RAS MUTANT METASTATİK KOLON KANSERİ OLGU SUNUMU. Dr. Evren YETİŞİR

RAS MUTANT METASTATİK KOLON KANSERİ OLGU SUNUMU Dr. Evren YETİŞİR

56 yaş, erkek hasta Şubat 2015 te karın ağrısı, kabızlık şikayeti ile başvurdu. Yapılan kolonoskopi sonucu transvers kolonda obstrüksiyona neden olmayan kitle saptandı. Kolonoskopi sırasında kitleden alınan bx sonucu adenokarsinom ile uyumlu olan hastanın BT incelemesinde karaciğerde her iki lobda en büyüğü 5 cm boyutunda olan multiple metastatik lezyonları saptandı.

ECOG PS:0 Hipertansiyon(+), antiht tedavi ile TA regüle DM(-) CEA: 232,3 CA19-9: 164,1

Bu aşamada ne yapılmalıdır? a) Primere yönelik cerrahi sonra kemoterapi planlanmalı b) KT+Anti-VEGF tedavi c) RAS wild ise KT+antiEGFR tedavi

Factors influencing a physician s What Influences Treatment Choice in mcrc? decision for the treatment Patient characteristics Molecular characteristics Comorbidities Prior adjuvant treatment RAS BRAF Age Performance status MSI high Tumour characteristics Patient preference Tumour burden Resectability Quality of life Toxicity profile Tumour location MSI, microsatellite instability; mcrc, metastatic colorectal cancer. NP/AVAC/1507/0013

ESMO kılavuzu: tedavi hedefi, tedavinin yoğunluğunu etkilemektedir Grup 0 Grup 1 Grup 2 Grup 3 Hasta Ağırlıklı olarak rezekte edilebilir Potansiyel olarak rezekte edilebilir Hastalığın kötüleşmesiyle semptomatik Asemptomatik Hedef İyileşme Maksimum küçülme Hızlı tümör küçülmesi/ hastalık kontrolü Hastalık kontrolü/ düşük toksisite Cerrahi girişim Tedavi yoğunluğu Üçlü tedavi + antikor İndüksiyon+ idame İkili tedavi + antikor Sürekli tedavi İndüksiyon+ idame Monoterapi + antikor Tüm hastalarda yüksek yoğunluklu tedavi gerekli değildir Van Cutsem, et al. Ann Oncol 2014

ESMO kılavuzu birinci basamak tedavi tabakalandırma grupları arasındaki mkrk hasta dağılımı Metastatik kolorektal kanser ~%15 1,2 ~%85 1,2 Başlangıçta R0 rezekte edilebilen Klinik tabloda rezekte edilemeyen %10-30 2 %70-90 2 Potansiyel olarak rezekte edilebilen Hiçbir zaman rezekte edilemeyen Grup 0 Grup 1 Grup 2* Grup 3 Schmoll HJ et al. Ann Oncol. 2012;23(10):2479-516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56-62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037-45. *Bazı hastalar tedaviye istisnai yanıtın ardından rezekte edilebilir hale gelebilir. KT, kemoterapi; R0, mikroskobik olarak negatif sınırlarla rezeksiyon.

ESMO 2012 Klinik Kılavuzu 1. basamak tedavi için mkrk hastalarının gruplandırılması Metastatik kolorektal kanser Grup 0 Grup 1 Grup 2 Grup 3 Başlangıçta R0 rezekte edilebilen Evet Grup 0 Hayır KT ile potansiyel olarak R0 rezekte edilebilen + hasta KT ve cerrahi girişimi tolere edebilir. Hayır Evet Grup 1 Semptomatik veya agresif hastalık Evet Grup 2 Hayır Çok ilerlemiş/yük oluşturan hastalık Evet Hasta KT'yi tolere edebilir. Evet Grup 2 Hayır Hayır Grup 3 Schmoll HJ et al. Ann Oncol. 2012;23(10):2479-516 KT, kemoterapi; R0, mikroskobik olarak negatif sınırlarla rezeksiyon.

