암 표적요법제의 부작용은 무엇인가?
과학자들은 암 표적요법이 기존의 화학요법보다 독성(부작용)이 덜할 것이라고 예상했었다. 왜냐하면 암세포가 일반 세포보다 표적에 더 의존하기 때문이다. 그러나 암 표적요법은 상당한 부작용을 낳을 수 있다.
표적요법에서 나타나는 가장 흔한 부작용은 설사와 간염과 간 효소의 상승 같은 간 질환이다. 표적치료에서 나타나는 다른 부작용은 다음과 같다.
-피부질환(여드름 모양의 발진, 건성 피부, 손톱 변형, 모발 탈색)
-혈액 응고 및 상처 치유의 장애
-고혈압
-위장관 천공(일부 표적치료의 드문 부작용)
몇몇 표적요법의 특정한 부작용은 더 나은 환자의 치료 결과와 연관되어 있다. 예를 들어 신호전달억제제인 에로티닙(상표명 : 타세바)이나 게피티니브(상표명 : 이레사)로 치료받으면서 여드름성 발진( 여드름을 닮은 피부 분출)을 일으키는 환자들은 발진이 발병하지 않은 환자(2)보다 이런 약물에 더 잘 반응하는 경향이 있다. 마찬가지로 혈관신생억제제제인 베바시주맙으로 치료받는 동안 고혈압이 발병하는 환자도 대체로 좋은 결과(3)가 나타났다.
어린이에게 사용하도록 승인된 몇 가지 표적요법은 면역억제와 정자생성(4) 능력 손상 등 성인과는 다른 부작용을 낳을 수 있다.
특정 유형의 암에 대해 어떤 표적요법이 승인되었는가?
FDA는 다음과 같은 유형의 일부 암환자의 치료에 대해 표적요법을 승인했다.
위나 위장 접합부의 암종: 트라스투주맙(상표명 : 허셉틴®), 라무시루맙(상표명 : 사이람자®)
방광암: 아테졸리주맙(테센트리크TM), 니볼루맙(옵디보®), 더발루맙(임핀지TM), 아벨루맙(바벤시오®), 펨브롤리주맙(키트루다®)
뇌종양: 베바시주맙(아바스틴®), 에롤리무스(아피니토르®)
유방암: 에버롤리무스(아피니토르®), 타목시펜(놀바덱스), 토레미펜(파레스톤®), 트라스투주맙(허셉틴®), 풀베스트란트(파스로덱스®), 아나스트로졸(아리미덱스®), 엑세메스테인(아로마신®), 라파티닙(타이커브), 레트로졸(페마라), 퍼투주맙(퍼제타), 아도-트라스투주맙 엔탄신(카드실라), 팔보시클립(이브란스), 리보시클립(키스쿠알리), 네라티닙 말레인산(네르링크스), 아베마시클립(베르제니오), 올라파립(린파자)
자궁경부암: 베바시주맙(아바스틴®), 펨브롤리주맙(키트루다®)
대장암: 세툭시맙(어비턱스®), 파니투무맵(벡티빅스®), 베바시주맙(아바스틴®), 지브-아프리브셉트(잘트랩®), 레고라페닙(스티바페닙), 라무시루맙(사이람자®), 니볼루맙(옵디보®), 이필리무맙(예르보이)
융기성 피부섬유육종 : 이마티닙 메실산 (글리벡®)
내분비/신경내분비계종양: 란레오티드 아세테이트(소마툴린® 디포), 아벨루맙(바벤시오®), 루테튬 루 177-도타테이트(루타테라®), 아이오벤구안 1 131(아제드라®)
두경부 암: 세툭시맙(어비툭스®), 펨브롤리주맙(키트루다®), 니볼루맙(옵디보®)
위장관계 기질암: 이마티닙 메실산염(글리벡®), 수니티닙(수텐트®), 레고라페닙(스티바가®)
뼈의 거대세포 암: 데노수맙(엑스제바®)
신장암: 베바시주맙(아바스틴®), 소라페닙(넥사바®), 수니티닙(수텐트®), 파조파닙(보트리엔트®), 템시롤리무스(토리세이®), 에브롤리무스(아피니토르), 악시티닙(인리타®), 니볼루맙(옵디보), 카보잔티닙(카보메틱스), 렌바티닙 메실산(렌비마), 이필리무맙(예르보이)
