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1 Korean J Gastroenterol Vol. 73 No. 4, pissn eissn BRIEF SUMMARY OF PRACTICE GUIDELINE 진행성및전이성대장암에서의전신항암치료 박재준 연세대학교의과대학세브란스병원소화기내과 Systemic Therapy for Advanced and Metastatic Colon Cancer Jae Jun Park Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Colon cancer is one of the three most common cancers in both men and women in Organization for Economic Cooperation and Development countries. Approximately one-quarter of colon cancer patients have a metastasis at the time of diagnosis, and systemic therapy is used in many of them as a first line therapy. In addition to existing cytotoxic drugs, target therapy has been introduced in colon cancer and immunotherapy has shown clinical benefits in the treatment of metastatic colon cancer. The purpose of this review was to briefly summarize the National Comprehensive Cancer Network guidelines for systemic therapy in colon cancer with special reference to targeted agents and novel agents. (Korean J Gastroenterol 2019;73: ) Key Words: Colon cancer; Advanced cancer; Metastatic cancer; Systemic therapy 서론 대장암은 Organization for Economic Co-operation and Development (OECD) 국가에서남녀모두대표적으로많이발생하는 3대암종중하나이다. 우리나라는전세계적으로대장암발생률이가장높은나라중하나이며, 2014년에 10만명당남자는 42.6명, 여자는 23.0명이었다. 대장암환자의약 1/4은진단당시에전이가확인된다고알려져있으며이환자들의상당수는전신항암치료가일차치료법으로고려된다. 전이성대장암의항암치료에는 5-fluorouracil/leucovorin, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab 그리고 nivolumab과같은다양한약제들이사용된다. 이들약제의작용기전은 DNA 복제억제, 혈관내피성장인자 (vascular endothelial growth factor, VEGF) 및표피성장인자 (epidermal growth factors, EGFR) 의활성억제등다양하다. 항암약제의선택에는치료목표, 이전치료의유형및시기, 종양의유전자변이양상및약제독성등이고려된다. National Comprehensive Cancer Network (NCCN, 는미국내 27개주요암센터의전문가들로구성된비영리학술연구및교육단체로, 최신연구결과를토대로발표하는항암치료가이드라인은전세계적으로많은의사들이참고하고활용하고있다. 본고에서는진행성및전이성대장암항암치료에대한최신 NCCN 가이드라인 1 을표적치료제및신약을중심으로알아보고자한다. Received February 18, Revised March 25, Accepted March 25, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 박재준, 03722, 서울시서대문구연세로 50-1, 연세대학교의과대학세브란스병원소화기내과 Correspondence to: Jae Jun Park, Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: , Fax: , jaejpark@yuhs.ac, ORCID: Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 73 No. 4, April

2 Park JJ. Systemic Therapy for Advanced and Metastatic Colon Cancer 203 본론 1. 표적치료제 1) VEGF 억제제 Bevacizumab은종양혈관신생에중요한역할을하는 VEGF의활성을차단하는 humanized monoclonal antibody 이다. 여러무작위임상 2상연구들의통합분석 (pooled analysis) 에의하면절제불가능한전이성대장암환자에서 5-fluorouracil/leucovorin에 bevacizumab을추가할경우생존율이증가하였다. 