자에서뚜렷하였다 (47). Erlotinib과 MetMAb을병용한 2상임상연구에서는 erlotinib+위약군에비하여 Met expression 양성환자에서는 PFS (HR, 0.56; p=0.05) 와 OS (HR, 0.55; p=0.11) 가연장되었으나, Met 음성환자에서는불량한 PFS와 OS를보였다 (49). 3) EGFR-TKI를이용한지속치료 (maintenance therapy) 현재 1차항암화학요법은 platinum-doublet 또는일부표적치료제를포함한 3가지를 4 6주기치료하는것이표준으로인정되고있고, 1차항암약물치료후의일반적인전략은이른바 watch and wait 로, 주기적인평가도중병의진행이확인되면 2차항암화학요법을시행하는것이다 (50,51). 그러나, 1차항암화학요법후병이진행할때까지의기간 (PFS) 이 2 3개월정도에불과하며, 1차항암화학요법후병이진행된폐암환자중약 50 70% 만이추가적인약물치료를받는다는사실은 watch and wait 전략에따를경우병의진행에따른수행상태의악화가다음단계의효과적인약물투여에걸림돌이될수있음을시사한다 (52). 유지요법은정해진주기의 1차항암화학요법에반응이있거나 (complete or partial response [CR or PR]) 변화가없는경우 (stable disease, SD), 1차약제에포함되었던약물가운데적어도한가지를 ( 지속유지요법, continuation maintenance), 혹은새로운약물을 ( 전환유지요법, switch maintenance) 병이진행할때까지혹은심각한부작용이나타날때까지지속적으로투여하는경우를말한다 (53). 최근세포독성항암제또는표적치료제를이용한유지요법에관한많은연구들이이루어져희망적인결과를보여주고있다 (52,54-57). 특히, pemetrexed와 erlotinib을사용한전환유지요법이 3상임상연구에서 OS의유의한향상이있었다 (52,57). SATURN연구에서는 4주기의 platinum doublet 후 SD이상의반응을보인환자들을대상으로 erlotinib 유지군과위약군의성적을비교하였다 (52). 위약군에비하여 Erloitnib 유지군은 PFS (12.3 주 vs. 11.1주 ; HR, 0.71; p<0.0001) 와 OS (12.0개월 vs. 11.0 개월 ; HR, 0.81; p=0.0088) 가우수하였으며, 소그룹분석에서 EGFR 유전자의돌연변이가있는군에서는 erlotinib 유지요법으로 PFS의극적인향상 (HR, 0.1; 95% CI, 0.04 0.25; p<0.0001) 이있었다. 이연구에서 OS의유의한연장은없었는데, 이러한결과는 EGFR 유전자돌연변이를가진 위약군환자들가운데상당수가이후에 EGFR-TKI 치료를받았기때문으로생각된다 (cross-over). EGFR 유전자돌연변이음성환자에서도 erlotinib 유지요법을시행한경우 PFS (HR, 0.78; p=0.0185) 및 OS (HR, 0.78; p=0.0243) 의유의한연장이있었다. ATLAS연구에서는 1차항암화학요법으로 platinum-doublet과 bevacizumab 투여후 SD 이상의반응을보였던환자들을대상으로 bevacizumab+erlotinib 유지군과 bevacizumab+위약투여군을비교하였는데 interim analysis에서 bevacizumab+erlotinib 투여군에서 PFS의유의한연장 (4.8개월 vs. 3.7개월 ; HR, 0.72; p=0.0012) 이입증되어이연구는조기종료되었다 (58). 4) EGFR-TKI와항암화학요법의병용요법 1차항암화학요법으로서고식적인항암화학요법 (platinum doublet) 에 1세대 EGFR-TKI를병용하여더나은결과를얻고자하는연구들이시도되었다. INTACT 1, 2 연구는각각 gemcitabine/cisplatin 또는 paclitaxel/carboplatin과 gefitinib을병용하여항암화학요법단독치료와비교하였다 (59,60). 이와유사하게 TALENT, TRIBUTE는각각 gemcitabine/cisplatin 또는 paclitaxel/carboplatin에 erlotinib을추가하여항암화학요법단독치료와비교하였다 (61,62). 이모든연구에서 EGFR-TKI의추가적이득을증명하지못했다. 이연구들이계획될당시에는 EGFR 돌연변이가 EGFR-TKI의효과에미치는영향에대해알려지지않아임상적예측지표또는표지자에따른선택적인환자를대상으로시행되지못했다는점이이러한시도의문제점으로지적되었다 (6). 