Primary Tumor Location and Primary Tumor Location and Potential Potential Treatments Treatments Anti-PD1 Right-sided MSI-H Left-sided Bev + Triplet CT BRAF MT HER2+ HER2-targeted agents KRAS MT KRAS WT AREG/EREG Right-sided tumours Incidence: ~40% Older patients Higher in female patients Microsatellite instability BRAF, PI3KCA, KRAS mut Worse prognosis Bevacizumab + CT Anti-EGFRs + CT Bufill JA. Ann Intern Med. 1990;113:779-788; Missiaglia E, et al. ASCO 2013. Abstract 3526; Brule SY, et al. ASCO 2013. Abstract 3528; The Cancer Genome Atlas Network. Nature. 2012490:61-70; Bendardaf R, et al. Anticancer Res. 2008;28:3865-3870. Left-sided tumours Incidence: ~60% Younger patients Predominantly wild type HER2 gain High AREG, EREG Better prognosis

Survival Probability % Overall Survival for Stage IV CRC in SEER by Primary Tumor Location, 2000-2012 Diagnoses All Right colon: 38% Transverse colon: 6% Cecum/Ascending: 32% 1 0,8 0,6 0,4 Right Colon Transverse Colon Left Colon Rectal 0,2 0 0 12 24 36 48 60 Months from Diagnosis Curves truncated at 60 months Presented by: D Schrag, MD

80405: Side of Primary Tumors TRANSVERSE N = 66 RIGHT N = 293 (27%) LEFT N = 732 (68%) COULD NOT DETERMINE N = 46 Presented by:

Hastanın lezyonu obstrüksiyon semptomları yapmadığı için direkt 1. basamak tedavi planlandı. Hastanın bu süreçte yapılan RAS mutasyon analizi sonucu KRAS kodon 12 de mutasyon saptandı.

Ras mutant gelen hastada tedavi olarak ne seçilmelidir? a) FOLFOX b) FOLFOX+Bevacizumab c) FOLFİRİ d) FOLFİRİ+Bevacizumab

Optimized Treatment Strategy mcrc, palliative setting, PS 0-1 Unresectable Liver and Retroperitoneal LN Metastases Molecular testing Any RAS mut (55%) All RAS wt (40%) BRAF mut (5%) PD1 Bevacizumab + CT doublet Bevacizumab + CT doublet EGFR inhibitor + CT doublet Bevacizumab + FOLFOXIRI PD2 VEGFi + CT doublet VEGFi + CT doublet Bevacizumab + CT doublet EGFR inhibitor? + /- chemotherapy PD3 Regorafenib EGFR inhibitor +/- irinotecan Regorafenib Regorafenib PD4 BSC Regorafenib BSC BSC BSC Sridharan et al., Oncology 2014

mkrk tedavisinde kemoterapi rejimleri Rejim Yanıt oranı (%) Sağkalım (ay) Irinotekan Okzaliplatin IFL 39 14.8 TEGAFIRI 1 4 21 42 14.9 20 XELIRI 5ı 44 47 17.0 20 FOLFIRI 6 49 17.4 bfufox TEGAFOX 4,7 9 34 51 14.1 19 CAPOX 10 42 55 19.5 FOLFOX 11 45 19.5 1.Delord JP, et al. Perspectives In Colorectal Cancer.,Barcelona, Spain, 2003,2. Douillard J-Y, et al. J Clin Oncol 2004;22(Suppl.) (Abstract 3545) 3. Mendez M, et al. Invest New Drugs 2005;23:243 251, 4. Bajetta E, et al. Br J Cancer 2007;96:439 444, 5. Bajetta E, et al. Cancer 2004;100:279 287, 6.Douillard JY, et al. Lancet 2000;355:1041 1047, 7.Rosati G, et al. Oncology 2005;69:122 129, 8.Feliu J, et al. Br J Cancer 2004;91:1758 1762, 9. Bennouna J, et al. Br J Cancer 2006;94:69 73, 10. Cassidy J, et al. J Clin Oncol 2004;22:2084 2091, 11. Goldberg RM, et al. J Clin Oncol 2004;22:23 30

