METASTATİK BÖBREK KANSERİNDE TEDAVİ İMMÜNOTERAPİ GERİ GELDİ

Transkript

1 METASTATİK BÖBREK KANSERİNDE TEDAVİ İMMÜNOTERAPİ GERİ GELDİ DR.AHMET BİLİCİ MEDİPOL ÜNİVERSİTESİ TIP FAKÜLTESİ, TIBBİ ONKOLOJİ B.D

2 Giriş İnsidans 2016 yılında US de ~ yeni tanı böbrek kanseri olgusu ve olgunun bu tümöre bağlı ölümü tahmin edilmektedir [1] ~ %75-80 clear cell RCC [2] Hastaların ~ %25-30 u metastatik evrede tanı alır [2] Hedefe yönelik tedaviler öncesi Sitokin bazlı tedaviler ile 3-5 aylık PFS [3-5] 17 aya kadar ortanca genel sağkalım [6] Güncel durum Hedefe yönelik ajanlar ile önemli iyileşme [5,7] Hedefe yönelik ajanlar ile 29 aya varan ortanca genel sağkalım [8] 1. Siegel RL, et al. CA Cancer J Clin. 2016;65: Motzer RJ, et al. N Engl J Med. 1996;335: Rini BI, et al. J Clin Oncol. 2008;26: Escudier B, et al. Lancet. 2007;370: Motzer RJ, et al. N Engl J Med. 2007;356: McDermott DF, et al. J Clin Oncol. 2005;23: Coppin C, et al. BJU Int. 2011;108: Motzer RJ, et al. N Engl J Med. 2013;369:

3 Giriş Tüm clear cell RCC lerin %80 inde vhl gen mutasyonu vardır vhl mutant RCC olgularında aktif olan yolaklar VEGF mtor

4 RCC tedavisi: Hem birinci basamak hem de sonraki basamaklar anjiogenezis yolunda çok sayıda hedef PI3K AKT mtor Cell growth survival Cell stimuli (eg, growth factors) Temsirolimus Everolimus HIFɑ Inactivated VHL tumor suppressor gene VHL HIFɑ HIFɑ HIFɑ HIFɑ Bevacizumab Hypoxia VEGF VEGFR PDGF Tumor PDGFR Sunitinib Sorafenib Pazopanib Axitinib Endothelial Cell Adapted from Rini BI, et al. Lancet. In press.

5 PERCY Quattro çalışması, mrcc: MPA Median OS, ay IFN 15.2 Survival (%) IL-2 IFN + IL Mos From Randomization 492 pts enrolled Primarily intermediate risk Negrier S, et al. Cancer. 2007;110:

6 Metastatik RCC de Kötü Risk Faktörleri: MSKCC Kriterleri Risk Grupları [1] İyi 0 Orta derecede 1 veya 2 Kötü MSKCC Kriterleri-Risk Faktörleri [1] KPS < 80% Tedaviye kadar geçen süre Hemoglobin LDH < 12 mos < LLN > 1.5 x ULN Düzeltilmiş serum kalsiyumu > 10.0 mg/dl [2] 3 veya daha fazla PLT ve Nötrofil sayıları > ULN VEGF-hedefli tedaviler için kötü prognostik faktörler [3] 1. Motzer RJ, et al. J Clin Oncol. 2002;20: Mekhail TM, et al. J Clin Oncol. 2005;23: Heng DY, et al. J Clin Oncol. 2009;27: Heng DY, et al. Lancet Oncol. 2013;14:

7 Tedavi Öncesi Tartışılacak Konular Nefrektominin rolü 1.seri tedaviye ne zaman başlanmalı Tedavi kararında dikkat edilecekler: Selektif etkinlik Terapötik indeks Daha önceki tedavilere yanıt Potansiyel yeni ajanlar ve klinik çalışmaların göz ardı edilmemesi