2 또한, 3상연구보고에의하면 bevacizumab을 oxaliplatin 기반의항암요법에추가한경우 bevacizumab을추가하지않은군 (hazard ratio [HR] 0.83, 97.5% CI, ) 과비교하여 1.4개월의무병생존율증가가있었고, 생존율은증가경향 (1.49, 97.5% CI, , p=0.077) 을보였다. 3 한편, 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) 항암요법에 bevacizumab 추가효과는무작위연구로확인되지못하였지만, 여러전향및후향연구들의메타분석에서 bevacizumab 병합은 51.4% 반응률, 중앙 10.8개월의무병생존율 (95% CI, ) 그리고중앙 23.7개월의생존율 (95% CI, ) 을보였다 명의환자를대상으로 bevacizumab의병합치료에대하여진행 (progression) 소견을보인후의 bevacizumab 지속투여에대한분석연구에의하면, bevacizumab 을지속투여하는것은전체생존율 (HR 0.76, 95% CI, ) 및진행후 (post-progression) 생존율 (HR 0.74, 95% CI, ) 의증가와관련이있었다. 5 유사하게 Avastin Regimens: Investigation of Effectiveness and Safety (ARIES) 의코호트분석에서도종양의진행 (progression) 후에도 bevacizumab을유지하는것은생존율증가 (HR 0.84, 95% CI, ) 와관련이있었다. 6 이들결과는 1차항암치료이후 2차항암치료에도 bevacizumab을병합하는것이어느정도의생존율증가효과를가져옴을보여준다. 한편, 최근의무작위대조연구에대한메타분석보고에의하면 bevacizumab을추가할경우, 비록출혈과천공의절대빈도는낮지만고혈압, 위장관출혈및천공의위험이유의하게증가함을보고하였다. 7 따라서 bevacizumab 투여환자에서이들합병증에대한주의가필요하다. 또한, bevacizumab 은창상치유 (wound healing) 를저해할수있다고알려져있으며주요수술을계획하는경우적어도 6주전에는 bevacizumab을중단하는것이권장된다. 2015년 Food and Drug Administration (FDA) 에서는 bevacizumab 사용후괴사성근막염, 치명적인창상치유합병증, 위장관천공, 누공이발생할수있다는경고라벨 (safety label warning) 을 승인하였다. Ziv-aflibercept는 humanized recombinant fusion protein으로 VEGF-A, VEGF-B, placental growth factor에결합하여혈관생성과정을방해한다. VELOUR 3상임상은 oxaliplantin이포함된항암요법후진행 (progression) 소견을보인전이성대장암환자에서 2차약제로서의 ziv-aflibercept 의효과를평가하였는데 FOLFIRI에 ziv-aflibercept을추가한군에서위약추가군에비하여생존율이증가하였다 (13.5개월 vs. 12.1개월 ; HR 0.82; 95% CI, ). 8 Ramucirumab은또다른 antiangiogenic 약제로 VEGF 수용체 2의세포외도메인을표적으로하여 VEGF 신호전달을차단하는 human monoclonal antibody이다. 일차항암제 fluoropyrimidine/oxaliplatin/bevacizumab 병합치료에대하여진행 (progression) 소견을보인전이성대장암환자에서 FORFIRI에 ramucirumab 또는위약병합군을무작위배정하여평가하였을때에 ramucirumab군이 13.3개월 vs. 11.7개월 (HR 0.84; 95% CI, ) 로생존율이증가하였다. 9 Regorafenib은종양성장과혈관신생을포함한다양한과정에관여하는 multiple kinase (VEGF 수용체, fibroblast growth factor 수용체, platelet derived growth factor 수용체, BRAF, KIT 및 RET) 에대한 small molecule inhibitor이다. CORRECT 3상시험에서표준치료후진행 (progression) 소견을보인환자들을최선의지지요법 (best supportive care) 에위약또는 regorafenib을추가하였을때에 regorafenib군에서생존기간의증가가관찰되었다 (6.4개월 vs. 5.0개월 ; HR 0.77; 95% CI, ). 10 Regorafenib 사용중발생할수있는 grade 3 이상의부작용으로는수족증후군 (17%), 피로 (10%), 고혈압 (7%), 설사 (7%) 및발진 / 표피탈락 (6%) 등이있다. 10 2) EGFR 억제제 Cetuximab과 panitumumab은 EGFR에대한단클론항체이며 EGFR의하위신호전달을억제한다. Panitumumab 은 fully human monoclonal antibody인반면 cetuximab은 chimeric monoclonal antibody이다. Cetuximab과 panitumumab은전이성대장암의일차치료약제로 FOLFIRI 또는 FOLFOX와의병합요법이평가되었다. 최근의무작위대조연구에대한메타분석에서 EGFR 억제제가 RAS wild type 전이성대장암환자의치료에명백한효과가있음을보고하였다. 11,12 (1) 암종의위치에따른영향여러연구보고에의하면전이성대장암의암종부위는 EGFR 억제제치료를받는환자의예후와치료반응과관련 Vol. 73 No. 4, April 2019