Daily practice* Phase III clinical trial Bevacizumab + irinotecan combinations: Overall survival in 1. line 20 months IFL alone (AVF2107g) 1 (n=411) 15,6 Bevacizmab + IFL (AVF2107g) 1 Bevacizumab + irinotecan-based chemotherapy (German registry) 2 Bevacizumab + FOLFIRI (AVIRI) 3 (n=402) (n=1,075) 20,3 22,2 25,8 Bevacizumab + FOLFIRI (BRiTE) 4 (n=209) 22,9 Becazimab + FOLFIRI (BEAT) 5 (n=279) 23,7 (n=503) *Large, prospective, observational trials Note: cross-trial comparison 0 5 10 15 20 25 30 Median OS (months) 1. Hurwitz, et al. NEJM 2004; 2. Arnold, et al. ASCO GI 2010 3. Sobrero, et al. Oncology 2009; 4. Kozloff, et al. Oncologist 2009 5. Van Cutsem, et al. Ann Oncol 2009

Daily Phase III practice* clinical trial Bevacizumab plus oxaliplatin combinations 20 months XELOX/FOLFOX4 alone (NO16966) 1 (n=701) 19,9 Avastin + XELOX/FOLFOX4 (NO16966) 1 Avastin + oxaliplatin-based chemotherapy (German registry) 2 Avastin + FOLFOX (BRiTE) 3 (n=699) (n=312) 21,3 24,4 27,0 Avastin + XELOX (BRiTE) 3 (n=1,093) 23,6 Avastin + FOLFOX (BEAT) 4 (n=94) 25,9 Avastin + XELOX (BEAT) 4 (n=552) 23,0 (n=346) *Large, prospective, observational trials Note: cross-trial comparison 0 5 10 15 20 25 30 Median OS (months) 1. Saltz, et al. JCO 2008; 2. Arnold, et al. ASCO GI 2010 3. Kozloff, et al. Oncologist 2009; 4. Van Cutsem, et al. Ann Oncol 2009

OS (mo) First-Line Bevacizumab in MCRC: Overall Survival AVF2107g NO16966 BICC-C TREE-2 30 25 20 15 15,6 20,3 19,9 21,3 23,1 28,0 17,6 19,2 20,7 26,0 27,0 10 5 0 IFL bfol + bevacizumab mifl + bevacizumab mifl FOLFIRI + bevacizumab FOLFIRI FOLFOX/CapeOx FOLFOX/CapeOx + Bev IFL + bevacizumab CapeOx + bevacizumab mfolfox + bevacizumab a P<0.001; b P=0.0769. Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510; Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.

Bevasizumab + KT ile KT lerin karşılaştırıldığı çalışmalar PRIME 7 AVF2107g 9 CRYSTAL 1 ITACa 11 CALGB/ SWOG 80405 5,6 FIRE-3 2 COIN 4 NO16966 10 PEAK 8 OPUS 3 1. Van Cutsem E, et al. J Clin Oncol 2015;33:692 700; 2. Heinemann V, et al. Lancet Oncol 2014;15:1065 1075; 3. Bokemeyer C, et al. Eur J Cancer 2015;51:1243 1252; 4. Maughan TS, et al. Lancet 2011;377:2103 2114 5. Venook AP, et al. ASCO 2014 (AbstraKT No. LBA3), updated information presented at meeting: http://meetinglibrary.asco.org/content/94399?media=sl (accessed June 30 2015); 6. Lenz H-J, et al. ESMO 2014 (AbstraKT No. 501O); updated information presented at the meeting: https://content.webges.com/library/esmo/browse/search/3py#9faw02sg (accessed June 30 2015); 7. Douillard JY, et al. Ann Oncol 2014;25:1346 1355; 8. Schwartzberg LS et al. J Clin Oncol 2014;32:2240 2247; 9. Hurwitz H, et al. New Engl J Med 2004;350:2335 2342; 10. Saltz LB, et al. J Clin Oncol 2008;26:2013 2019; 11. Passardi A, et al. Ann Oncol 2015;26:1201 1207; 12. Erbitux SmPC June/2014

PFS estimate Phase III trial of IFL ± bevacizumab in mcrc: PFS 1.0 0.8 HR=0.54, p<0.001 Median PFS: 6.2 vs 10.6 months 0.6 0.4 0.2 0 IFL + placebo IFL + bevacizumab 0 10 20 30 Time (months) Hurwitz, et al. NEJM 2004