8 1.Basamak Sistemik Tedavi

9 Metastatik RCC de Güncel Tedavi İyi ya da orta risk grubu Kötü risk gurubu 1.Basamak Tedavi *Pazopanib veya *Sunitinib, bevacizumab + IFN* (veya diğer TKI, HD IL-2, or temsirolimus) Temsirolimus Veya sunitinib veya pazopanib 2. Basamak Tedavi *Kabozantinib, *Nivolumumab *axitinib (after TKI), Lenvatinib-everolimus (veya diğer TKI, temsirolimus, ya da bevacizumab) Axitinib, sorafenib, sunitinib, veya pazopanib (sitokin sonrası) (veya temsirolimus or bevacizumab) Standart yok (clinical trial, supportive care) *Category 1 NCCN. Clinical practice guidelines in oncology: kidney cancer. v

10 Phase III COMPARZ: 1.Basamak Pazopanib vs Sunitinib (Non-inferiority) Pts with mrcc clear-cell histology and no previous systemic therapy (N = 1110) Pazopanib 800 mg/day Sunitinib 50 mg/day (schedule 4/2) Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, safety, QoL, medical resource utilization Motzer RJ, et al. N Engl J Med. 2013;369:

11 COMPARZ: Etkinlik PFS (%) N Median PFS, Mos (95% CI) Pazopanib ( ) Sunitinib ( ) HR: 1.05 (95% CI: ) 20 Pazopanib Sunitinib Mos OS (%) Pazopanib Sunitinib N Median OS, Mos (95% CI) Pazopanib ( ) Sunitinib ( ) HR: 0.92 (95% CI: ); P = Mos Since Randomization Mean change from baseline in 11 of 14 health-related QoL during first 6 mos of treatment favored pazopanib (P <.05 for all 11 comparisons) Significantly less fatigue and foot soreness with pazopanib than with sunitinib Motzer RJ, et al. N Engl J Med. 2013;369: Motzer RJ, et al. N Engl J Med. 2014;370:

12 PISCES: Primer Sonlanım: Hasta Tercihi Difference (pazopanib vs sunitinib), % % CI for difference P value <.001 Pts (%) % 22% 8% Pazopanib Preferred Sunitinib Preferred No Preference Escudier BJ, et al. J Clin Oncol. 2014;32:

13 2.Basamak Sistemik Tedavi

14 Progresyon Sonrası Tedavi Seçimi Önceki tedaviye yanıt durumu Hastanın tercihi Tedavi opsiyonlarındaki terapötik indeks: Geneneksel tedaviler Yeni yaklaşımlar

15 İkinci Basamak Tedavideki Pivotal Faz-III Data VEGF Inhibitors mtori Drug Control Study Design PFS, Mos OS, Mos Sorafenib [1,2] Axitinib [3,4] Everolimus [5] Temsirolimus [6] Placebo Sorafenib Placebo Sorafenib Pts previously treated with IL-2 or IFN-α Pts previously treated with sunitinib, bevacizumab with IFNα, temsirolimus, or cytokines Pts previously treated with VEGFR TKI Pts previously treated with sunitinib 5.5 vs 2.8 (HR: 0.44; P < ) 8.3 vs 5.7 (HR: 0.66; P <.0001) 4.9 vs 1.9* (HR: 0.33; P <.001)* 5.5 vs 1.9 (HR: 0.32; P <.001) 4.3 vs 3.9* (HR: 0.87; P =.19) *Independent review. Investigator. Post-crossover placebo-censored OS data vs 15.2 (HR: 0.88; P =.146) 17.8 vs 14.3 (HR: 0.78; P =.029) 20.1 vs 19.2 (HR: 0.97; P =.374) 14.8 vs 14.4 (HR: 0.87; P =.162) 12.3 vs 16.6 (HR: 1.31; P =.01) 1. Escudier B, et al. N Engl J Med. 2007;356: Escudier B, et al. J Clin Oncol. 2009;27: Rini BI, et al. Lancet. 2011;378: Motzer RJ, et al. Lancet Oncol. 2013;14: Motzer R, et al. Cancer. 2010;116: Hutson TE, et al. J Clin Oncol. 2014;32:

16 Metastatik RCC Tedavisinde Yeni Ufuklar ve İmmünoterapi

17 Phase III METEOR Trial: Cabozantinib vs Everolimus in RCC After PD on VEGFR TKI Patients with clear-cell RCC with measurable disease and progression within 6 mos of treatment with a VEGFR TKI, Karnofsky PS > 70% (N = 658) Cabozantinib 60 mg/day* (n = 324) Everolimus 10 mg/day* (n = 324) *Dose reductions as needed for AEs: cabozantinib 40 mg then 20 mg, everolimus 5 mg then 2.5 mg Treat until clinical benefit no longer evident or unacceptab le toxicity Primary endpoint: PFS Secondary endpoints: OS, ORR Choueiri T, et al. N Engl J Med. 2015;

18 Phase III METEOR: PFS 100 Pts, n Median PFS, Mos (95% CI) Events, n 80 Cabozantinib Everolimus ( ) 3.8 ( ) PFS (%) HR: 0.58 (95% CI: ); P <.001 Everolimus Cabozantinib Choueiri T, et al. N Engl J Med Mos

19 Phase III METEOR: Güvenlik AEs as expected and managed with dose reductions: occurred in 60% with cabozantinib, 25% with everolimus Cabozantinib Most common grade 3/4 AEs Hypertension (15%) Diarrhea (11%) Fatigue (9%) Most common leading to d/c Diarrhea (16%) Hand foot syndrome (11%) Fatigue (10%) Everolimus Most common grade 3/4 AEs Anemia (16%) Fatigue (7%) Hyperglycemia (5%) Most common leading to d/c Pneumonitis (4%) Fatigue (3%) Stomatitis (3%) Choueiri T, et al. N Engl J Med. 2015

20 Primary endpoint: PFS by IRC PFS: 259 events among first 375 enrolled patients Hypothesized hazard ratio: Secondary endpoints: OS, and ORR by IRC OS: 408 events among 650 planned patients Hypothesized hazard ratio: 0.75 Advanced RCC OS Population (N = 650) PFS Population N = First 375 randomized IRC, independent radiology review committee; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

21 Characteristic Hasta Özellikleri Cabozantinib (N=330) Everolimus (N=328) Median age, years (range) 63 (32 86) 62 (31 84) Male, % Enrollment Region, % Europe / North America / APAC+LA 51 / 36 / / 37 / 16 ECOG Performance Status, % 0 / 1 68 / / 34 MSKCC risk group 1, % Favorable Intermediate Poor Metastatic sites per IRC, % Lung Liver Bone APAC, Asia Pacific; LA, Latin America

22 Tüm 658 hastadaki PFS ve Yanıt Oranları Progression-Free Survival per IRC 1 Objective Response Rate 1,2 Cabozantinib (N=330), % Everolimus (N=328), % 3.9 ay 7.4 ay ORR per IRC (95% CI) 17 (13, 22) 3 (2, 6) Stable disease Progressive disease Unable to determine 5 8 ORR per Investigator (95% CI) 24 (19, 29) 4 (2, 7) Stable disease Progressive disease 9 27 Unable to determine Escudier B et al, J Clin Oncol, 2016; 34(suppl 2S): Abstr 499, 2 Confirmed responses per RECIST version 1.1. All responses were partial responses. Cut-off for PFS and ORR: May 22, 2015

23 OS 21.4 ay 16.5 ay

24 Subgrup Analizi: OS No. of pts Overall Survival Median, months Hazard Ratio Cabozantinib Everolimus Overall MSKCC risk group Favorable NE 19.3 Intermediate Poor Prior VEGFR TKI Duration of 1st VEGFR TKI 6 months > 6 months Bone metastases No NE 17.5 Yes Visceral+bone metastases No Yes Tumor MET status High Low Unknown ,125 0,25 0, Favors cabozantinib Favors everolimus