또한이러한시도의실패의한원인으로 EGFR-TKI는 G1기의세포주기정지 (cell cycle arrest) 를초래하여 S1, G2/M기의세포주기정지를일으키는세포독성항암제로부터암세포를보호하는결과를초래함으로써병용투여의효과가상쇄될수있다는이론이제기되었다 (63,64). 이에근거한여러전임상및임상연구에서 EGFR-TKI와세포독성항암제의순차적투여의효과를보고하였다 (63-66). 이를바탕으로 1st line으로 erlotinib과 gemcitabine/platinum 항암제의순차적투여효과를시험한 2상임상연구 (FAST-ACT) 에서항암제단독치료에비하여 PFS의유의한연장을보고하였다 (HR, 0.47; p=0.0002) (63). 이러한시도는현재 3상임상연구로이어져진행되고있다 (FAST-ACT II). 5) Anti-EGFR monoclonal antibody ( 항EGFR 단클론항체 ) Cetuximab (Erbitux R ) 은 EGFR의세포외부위의 ligand 결합을억제함으로써 EGFR의 activation을차단한다. FLEX연구는 EGFR expression 양성인환자 ( 선별대상환자의 85% 에

Molecular Targeted Therapy in Lung Cancer 7 서양성 ) 들을대상으로하여 1st line으로 vinorelbine/cisplatin 에 cetuximab을병용하였을때 vinorelbine/cisplatin에비하여 OS가연장됨을보고하였다 (11.3개월 vs. 10.1개월 ; HR, 0.87; p=0.04) (67). BMS099 연구는 1st line으로 taxane/cisplatin에 cetuximab을병용투여하였으나 PEP인 PFS의연장이없었다 (68). 최근의한메타연구 (meta-analysis) 는 2,018명의환자에서 1st line cetuximab과항암화학요법병용군과항암화학요법단독군의치료성적을비교분석하였는데, OS, RR은병합치료군이우수 (HR for OS, 0.87; p=0.004; Relative risk for RR, 1.19; p=0.013) 하였으나 PFS는유의한차이가없었다 (HR, 0.91; p=0.06) (69). Cetuximab은 Food and Drug Administration (FDA) 의승인을얻지못했으나, National Comprehensive Cancer Network (NCCN) 는 IHC로 EGFR expression이확인된비소세포폐암환자의치료에 cisplatin/ vinorelbine과 cetuximab의병용요법을선택사항으로제시하고있다 (70). 아직까지 cetuximab 치료의반응을예측할수있는표지자는밝혀지지않았다. Anti-angiogenic Therapy 1) Anti-vascular endothelial growth factor (VEGF) monoclonal antibody ( 항VEGF 단클론항체 ) Bevacizumab (Avastin R ) 은 vascular endothelial growth factor (VEGF) 와결합하여활성을막는다. Bevacizumab과항암화학요법의병합요법에관한 2상임상연구에서는치료의효능이있었으나, 편평상피세포암에서는치명적인폐출혈이높은빈도 (9.1%) 로발생함을보고하였다 (71). 두개의 3상임상연구 (ECOG 4599, AVAiL) 에서진행병기비편평상피세포형비소세포폐암환자의 1st line 치료로각각 paclitaxel/carboplatin과 gemcitabine/cisplatin에 bevacizumab을병용하는치료와항암화학요법단독치료를비교하였다 (72,73). ECOG 4599 연구는 PEP인 OS의연장 (12.3개월 vs. 10.3개월 ; HR, 0.80; p=0.013) 과 PFS, RR의향상됨을보고하였으며, AVAiL연구도 PFS와 RR의이득을보고하였다. 특히 ECOG 4599연구는진행병기비소세포폐암의 1st line 치료에대한 3상임상연구로서는최초로 12개월이넘는중앙생존기간을보고하였다. ECOG 4599연구에서심각한폐출혈의빈도는 1.9% 로보고하였고 AVAiL 연구에서도 bevacizumab 7.5 mg/kg군, 15 mg/kg군에서각각 1.5% 와 0.9% 의빈도를보고하였다. 두 4상임상연구 (SAiL, ARIES) 는실제처방된 bevacizumab 포함 1st line 항암치료의안전성과효과를조사하였다 (74,75). 