Genel sağkalım, % Bevasizumab + KT vs KT: Benzer çalışamalarda farklı OS sonuçları AVF2107g çalışması: 1. basamak mcrc de Bevacizumab + IFL vs IFL (n=813) 1 100 Bevacizumab + IFL (n=402) Placebo + IFL (n=411) 80 60 15.6 20.3 HR=0.66 p<0.001 40 20 0 0 10 20 30 40 Ay *IFL is no longer a recommended chemotherapy regimen 2 Figure adapted from Hurwitz H, et al. New Engl J Med 2004;350:2335 2342 IFL, KT regimen consisting of Irinotecan, 5-fluorouracil and Leucovorin 1. Hurwitz H, et al. New Engl J Med 2004;350:2335 2342; 2. NCCN clinical praktice guidelines; Colon Cancer, Version 2.2015. Available at www.nccn.org/professionals/physician_gls/pdf/colon.pdf (accessed April 2015)

XELOX vs FOLFOX4 ± bevacizumab: NO16966 study design Recruitment June 2003 May 2004 Recruitment Feb 2004 Feb 2005 XELOX (n=317) Placebo + XELOX (n=350) Bevacizumab + XELOX (n=350) FOLFOX4 (n=317) Placebo + FOLFOX4 (n=351) Bevacizumab + FOLFOX4 (n=349) Initial 2-arm, open-label study (n=634) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data became available (n=1,400) Cassidy & Saltz. JCO 2008

PFS estimate PFS chemotherapy + bevacizumab superiority: primary endpoint 1.0 0.8 HR=0.83 (97.5% CI: 0.72 0.95) (ITT) p=0.0023 0.6 0.4 0.2 0 8.0 9.4 0 5 10 15 20 25 Time (months) FOLFOX4 + placebo/xelox + placebo FOLFOX4 + bevacizumab/xelox + bevacizumab n=701; 547 events n=699; 513 events Saltz, et al. JCO 2008

PFS estimate PFS estimate PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX4 subgroups 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 0 7.4 9.3 0 5 10 15 20 25 Time (months) XELOX + placebo, n=350; 270 events XELOX + bevacizumab, n=350; 258 events XELOX subgroup HR=0.77 (97.5% CI: 0.63 0.94) p=0.0026 8.6 9.4 0 0 5 10 15 20 25 Time (months) FOLFOX4 + placebo, n=351; 277 events FOLFOX4 + bevacizumab, n=349; 255 events FOLFOX4 subgroup HR=0.89 (97.5% CI: 0.73 1.08) p=0.1871 Saltz, et al. ASCO GI 2007

Hasta oranı Bevasizumab + KT vs KT: Benzer çalışamalarda farklı OS sonuçları NO16966 çalışması: 1. basamak mcrc de Bevacizumab + XELOX/FOLFOX4 vs XELOX/FOLFOX4 (n=1400) 1.0 Bevacizumab + XELOX/FOLFOX4 (n=699) Placebo + XELOX/FOLFOX4 (n=701) 0.8 0.6 19.9 21.3 HR=0.89 p=0.077 0.4 0.2 0.0 0 6 12 18 24 30 36 Ay Figure adapted from Saltz LB, et al. J Clin Oncol 2008;26:2013 2019

OS Bevasizumab + KT vs sadece KT: Benzer çalışamalarda farklı OS sonuçları ITACa çalışması: : 1. basamak mcrc Bevacizumab + FOLFOX4/FOLFIRI vs FOLFOX4/FOLFIRI (n=370) 1.0 Bevacizumab + FOLFOX4/FOLFIRI (n=176) FOLFOX4/FOLFIRI (n=194) 0.8 0.6 20.8 21.3 HR düzeltilmiş*=1.13 p=0.317 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 Ay *adjusted by centre, KT regimen and KRAS status Figure adapted from from Passardi A, et al. Ann Oncol 2015;26:1201 1207

RAS mutant olan olguya FOLFOX+BEVACIZUMAB tedavisi başlandı. 3 kür sonra yapılan değerlendirmede görüntülemede parsiyel yanıt ve tm markerlarında regresyon saptandı. G1 periferik nöropati nedeniyle nörolojiye konsulte edilen hastaya gabapentin başlandı.