25 MSKCC Risk Grubuna Göre Genel Sağkalım Favorable Risk Intermediate Risk Poor Risk HR 0.66 (95% CI ) HR 0.67 (95% CI ) HR 0.65 (95% CI ) Cabozantinib (N=150) Everolimus (N=150) Median (mo) NE 19.3 Cabozantinib (N=139) Everolimus (N=135) Median (mo) Cabozantinib (N=41) Everolimus (N=43) Median (mo) MSKCC Risk Groups: Motzer R et al, J Clin Oncol, 2004

26 Kemik Metastazlarında Genel Sağkalım Bone Metastases Bone and Visceral Metastases HR 0.54 (95% CI ) HR 0.45 (95% CI ) Median (mo) Median (mo) Cabozantinib (N=77) 20.1 Cabozantinib (N=60) 20.1 Everolimus (N=65) 12.1 Everolimus (N=52) 10.7

27 METEOR: Kabozantinib Sonuçlar Kabozantinib metastatik RCC 2.basamak tedavisinde anlamlı olarak hem PFS hem de genel sağkalımı arttırmıştır Klinik yarar tüm alt gruplarda Kabozantinib VEGF-TKİ sonrası metastatik RCC tedavisinde yeni standart Motzer et al, J Natl Compr Canc Netw, 2015, 2 Powles et al, Eur Urol, 2016, 3 CABOMETYX USPI, 2016.

28 Metastatik RCC Tedavisinde İmmünoterapi Geri Geldi High-dose IL-2 Level of Research IFN-α and IL-2 based regimens Rise of the targeted therapies Checkpoint inhibitors Vaccines* Recombinant T-cell receptors* Bispecific T-cell engagers* Bevacizumab + IFN-α < 1980s *Not approved for metastatic RCC as of January McDermott DF, et al. Semin Oncol. 2013;40: Figure adapted from L Harshman, MD

29 Interleukin-2 Doğal bir biyolojik immünomodülatör ajan T hücre proliferasyonu ve aktivasyonu İmmün cevap amplifikasyonu B hücreleri tarafından antikor üretimi NK hücre aktivasyonu T hücre sekresyonu (TNF ve diğer sitokinler) Abbas AK and Lichtman AH. Cellular and Molecular Immunology. 2003

30 HD-Interleukin-2 Tedavisi High-dose IL-2 (HD IL-2) az sayıda hasta grubunda durable tam yanıta yol açma potansiyeli 600,000 IU/kg (0.037 mg/kg) delivered by 15-min bolus i.v. infusion q8h for 14 doses 720,000 IU/kg delivered by 15-min bolus i. v. infusion q8h for 12 doses Typical Proleukin Treatment Schedule Treatment Course Recovery Period Cycle 1: Proleukin q8h NO TREATMENT Cycle 2: Proleukin q8h Resume NormalActivities ASSESMENT ~Day 47 Days 1-5 Days 6-14 Days About 4 Weeks Additional courses of treatment are given if there is some shrinkage following the last course. Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.

31 Interleukin-2: Metastatik RCC de Tedavi Sonuçları Therapy Trials N Patients N ORR (CR), % Survival Median, Months Trial Phase Observation LD IL-2 + IFN HD IL (3) 23 (8) III HD IL (7) 16 II HD IL-2 LD IL (7) 13 (4) III HD IL-2 IV LD IL-2 IV LD IL-2 SC (7) 11 (1) 10 (2) III Yagoda, Semin Oncol 1993; McDermott, J Clin Oncol 2005; Fisher, Cancer J 2000; Yang, J Clin Oncol 2003