두연구는각각 2,166명과 1,758명의환자를대상으로하였고고령의환자, 수행상태가불충분 한환자 (ECOG 2), 항응고치료를받고있는환자를일부포함하였으며, 다양한 platinum-doublet과의병용치료결과를포함하였다. 기존의 3상연구에서보고되었던안전성을재확인하였는데, 심각한출혈의빈도는 3상연구에비하여높지않았다. 특히 bevacizumab+erlotinib 지속치료를연구한 ATLAS 연구와, 1st/2nd line에서항암화학요법또는 erlotinib과병용한 bevacizumab의안정성을시험한 2상연구인 PASSPORT 연구는뇌전이를치료받은환자를포함하였지만이들에있어서뇌출혈의빈도가증가되지는않았다 (76). 현재 European Medicines Agency에서는뇌전이가있는환자에서의 bevacizumab의사용을허가하고있으며, 아직까지 bevacizumab에대한반응을예측할수있는표지자로밝혀진것은없다. 2) Vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) 다른암과마찬가지로폐암은매우복잡하고얽힌여러신호경로의이상을동반하므로, 어느하나의경로만차단하는치료는불완전할수밖에없다. VEGFR-TKI 중많은수가혈관신생에관여하는다른주요신호경로, 즉 EGFR, PDGFR 경로등을동시에차단할수있다 (77). 특히 VEGFR 과 EGFR는하부신호경로를공유하므로, EGFR과 VEGFR 을동시에억제할수있는약물들이임상적으로많이연구되었다 (78). Vandetanib (Zactima R ) 은 EGFR, VEGFR2, RET 억제제로 VEGFR 억제약물가운데연구가가장많이진행된약물이다. 4개의 3상임상연구가이전에항암치료를받았던진행병기비소세포폐암환자에서 vandetanib 치료의효과를평가하였다. ZEAL연구 (79) 에서는 pemetrexed 단독치료에비하여 pemetrexed+vandetanib을투여한경우 PFS 의유의한연장은없었지만 (17.6주 vs. 11.9주 ; HR, 0.86; p=0.108), ZODIAC연구 (80) 에서는 docetaxel 단독치료에비하여 vandetanib을병용하였을때 PFS가유의하게연장되었다 (4개월 vs. 3.2개월 ; HR, 0.79; p<0.001). ZEST연구 (81) 에서는 erlotinib 치료에비하여 vandetanib 치료로 PFS의연장을증명하지는못했지만비열등성을만족하였다. ZEPHYR 연구 (82) 는 erlotinib 치료실패후 vandetanib과최선의지지요법을비교하였는데, PEP인 OS의향상은없었으나 PFS와 RR이유의하게향상되었다. 이러한결과들은 vandetinib을비소세포폐암의치료에임상적으로투여하기에는충분하지못한성적이었다. BMS-690514는 EGFR, HER2/4, VEGFR1/2/3 억제제로 2상연구에서 erlotinib 치료를받은적이없는환자와 erlotinib 치료후내성이발생한환자에투여하여각각 39%, 22% 의질병조절률 (disease control rate, DCR) 을얻었다

8 J Lung Cancer 2011;10(1):1-12 (83). 이연구에서는특히 EGFR 돌연변이양성과음성환자에서각각 75%, 28% 의 DCR을보고하였고, KRAS codon 13 돌연변이를가지는 erlotinib naïve 환자에서종양크기의 48% 감소와 EGFR T790M 돌연변이를가지는 erlotinib 내성환자 2명에서 SD의반응을보고하였다. 현재진행병기비소세포폐암에서 BMS-690514와 erlotinib의효과를비교하는 2상임상연구가진행중이다. Sorafenib은 VEGFR2/3, PDGFR, RAF, c-kit 억제제로신장암과간암의치료에사용되고있으며, 비소세포폐암을대상으로한 3상임상연구 (ESCAPE) 에서 1st line 치료로 paclitaxel/carboplatin과 sorafenib 병용의효과를시험하였는데, 중간분석에서실패가예상되어조기종료되었다 (84). Sunitinib은 VEGFR1/2/3, PDGFR, c-kit, RET, Flt3 억제제로신장암과위장관기질종양 (gastrointestinal stromal tumor) 의치료로사용되고있다. 