6 siklus sonrası marker yanıtı devam eden hastanın BT de stabil hastalık tespit ediliyor G2 periferik nöropatisi!!!!

6 siklus sonrası marker yanıtı devam etmekte, G2 periferik nöropatisi ve BT de stabil hastalık mevcuttur. Nasıl bir yol izlenmelidir? a) Tedaviye devam edilmeli b) FU-Anti-VEGF ile idame tedavisine geçilmeli c) İlaçsız izleme geçilmeli

mcrc de Bevacizumab idame tedavilerinin özeti Trial Maintenance Regimen Median PFS, Mos P Value Median OS, Mos P Value STOP and GO [1] Experimental Bevacizumab+XELOX 8.3 0.002 20.2 0.100 Control Bevacizumab+Xeloda 11 23.8 0.06 MACRO [2] Experimental CAPOX-B 10.4 23.2.38 Control Bevacizumab 9.7 19.99.65 CAIRO-3 [3] Experimental CAPOX-B 11.7* 21.6 <.0001 Control Observation 8.5* 18.1.22 SAKK 41/06 [4] Experimental Bevacizumab 9.5 25.1.021 Control Observation 8.5 22.8.218 AIO 0207 [5] Experimental FP + Bev/Bev 6.2/4.2 23.8/26.2 <.0001 Control Observation 3.6 23.1.70 1. Stop and Go Yalcın et.al. Oncology 2013 2. Diaz-Rubio E, et al. Oncologist. 2012;17:15-25. 3. Koopman M, et al. ASCO 2014. Abstract 3504. 4. Koeberle D, et al. ASCO 2013. Abstract 3503. 5. Arnold D, et al. ASCO 2014. Abstract 3503.

STOP AND GO ÇALIŞMASI Yalcin, ve ark. Oncology 2013;85:328 335

Stop and Go : Çalışma Tasarımı Daha önce tedavi almamış A Kolu Altuzan + XELOX (n=62) Altuzan + XELOX PD mkrk ECOG 2 (n=123) R B Kolu Altuzan + XELOX (6 SİKLUS) (n=61) Altuzan + Xeloda PD Çok merkezli, 1:1 randomize, faz III çalışma Yalcin, ve ark. Oncology 2013;85:328 335

Stop and Go: Progresyonsuz Sağkalım 8,3 ay 11 ay Median, ay (%95 GA) A kolu B kolu 8,3 (7,1-9,5) 11 (9,1-12,9) HR p-value 0,6 p=0,002 Yalcin, ve ark. Oncology 2013;85:328 335

Stop and Go : Genel Sağkalım A kolu B kolu 23,8 ay Median, ay (%95 GA) 20,2 (22-28,8) 23,8 (18,4-23,5) 20,2 ay p-value p=0,100 Yalcin, ve ark. Oncology 2013;85:328 335

Yalcin, ve ark. Oncology 2013;85:328 335 Stop and Go: Yanıt oranları

Hastanın tedavisine FUFA+BEVACIZUMAB ile devam ediliyor. 6 ay sonra yanıt değerlendirilmesi amacıyla yapılan görüntülemede progresyon saptanıyor. ECOG PS:1

Bu aşamada PS:1 olan hastada 2. basamak tedavi olarak ne seçelim? a) Folfiri+Bevacizumab b) FOLFİRİ+Aflibercept c) Oxaliplatin reintroduction

Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Phase III ML18147 (TML): Continuing Bevacizumab Beyond Progression Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS ( 9 vs > 9 mos), time from last BEV dose ( 42 vs > 42 days), ECOG PS at baseline (0/1 vs 2) Progressive mcrc after BEV + standard first-line CT (either oxaliplatin or irinotecan based) (n = 820) Standard second-line CT (oxaliplatin or irinotecan based) until PD (n = 411) Bevacizumab 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD (n = 409) Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