백혈병: 트레티노인(베사노이드®), 이마티닙 메실레이트(글리벡®), 다사티닙(스프리셀®), 닐로티닙(타시그나®), 보수티닙(보슬리프®), 리툭시맙(리툭산®), 알렘투주맙(캠파스®), 오파투무맙(아르제라®), 오빈누투주맙(가지바), 이브루티닙(임브루비카), 이델라리십(자이델릭),
간암: 소라페닙(넥사바®), 레고라페닙(스티바페닙), 니볼루맵(옵디보®), 렌바티니브 메실레이트(렌비타®), 펨브로리주맙(키트루다®), 카보잔티닙(카보메틱스TM)
폐암: 베바시즈맵(아바스틴®), 세리조티닙(잘코리®), 엘로티닙(이레사®), 게피티니브(이레사®), 아파티닙 디말레이트(길로트리프®), 세리티닙브(LDK378/자이카디아TM),라무시룸맙(사이람자), 니볼루맙(옵디보), 펨브롤리줌맙(키트루다), 오시메티닙(타그리쏘), 네시투무맙(포트라자), 알렉티닙(알렉센사), 아테졸리주맙(텍센트릭), 브리가티닙(알룬브릭), 트라메티닙(메키니스트), 다브라페닙(타핀라르), 두르발루맙(임핀지), 다코미티닙(비짐프로)롤라티닙(로르브레나)
림프종: 이브리투모맙 투우세탄, 데닐루킨 디프티톡스(Ont탁®), 브렌툭시맙 베도틴(아드세트리스®), 리툭시맙(리툭산®), 보리노스타트(벨카데), 프랄라트렉세이트(폴로틴), 이브루티닙(임브루비카), 실툭시맙(실반트), 이델라리십(자이델릭), 벨리노스타트(벨레오닥), 오비누투주맙(가지바), 니볼루맙(옵디보), 펨브롤리주맙(키트루다), 리툭시맙 및 히알루로니다제 휴먼(리툭산 히셀라), 코판리십 염산염(알리코파)악시캅타진 실로류셀(예스카타), 아칼라브루티닙(칼쿠엔스), 티사젠레클루셀(킴리아), 베네토클락스(벤클렉스타), 모가물리주맙-kpkc(포텔리지오)두벨리십(코픽트라)
미소부수체 고-불안정 혹은 불일치 복구 결손 고형암: 펨브로리주맙(키트루다®)
다발성 골수종: 보르테조밉(벨카데®), 카필조밉(키프롤리스®), 파노비노스타트(파리닥®), 다라투무맙(다잘렉스TM), 익사조밉구연산 (닌라로®), 엘로투주맙(엠플리시티TM)
골수 악성/골수 증식성 장애: 이마티닙 메실레이트(글리벡®), 룩솔리티닙 인산염(자카피®)
신경교종: 디누투시맙 (유니툭신TM)
난소 상피/나팔관/원발 복막암: 베바시주맙(아바스틴®), 올라파립(린파자TM), 루카파립 캄실레이트(루브라카TM), 니라파니라파립 토실레이트 모노히드레이트(제줄라TM)
췌장암: 에를로티닙(타세바®), 에버롤리무스(아피니토르®), 수니티닙(수텐트®)
전립선암: 카바지탁셀(제브타나®), 엔잘루타미드(스탄디®), 아비라테론 아세테이트(자이티가®), 라듐 223 디클로라이드(소피고®), 아팔루타미드(에를리아다TM)
피부암: 비스모디집(에리베지®), 소니데집(오돔조®), 이필리무맙(예르보이®), 베무라페닙(메키니스트®), 다브라페닙(타핀라®), 펨브롤리주맙(키트루다®), 니볼루맙(옵디보), 코비메티닙(코텔릭), 알리트레틴노인(판레틴), 아벨루맙(바벤시오), 엔코라페닙(브라프토비), 비니메티닙(멕토비), 세미플리맙-rwlc(립ㅌ타요) 등
연부조직 육종 : 파조파닙(보트리엔트®), 알리트레티노인(판레틴®)
NTRK 유전자 융합 고형 암: 라로트렉티닙 황산염(비트라키비)
위암: 펨브로리주맙(키트루다®)
전신 비만 세포증: 이마티닙 메실산염(글리벡®), 미도스타우린(라이답트®)
갑상선암: 카보잔티닙(코메트릭®), 반데타닙(카프렐사®), 소라페닙(넥사바®), 레바티닙 메실레이트(렌비마®), 트라메티닙(메케니스트®), 다브라페닙(타핀라r®)
표적요법의 임상시험에 관한 정보는 어디에서 찾을 수 있는가?