3 204 박재준. 진행성및전이성대장암에서의전신항암치료 이있다고보고된다. 13,14 3상 CALGB/SWOG 임상시험연구에의하면 1차항암치료에서 RAS wild type 우측대장암 ( 맹장부터간막곡부위 ) 은 bevacizumab이투여된경우가 cetuximab이투여된경우에비하여생존율이더높았다 (HR 1.36; 95% CI, ; p=0.100). 반면, 좌측대장암 ( 비만곡부터직장 ) 은 cetuximab이투여된경우가 bevacizumab이투여된경우보다생존율이의미있게더높았다 (HR 0.77; 95% CI, ; p=0.04). 15 또한 cetuximab군이 bevacizumab군에비하여좌측대장암에서생존율이연장 (39.3개월 vs. 32.6개월 ) 되었으나우측대장암에서는단축되었다 (13.6개월 vs 개월 ). 이연구를포함한여러연구들은 cetuximab과 panitumumab이원발종양이우측에위치한전이성대장암에서효과가제한적임을제시하였으며, cetuximab 또는 panitumumab은원발종양이좌측 ( 비만곡부터직장 ) 대장에위치한경우전이성질환의 1차약제로고려된다. 한편, 2차이후의치료에서도종양의위치가 EGFR 억제제에대한반응과관련이있다는일부보고들이있지만, 13,16 아직까지근거는충분하지않다. (2) RAS mutation 여러연구들은 KRAS 유전자 exon 2의 codon 12 또는 13에 mutation이있는종양은 cetuximab 또는 panitumumab 치료에반응하지않음을보고하였다 한편, 최근연구에의하면 KRAS에서 exon 2 이외의 mutation 그리고 NRAS의 mutation도 cetuximab과 panitumumab의치료효과와관련이있다고보고된다. 12,23 AGITG MAX 연구에서 KRAS exon 2 wild-type 환자의 10% 는 KRAS exon 3 또는 4, 또는 NRAS exon 2, 3, 4의 mutation이확인되었다. 24 또한, PRIME 임상시험에서 KRAS exon 2 mutation이없는 641명의환자중 17% 에서 KRAS exon 3, 4 또는 NRAS exon 2, 3, 4 mutation 이있음이보고되었다. 23 이 PRIME 연구의하위그룹후향적분석에서 FOLFOX 단독투여군에비하여 panitumumab과 FOLFOX를투여한 KRAS 또는 NRAS에하나라도 mutation 이있는환자에서무병생존율 (HR 1.31, 95% CI, ) 및생존율 (HR 1.21, 95% CI, ) 이감소하였다. 23 FIRE-3 임상시험의후속분석연구에서모든 RAS (KRAS 및 NRAS) mutation이고려되었을때, RAS mutant type 환자에서 FOLFIRI+bevacizumab을투여받은환자에비하여 FOLFIRI+cetuximab을투여받은환자가무병생존기간이유의하게더짧았다 (6.1개월 vs. 12.2개월, p=0.004). 한편, KRAS/NRAS wild-type 환자에서는이들약제조합간무병생존기간의차이가없었다 (10.4개월 vs. 10.2개월, p=0.54). 이들결과는 cetuximab이 KRAS 또는 NRAS mutation 환자에서효과가저하됨을시사한다. (3) BRAF V600E mutation KRAS/NRAS mutation은 EGFR 억제제에대한반응저하를예측하지만, KRAS/NRAS wild type 종양의상당수도이치료에반응하지않는다. 따라서, KRAS/NRAS의하위 (downstream) 신호단계에서 cetuximab 또는 panitumumab 의추가적인치료반응표지자를찾기위한연구들이수행되었다. 대장암의약 5-9% 에서 BRAF 유전자 (V600E) 의특정부위에 mutation이있음이보고된다. 25,26 Non-mutant BRAF 유전자의단백질생성물의활성화는 EGFR 경로에서활성화된 KRAS 단백질의하위 (downstream) 단계에서나타난다. Mutant BRAF 단백질생성물은구조적으로활성화되어있는것으로여겨지며이러한분자생물학적상황은 EGFR 억제제치료에저항을나타낼것으로추정된다. 27,28 항암화학요법을받은전이성대장암환자들의후향적분석연구에의하면, BRAF V600E mutation은치료종류에상관없이불량한예후와관련이있었지만 cetuximab이일차치료에추가된경우일정부분의효과는확인되었다. 26 한편, 전이성대장암에서 2차이후의약제에서 BRAF mutation은 EGFR 억제제치료저항성과관련이있었다. 29,30 대체적으로전문가들은 BRAF V600E mutation이동반된환자에서 panitumumab 또는 cetuximab을단일약제또는세포독성화학요법과병용으로투여시치료반응이낮을것으로생각하고있으며전이성대장암환자진단시에종양조직을통하여 BRAF genotyping 을시행할것을권고하고있다. Cetuximab이나 panitumumab 투여후에심한주입반응이 3% 에서발생한다고보고되며, 약물투여후발생하는피부발진의유무및중증도는치료반응및생존율증가와관련이있다. 31,32 또한, cetuximab과 panitumumab 사용은정맥혈전증발생증가와관련이있다고알려져있어임상의의주의가필요하다 기타신약및면역항암제 1) Trifluridine/tipiracil (TAS-102) Trifluridine/tipiracil은 cytotoxic thymidine 유사체인 trifluridine과 thymidine phosphorylase 억제제인 trifluridine 의경구복합제이다. RECOURSE 3상임상시험에서 2차약제에도진행 (progression) 소견을보인 800명의전이성대장암환자를 Trifluridine/tipiracil군과위약군으로무작위배정하였을때 Trifluridine/tipiracil군에서생존기간의증가 (7.1개월 vs. 5.3개월 ; HR 0.68; 95% CI, ) 가확인되었다. 34 Trifluridine/tipiracil 사용과관련된가장흔한부작용은호중구감소증 (38%), 백혈구감소증 (21%), 열성호중구감소증 (4%) 이었으며한예에서약물관련사망이발생하였다. 34 The Korean Journal of Gastroenterology