4.1 mo OS (%) PFS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Continuing Bevacizumab Beyond Progression (TML): OS, PFS Overall Survival Progression-Free Survival 100 80 60 Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P =.0062) Stratified HR: 0.83 (95% CI: 0.71-0.97; log-rank P =.0211) 100 80 60 Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P <.0001) Stratified HR: 0.67 (95% CI: 0.58-0.78; log-rank P <.0001) 40 40 20 0 9.8 mos 11.2 mos 0 6 12 18 24 30 36 42 48 Mos 20 0 CT (n = 410) BEV + CT (n = 409) 5.7 mo 0 6 12 18 24 30 36 42 Mos *Primary analysis method. Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS ( 9 mos, > 9 mos), time from last dose of BEV ( 42 days, > 42 days), ECOG PS at baseline (0, 1). Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Phase III VELOUR Study: FOLFIRI ± ziv- Aflibercept as Second-line Therapy in mcrc Stratified by previous bevacizumab (yes vs no), ECOG PS (0 vs 1 vs 2) Patients with mcrc progressing on first-line oxaliplatin-based chemotherapy* (planned N = 1226) FOLFIRI + ziv-aflibercept 4 mg/kg q2w (n = 612) FOLFIRI + Placebo q2w (n = 614) *30% had previous bevacizumab. Primary endpoint: OS Secondary endpoints: PFS, ORR, safety, immunogenicity No correlatives Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.

OS (%) PFS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology FOLFIRI ± ziv-aflibercept as Second-line Therapy in mcrc (VELOUR): OS, PFS Overall Survival Progression-Free Survival 100 Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P =.0032) 100 Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P <.0001) 80 80 60 40 Aflibercept/FOLFIRI Median: 13.50 mos 60 40 Aflibercept/FOLFIRI Median: 6.90 mos 20 Placebo/FOLFIRI Median: 12.06 mos 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Mos 20 Placebo/FOLFIRI Median: 4.67 mos 0 0 3 6 9 12 15 18 21 24 27 30 Mos Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.

OS (%) OS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology 2 nd -Line FOLFIRI ± ziv-aflibercept in mcrc (VELOUR): OS by Prior Bevacizumab Previous Bevacizumab No Previous Bevacizumab 100 HR: 0.862 (95.34% CI: 0.673-1.104) 100 HR: 0.788 (95.34% CI: 0.699-0.927) 80 80 60 40 Aflibercept/FOLFIRI Median: 12.5 mos 60 40 Aflibercept/FOLFIRI Median: 13.9 mos 20 Pts at Risk, n Placebo 187 AFL 186 Placebo/FOLFIRI Median: 11.7 mos 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 170 178 138 115 150 121 81 89 54 59 Mos 37 36 22 22 13 13 Tabernero J, et al. Eur J Cancer. 2014;50:320-331. 20 Pts at Risk, n Placebo 427 AFL 426 Placebo/FOLFIRI Median: 12.4 mos 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 403 347 286 388 348 295 205 139 222 157 Mos 94 65 112 82 38 62

Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Phase III RAISE Study: Second-Line Ramucirumab/FOLFIRI vs FOLFIRI Stratified by geographic region, KRAS mutation status, TTP after start of first-line therapy Patients with CRC and progression during or within 6 months of first-line bevacizumab, oxaliplatin, and a fluoropyrimidine (N = 1072) Ramucirumab 8 mg/kg + FOLFIRI q2w per cycle (n = 536) Placebo + FOLFIRI q2w per cycle (n = 536) Treat until PD or unacceptable toxicity Ramucirumab: anti-vegfr2 antibody Primary endpoint: OS Tabernero J, et al. Lancet Oncol. 2015;16:499-508.

Overall Survival Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Second-Line Ramucirumab/FOLFIRI vs FOLFIRI (RAISE): Overall Survival 1.0 0.8 0.6 0.4 Median OS, mo (95% CI) HR (95% CI) P Value (log-rank) Ramucirumab + Placebo + FOLFIRI FOLFIRI 13.3 11.7 (12.4-14.5) (10.8-12.7) 0.844 (0.73-0.976) (stratified).0219 (stratified) 0.2 Ramucirumab + FOLFIRI Placebo + FOLFIRI 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Pts at Risk, n Ram + FOLFIRI 536 497 421 345 269 195 114 78 53 34 22 12 4 0 0 Placebo + FOLFIRI 536 486 400 329 228 166 108 66 44 22 10 2 2 1 0 Tabernero J, et al. Lancet Oncol. 2015;16:499-508. Mos