FDA가 승인한 특정 유형의 암에 대한 실험 표적요법은 임상 시험에서 연구되고 있다. 국립암연구소(NCI)의 암 임상시험 목록을 검색하면 암환자의 표적치료 유형을 테스트하는 지속적인 임상시험에 대한 설명을 볼 수 있다. NCI의 암 임상시험 목록에는 메릴랜드 주 베데스다에 있는 국립보건원(국립암연구소의 상급기관) 임상센터를 포함하여 미국과 캐나다 전역에서 진행되고 있는 모든 NCI 지원 임상시험이 포함된다. 목록을 검색하는 다른 방법에 대한 자세한 내용은 NCI 지원 임상시험 찾기를 참조하십시오.
또는 표적요법의 임상시험에 관한 정보는 1-800-4-CANCER (1-800-422-6237)로 전화하면 된다.
What are the limitations of targeted cancer therapies?
Targeted therapies do have some limitations. One is that cancer cells can become resistant to them. Resistance can occur in two ways: the target itself changes through mutation so that the targeted therapy no longer interacts well with it, and/or the tumor finds a new pathway to achieve tumor growth that does not depend on the target.
For this reason, targeted therapies may work best in combination. For example, a recent study found that using two therapies that target different parts of the cell signaling pathway that is altered in melanoma by the BRAF V600E mutation slowed the development of resistance and disease progression to a greater extent than using just one targeted therapy (1).
Another approach is to use a targeted therapy in combination with one or more traditional chemotherapy drugs. For example, the targeted therapy trastuzumab (Herceptin®) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu.
Another limitation of targeted therapy at present is that drugs for some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell. One example is Ras, a signaling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer). To date, it has not been possible to develop inhibitors of Ras signaling with existing drug development technologies. However, promising new approaches are offering hope that this limitation can soon be overcome.
What are the side effects of targeted cancer therapies?
Scientists had expected that targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have substantial side effects.
The most common side effects seen with targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects seen with targeted therapies include:
-Skin problems (acneiform rash, dry skin, nail changes, hair depigmentation)
-Problems with blood clotting and wound healing
-High blood pressure
-Gastrointestinal perforation (a rare side effect of some targeted therapies)
Certain side effects of some targeted therapies have been linked to better patient outcomes. For example, patients who develop acneiform rash (skin eruptions that resemble acne) while being treated with the signal transduction inhibitors erlotinib (Tarceva®) or gefitinib (Iressa®), both of which target the epidermal growth factor receptor, have tended to respond better to these drugs than patients who do not develop the rash (2). Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have had better outcomes (3).
The few targeted therapies that are approved for use in children can have different side effects in children than in adults, including immunosuppression and impaired sperm production (4).
What targeted therapies have been approved for specific types of cancer?
The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):
Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®), ramucirumab (Cyramza®)
Bladder cancer: Atezolizumab (Tecentriq™), nivolumab (Opdivo®), durvalumab (Imfinzi™), avelumab (Bavencio®), pembrolizumab (Keytruda®)
Brain cancer: Bevacizumab (Avastin®), everolimus (Afinitor®)
Breast cancer: Everolimus (Afinitor®), tamoxifen (Nolvadex), toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta®), ado-trastuzumab emtansine (Kadcyla®), palbociclib (Ibrance®), ribociclib (Kisqali®), neratinib maleate (Nerlynx™), abemaciclib (Verzenio™), olaparib (Lynparza™)
Cervical cancer: Bevacizumab (Avastin®), pembrolizumab (Keytruda®)
Colorectal cancer: Cetuximab (Erbitux®), panitumumab (Vectibix®), bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), regorafenib (Stivarga®), ramucirumab (Cyramza®), nivolumab (Opdivo®), ipilimumab (Yervoy®)
Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®)
Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot), avelumab (Bavencio®), lutetium Lu 177-dotatate (Lutathera®), iobenguane I 131 (Azedra®)
Head and neck cancer: Cetuximab (Erbitux®), pembrolizumab (Keytruda®), nivolumab (Opdivo®)
Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), sunitinib (Sutent®), regorafenib (Stivarga®)
Giant cell tumor of the bone: Denosumab (Xgeva®)