이전에항암화학요법을받은비소세포폐암환자에서 erlotinib+sunitinib와 erlotinib 단독치료의효과를비교하기위한연구와 sunitinib 를사용한지속치료에관한 3상임상연구가진행되고있다. Echinoderm Microtubule-associated Protein-like 4 (EML4) - Anaplastic Lymphoma Kinase (ALK) Fusion Protein (EML4-ALK) EML4-ALK 융합단백은비소세포폐암의새로운분자표적이다. 염색체 2번단완의역위 (inversion) 에의해 EML4가 ALK에융합되어생성되며, 융합단백은발암성을가진다 (85). ALK는 anaplastic large cell lymphoma와연관된염색체전위로발견되었으며, 폐암에서는최초로발견된발암성재배열 (oncogenic rearrangement) 이다 (85). NSCLC에서빈도는 2 7% 로알려졌으며, 선암, 비흡연혹은 10갑년이하의경량흡연자, 젊은환자에서높은빈도로발견된다 (85-88). EML4-ALK는 EGFR 및 KRAS 돌연변이와는동시에발견되지않는 (mutually exclusive) 것으로알려져있다 (85,86). 이러한특징으로인하여 EGFR 돌연변이양성을시사하는임상적특징을가지는환자들을대상으로하였을때, EGFR 돌연변이음성인환자의 1/3 정도에서 EML4-ALK가발견된다 (87). PF02341066 (crizotinib) 은 MET와 ALK 동시억제제로 82명의 EML4-ALK 양성환자를대상으로한 1/2상임상연구에서 57% 의반응률 (CR/PR) 과 33% 의 SD를보고하였다 (88). EGFR이라는분자표적의경험을바탕으로 EML4-ALK 의발견이후에는전향적인종양유전자검사를통해약물개발과임상연구의진행을매우앞당길수있었다 (85). 현재 EML4-ALK 양성환자에서 crizotinib과표준 2차치료인 docetaxel, pemetrexed를비교 (NCT00932893), 또는 crizotinib 의 1차치료로서의효과를평가 (NCT01154140) 하는 3상임상연구가진행되고있다. 또한 crizotinib은 MET 억제제로서 EML4/ALK 여부에관계없이여러항암화학요법에실패한환자들에서 erlotinib과병합요법 (NCT00965731) 에대한연구가진행되고있다. 기타분자표적치료제 Insulin-like growth factor-1 수용체 (IGF1R) 를표적으로하는약물중에는단클론항체인 figitumumab (CP-751,871) 이가장많이연구되었다. 2상연구에서 paclitaxel/carboplatin과 figitumumab를병용시항암제단독치료에비하여반응률이우수하였으며 (55% vs. 42%), 이러한효과는특히편평상피세포암환자에서더욱뚜렷하였다 (72% vs. 42%) (89). 이러한성적을바탕으로 3상연구가진행되었는데, ADVIGO 1016은 1차요법으로 paclitaxel/cisplatin과 fagitumumab의병용요법을조사하였으나, 중간분석후실패가예상되어조기에종료되었다 (90). 주요부작용으로는 dehydration, hyperglycemia, hemoptysis가보고되었다. 그외에도 EGFR의하부신호경로인 PI3K/AKT/mTOR 경로, RAS/RAF/MAPK/ MEK 경로, STAT 신호경로를차단하는표적치료가개발되고있다 (6,36,39). 또한 EGFR family 수용체, MET 등다양한 kinase의과발현단백또는돌연변이의형태적인안정화에기여하는 Heat shock protein 90 (Hsp90) 을억제하는약물도개발되고있다 (91). 결론폐암의표적치료는 EGFR-TKI를통해성공적인시작을알렸다. 진행병기폐암환자의중간생존기간은최선의지지치료로 4 5개월, 항암화학요법으로 8 11개월에불과하였지만, EGFR-TKI 치료는임상적인예측인자를가진환자들의생존기간을 19개월로 (32), EGFR 돌연변이라는 biomarker를가진환자들의생존기간을약 30개월로증가시켰다 (34,35). 폐암의정복을위한연구는새로운표적으로 EML4-ALK를등장시켰고빠른속도로치료를향해나아가고있다. 하지만, EGFR-TKI 치료가획득내성의극복이라는난제를앞두고있는사실에서보듯, 암세포들은표적의내성돌연변이를만들거나표적을우회하는신호활성화경로를이용하여그들을제거하려는우리의시도를무마하려는노력을지속하고있다. 따라서, 우리는폐암의분자생물학적인특성에대한더욱깊은통찰을통해새로운치료의표적을발굴하고, 치료결과를예측할수있는 biomarker

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