Hastaya FOLFIRI+BEVACIZUMAB tedavisi başlanıyor. 3 kür sonrası stabil hastalık saptanan olguda 6. kür sonrası yapılan değerlendirmede progresif hastalık tespit ediliyor. Hastanın ECOG PS:1

Bu aşamada PS: halen 1. Ne yapalım? a) Regorafenib b) Rechallange sadece FOLFOX c) Rechallange Oxaliplatin+ Fluoropirimidin+antiVEGF tedavi devam

Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Phase III CORRECT: Regorafenib After Failure of Standard Therapy in mcrc Patients with progression after all available standard therapy (N = 760) 2:1 Arm A: Regorafenib 160 mg po qd + BSC 3 wks on, 1 wk off (n = 505) Arm B: Placebo + BSC 3 wks on, 1 wk off (n = 255) Primary endpoint: overall survival Prior systemic, anticancer therapies (palliative) 1-2 prior lines: 26% 3 prior lines: 26% 4 prior lines: 48% Grothey A, et al. Lancet. 2013;381:303-312.

OS (%) PFS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Regorafenib After Failure of Standard Therapy in mcrc (CORRECT): OS, PFS 100 75 Overall Survival HR: 0.77 (95% CI: 0.64-0.94; P =.0052) 100 75 Progression-Free Survival HR: 0.49 (95% CI: 0.42-0.58; P <.0001 ) 50 25 0 Placebo (n = 255) Regorafenib (n = 505) 0 2 4 6 8 10 12 14 50 25 0 Placebo (n = 255) Regorafenib (n = 505) 0 2 4 6 8 10 12 Mos From Randomization Mos From Randomization Regorafenib Placebo Median OS, mo 6.4 5.0 IQR 3.6-11.8 2.8-10.4 Regorafenib Placebo Median PFS, mo 1.9 1.7 IQR 1.6-3.9 1.4-1.9 Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P.009279 at approximately 74% of events required for final analysis) Grothey A, et al. Lancet. 2013;381:303-312.

Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Phase III CONCUR Study: Regorafenib in Previously Treated Asian mcrc Patients Stratified by number of metastatic sites (single vs multiple organs), time from diagnosis of metastatic disease (< 18 vs 18 mo) Asian patients with previously treated* mcrc, ECOG PS 0-1 (N = 204) Regorafenib 160 mg PO QD, D1-21 Q4W + Best Supportive Care (n = 136) Placebo + Best Supportive Care PO QD, D1-21 Q4W (n = 68) * 2 lines or unable to tolerate standard treatment Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR Li J, et al. Lancet Oncol. 2015;16:619-629.

OS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Regorafenib in Previously Treated Asian mcrc Patients (CONCUR): OS 100 75 50 Median OS (Primary Endpoint) Regorafenib: 8.8 months (95% CI: 7.3-9.8) Placebo: 6.3 months (95% CI: 4.8-7.6) HR: 0.55 (95% CI: 0.40-0.77) P =.00016 Regorafenib Placebo 25 0 Pts at Risk, n Regorafenib Placebo 0 2 4 6 8 10 12 14 16 18 Mos After Randomization 136 68 131 63 113 45 Li J, et al. Lancet Oncol. 2015;16:619-629. 88 35 72 23 52 15 42 11 24 4 4 1

PFS (%) Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment clinicaloptions.com/oncology Regorafenib in Previously Treated Asian mcrc Patients (CONCUR): PFS 100 75 Regorafenib: Median PFS: 3.2 months (95% CI: 2.0-3.7) Placebo: Median PFS: 1.7 months (95% CI: 1.6-1.8) HR: 0.31 (95% CI: 0.22-0.44) P <.0001 50 25 Regorafenib Placebo 0 0 2 4 6 8 10 12 14 16 18 No. at Risk Regorafenib Placebo 136 68 74 6 46 2 Mos after Randomization 27 1 14 1 10 0 9 0 5 0 1 0 - - Li J, et al. Lancet Oncol. 2015;16:619-629.

Hastaya REGORAFENİB tedavisi başlandı. 6 aydır tedavisine devam edilen hastanın stabil hastalığı mevcut.

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