Kidney cancer: Bevacizumab (Avastin®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), temsirolimus (Torisel®), everolimus (Afinitor®), axitinib (Inlyta®), nivolumab (Opdivo®), cabozantinib (Cabometyx™), lenvatinib mesylate (Lenvima®), ipilimumab (Yervoy®)
Leukemia: Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), blinatumomab (Blincyto®), venetoclax (Venclexta™), ponatinib hydrochloride (Iclusig®), midostaurin (Rydapt®), enasidenib mesylate (Idhifa®), inotuzumab ozogamicin (Besponsa®), tisagenlecleucel (Kymriah®), gemtuzumab ozogamicin (Mylotarg™), rituximab and hyaluronidase human (Rituxan Hycela™), ivosidenib (Tibsovo®), duvelisib (Copiktra™), moxetumomab pasudotox-tdfk (Lumoxiti™), glasdegib maleate (Daurismo™), gilteritinib (Xospata®), tagraxofusp-erzs (Elzonris™)
Liver cancer: Sorafenib (Nexavar®), regorafenib (Stivarga®), nivolumab (Opdivo®), lenvatinib mesylate (Lenvima®), pembrolizumab (Keytruda®), cabozantinib (Cabometyx™)
Lung cancer: Bevacizumab (Avastin®), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), alectinib (Alecensa®), atezolizumab (Tecentriq™), brigatinib (Alunbrig™), trametinib (Mekinist®), dabrafenib (Tafinlar®), durvalumab (Imfinzi™), dacomitinib (Vizimpro®), lorlatinib (Lorbrena®)
Lymphoma: Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®), belinostat (Beleodaq®), obinutuzumab (Gazyva®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), rituximab and hyaluronidase human (Rituxan Hycela™), copanlisib hydrochloride (Aliqopa™), axicabtagene ciloleucel (Yescarta™), acalabrutinib (Calquence®), tisagenlecleucel (Kymriah®), venetoclax (Venclexta™), mogamulizumab-kpkc (Poteligeo®), duvelisib (Copiktra™)
Microsatellite instability-high or mismatch repair-deficient solid tumors: Pembrolizumab (Keytruda®)
Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), daratumumab (Darzalex™), ixazomib citrate (Ninlaro®), elotuzumab (Empliciti™)
Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®)
Neuroblastoma: Dinutuximab (Unituxin™)
Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin®), olaparib (Lynparza™), rucaparib camsylate (Rubraca™), niraparib tosylate monohydrate (Zejula™)
Pancreatic cancer: Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®)
Prostate cancer: Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223 dichloride (Xofigo®), apalutamide (Erleada™)
Skin cancer: Vismodegib (Erivedge®), sonidegib (Odomzo®), ipilimumab (Yervoy®), vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), cobimetinib (Cotellic™), alitretinoin (Panretin®), avelumab (Bavencio®), encorafenib (Braftovi™), binimetinib (Mektovi®), cemiplimab-rwlc (Libtayo®)
Soft tissue sarcoma: Pazopanib (Votrient®), alitretinoin (Panretin®)
Solid tumors with an NTRK gene fusion: Larotrectinib sulfate (Vitrakvi®)
Stomach cancer: Pembrolizumab (Keytruda®)
Systemic mastocytosis: Imatinib mesylate (Gleevec®), midostaurin (Rydapt®)
Thyroid cancer: Cabozantinib (Cometriq®), vandetanib (Caprelsa®), sorafenib (Nexavar®), lenvatinib mesylate (Lenvima®), trametinib (Mekinist®), dabrafenib (Tafinlar®)
Where can I find information about clinical trials of targeted therapies?
Both FDA-approved and experimental targeted therapies for specific types of cancer are being studied in clinical trials. Descriptions of ongoing clinical trials that are testing types of targeted therapies in cancer patients can be accessed by searching NCI’s list of cancer clinical trials. NCI’s list of cancer clinical trials includes all NCI-supported clinical trials that are taking place across the United States and Canada, including the NIH Clinical Center in Bethesda, MD. For information about other ways to search the list, see Help Finding NCI-Supported Clinical Trials.
Alternatively, call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for information about clinical trials of targeted therapies.
Selected References
1.Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine 2012; 367(18):1694-1703.
[PubMed Abstract]
2.Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: A literature-based meta-analysis of 24 trials. Lung Cancer 2012; 78(1):8-15.
[PubMed Abstract]
3.Cai J, Ma H, Huang F, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World Journal of Surgical Oncology 2013; 11:306.
[PubMed Abstract]
4.Gore L, DeGregori J, Porter CC. Targeting developmental pathways in children with cancer: what price success? Lancet Oncology 2013; 4(2):e70-78.
[PubMed Abstract]