4 Park JJ. Systemic Therapy for Advanced and Metastatic Colon Cancer 205 2) Pembrolizumab과 nivolumab 여러코호트연구에따르면 4기대장암환자중에서 high microsatellite instability (MSI-H) mismatch repair-deficient (dmmr) 소견을보이는경우는 % 로보고된다 MSI-H 종양에는수천개의돌연변이가포함되어있으며이들은면역계에인지되고표적화될수있는돌연변이단백질을생성한다. 그러나종양세포의 programmed cell death ligands 1 and 2 (PD-L1과 PD-L2) 는 T세포의 programmed cell death protein 1 (PD-1) 수용체에결합하여면역반응을저하시킬수있다. MSI-H 종양들은 PD-L1이과발현되어있으며이로인하여면역반응을회피할수있게되지만, 한편으로는 PD-1 억제제에좋은반응을보일수있다. Pembrolizumab은 humanized, IgG4 monoclonal antibody로 PD-1에높은친화력으로결합하여 PD-L1 및 PD-L2 와의상호작용을방지하여면역계에의한인지및반응을유도한다. Pembrolizumab은전이성또는절제불가능한흑색종, 전이성비소세포폐암에 FDA 승인을받았다. 또다른약제인 Nivolumab은 humanized IgG4 PD-1 blocking antibody로흑색종및비소세포폐암에서 FDA 승인을받았다. 최근발표된 2상연구는 MSI-H 대장암환자 11명, MSS 대장암환자 21명그리고 MSI-H 비대장암환자 9명에서 pembrolizumab의효과를평가하였다. 38 포함된모든환자들은진행성전이성질환으로대장암환자의경우 2-4차례의선행항암치료력이있었다. 연구의일차목표변수는면역관련객관적반응률 (immune related objective response rates) 로 MSI-H 대장암군에서 40% (95% CI, 12-74%), MSS 대장암군에서 0% (95% CI, 0-20%), MSI-H 비대장암군에서 71% (95% CI, 29-96%) 였다. 이는 MSI가 pembrolizumab의효과를예측하는지표임을시사한다. 또한, 중앙 (median) 무병생존기간및생존기간은 MSI-H 대장암에서는재발또는사망발생이적어중앙기간이산출되지못하였으며, MSS 대장암에서는각각 2.2개월과 5.0개월이었다 ( 질병진행또는사망에대한 HR 0.10, p<0.001). Pembrolizumab과 nivolumab은 NCCN 최신지침에 MSI-H 대장암의 2차이후의치료제로제시되어있다. 결론 2018년도세계암연구기금 (World Cancer Research Fund International) 의대장암발생률자료에의하면, 우리나라는세계에서두번째로대장암이많이발생 (10만명당 45명 ) 하는국가이다. 근래에내시경등대장암검진이활발히시행되면서대장전암병변의발견이증가하고있지만, 1/4의환자들은진단시전이병변이발견되고이환자들의상당수는전신 항암치료가일차치료로시행된다. 분자생물학적기술이발달함에따라최근전이성대장암의항암치료에여러표적치료제가개발되어임상에적용되고있으며, 아직좀더많은임상결과들이필요하지만면역항암제도대장암의새로운약제로주목받고있다. 아울러, 최근분석기술의발전에따라대장암의전신항암치료도점차정밀의료에기반한맞춤형치료를향하여나아가고있다. 새로운약제의도입및임상자료들이축적됨에따라진료가이드라인은지속적으로수정및개정되고있다. 가용한의료자원내에서환자들에게최선의치료를제공하기위하여최신진료가이드라인에대한숙지및치료동향에대한지속적인관심이필요하다. REFERENCES 1. Benson AB 3rd, Venook AP, Cederquist L, et al. Colon cancer, version , NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15: Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23: Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26: Petrelli F, Borgonovo K, Cabiddu M, et al. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin Colorectal Cancer 2013;12: Cartwright TH, Yim YM, Yu E, Chung H, Halm M, Forsyth M. Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology. Clin Colorectal Cancer 2012;11: Grothey A, Flick ED, Cohn AL, et al. Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study. Pharmacoepidemiol Drug Saf 2014;23: Dai F, Shu L, Bian Y, et al. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig 2013;33: Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30: Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015;16: Vol. 73 No. 4, April 2019

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레이아웃 1

레이아웃 1 대한위장관기질종양연구회 01 GIST 06 02 11 03 Imatinib 14 04 05 06 07 Sunitinib 32 40 44 48 GIST 6 01 7 GIST Guide book GIST 8 01 9 GIST Guide book GIST (CT) MRI FDG-PET 10 02 11 GIST Guide book 12 02 (Imatinib)