32 Metastatik RCC de HD-IL-2 ile Yanıt Oranları %15 ORR (%7 CR, %8 PR) 1 Yanıt verenlerde median yanıt süresi: 54 ay (PR de 20 ay ve CR de ulaşılamadı 1 ) Parsiyel yanıtlıların %60 ında tüm ölçülebilir lezyonların > %90 regresyon 1 Tam yanıtlıların %60 ı 30 aydan fazla remisyonda kalmış Bazı parsiyel yanıtlılarda bazı rezidü lezyonlar rezeke edilebilmiş Hastalar minimum 65+ ay hastalıksız olarak yaşamış Response Duration for Patients receiving HD IL McDermott, Med Oncol 2009; 26:S13-S17; 2. Atkins, Kidney Int 2005; 67:

33 HD-Interleukin-2 Tedavisi İyi prognostik grupta Deneyimli merkezlerde Yanıt oranları %10 Yanıt süresi uzun Hala akılda tutulması gereken bir ajan Ancak çok iyi hasta seçimi şart

34 Mechanisms of Immune System Evasion/Suppression by Tumors Inhibition of tumor antigen presentation eg, MHC 1 Tumor eg, PD-L1 Inhibition of immune cell attack through checkpoint proteins eg, TGFβ Secretion of immunosuppressive factors Recruiting of immunosuppressive cells (Treg, MDSC) Drake CG, et al. Adv Immunol. 2006;90: Vesely MD, et al. Annu Rev Immunol. 2011;29:

35 Anti PD-1: T-Cell Suppresyonun Blokajı Activation (cytokines, proliferation, migration) B7-1 B7-2 CD28 + T cell T cell T cell APC or tumor cell PD-L1 TCR T cell PD Anti PD-1 blockade PD-L1 Suppression (anergy, exhaustion, T-cell death) Reprinted with permission of Dove Medical Press, Ltd. from Srivastava N, McDermott, D. Cancer Manag and Res. 2014;6: Cytokines Lysis Tumor cell death

36 PD-1 Pathway İnhibitörlerindeki Gelişmeler Agent Target Tumor Type Clinical Development Stage Nivolumab Pembrolizumab Atezolizumab (MPDL3280A) Durvalumab (MEDI4736) Avelumab PD-1 PD-1 PD-L1 Melanoma, NSCLC, RCC, Bladder/urothelial Hodgkin s lymphoma Brain, gastric/gej, HCC, HNSCC, SCLC Melanoma, NSCLC mcrc (MSI-high) Breast, bladder/urothelial, gastric/gej, HNSCC, multiple myeloma Bladder/urothelial, NSCLC Breast, RCC Approved (US) Breakthrough Therapy (US) Phase III Approved (US) Breakthrough Therapy (US) Phase III Breakthrough Therapy (US) Phase III PD-L1 Bladder, NSCLC, HNSCC Phase III PD-L1 Merkel cell NSCLC, gastric, ovarian, urothelial Breakthrough Therapy (US) Phase III

37 Nivolumab Klinik aktivite: Multipl Tümörlerde Faz 1 veriler Tumor Type N Dose, mg/kg ORR (CR/PR), n (%) 28 responses (16 melanoma, 6 RCC, and 6 NSCLC) lasted 1 yr among 54 pts with treatment initiation 1 yr before data analysis SD 24 Wks, n (%) Melanoma (28) 6 (6) NSCLC (18) 5 (7) RCC 33 1 or 10 9 (33) 9 (27) 13 pts (4 melanoma, 6 NSCLC, 3 RCC) demonstrated nonconventional patterns of response but were not included as responders Topalian SL, et al. N Engl J Med. 2012;366:

38 Nivolumab : Daha önce tedavi almış metastatik RCC de Phase I Çalışması ORR Duration of Response Best Tumor Burden Change (%) mg/kg nivolumab 10 mg/kg nivolumab Pts Responders (per RECIST) Wks Time to and duration of response up to discontinuation of therapy Response duration after discontinuation of therapy Ongoing response Time to response McDermott DF, et al. J Clin Oncol. 2015;33:

39 Atezolizumab ın metastatik RCC de etkinliği : Phase Ia Maximum SLD Reduction From Baseline (%) Clear-cell RCC (n = 62) ORR: 15% Median PFS: 5.6 mos Median OS: 28.9 mos 20 mg/kg 15 mg/kg 10 mg/kg 3 mg/kg 1200 mg Similar activity in VEGF-targeted therapy naive and refractory pts McDermott DF, et al. J Clin Oncol. 2016;[Epub ahead of print].

40 CheckMate-025: Nivolumab in Previously Treated Metastatic RCC Metastatic RCC with 2 prior antiangiogenic therapies and 3 total prior systemic regimens (N = 821) Nivolumab 3 mg/kg IV every 2 wks Everolimus 10 mg PO daily Primary endpoint: OS Secondary endpoints: PFS, ORR, OR duration, Safety Motzer R, et al. N Engl J Med. 2015;373:

41 CheckMate-025: OS Nivolumab (n = 410) Median OS, Mos (95% CI) 25.0 (21.8-NE) Everolimus (n = 411) 19.6 ( ) HR: 0.73 (98.5% CI: ; P =.0018) OS (%) Everolimus Nivolumab Mos Pts at Risk, n Nivolumab Everolimus Motzer R, et al. N Engl J Med. 2015;373:

42 CheckMate-025: Yanıt Özellikleri Pts Nivolumab Everolimus On treatment First response Ongoing response Off treatment Wks Motzer R, et al. N Engl J Med. 2015;373:

43 PFS (%) CheckMate-025: PFS Everolimus Mos Median PFS, Mos (95% CI) Nivolumab Pts at Risk, n Nivolumab Everolimus Events, n Nivolumab 4.6 ( ) 318 Everolimus 4.4 ( ) 322 HR (95% CI), 0.88 ( ); P = Median PFS was 15.6 mos (nivolumab, 95% CI: ) vs 11.7 mos (everolimus, 95% CI: ) (HR: 0.64; 95% CI: ) by a sensitivity analysis in pts who had not progressed or died at 6 mos Motzer R, et al. N Engl J Med. 2015;373:

44 AE, % CheckMate-025: Treatment-Related AEs ( 10% of Pts) Nivolumab (n = 406) Everolimus (n = 397) Any Grade Grade 3/4 Any Grade Grade 3/4 Treatment-related AEs Fatigue Nausea 14 < Pruritus Diarrhea Decreased appetite 12 < Rash 10 < Cough Anemia Dyspnea < 1 Edema peripheral < 1 Pneumonitis Mucosal inflammation Dysgeusia Hyperglycemia Stomatitis Hypertriglyceridemia Epistaxis Motzer R, et al. N Engl J Med. 2015;373:

45 CheckMate-025: QoL Skorlarındaki A clinically meaningful and statistically significant improvement in QoL was seen with nivolumab vs everolimus for the duration of the study FKSI-DRS: Mean Change From Baseline Worse Better Değişim Questionnaire completion rate: 80% during the first yr of follow-up Nivolumab Everolimus Pts at Risk, n Nivolumab Everolimus Motzer R, et al. N Engl J Med. 2015;373: Wks

46 CheckMate-025:PD-L1 Ekspresyon Durumuna Göre OS PD-L1 1% (n = 181/756, 24%) Median OS, Mos (95% CI) Nivolumab 21.8 ( ) Everolimus 18.8 ( ) HR: 0.78 (95% CI: ) PD-L1 < 1% (n = 575/756, 76%) Nivolumab Median OS, Mos (95% CI) 27.4 (21.4-NE) Everolimus 21.2 ( ) HR: 0.76 (95% CI: ) OS (%) Everolimus Nivolumab Everolimus Nivolumab Mos Pts at Risk, n Nivolumab Everolimus Mos Motzer R, et al. N Engl J Med. 2015;373:

47 CheckMate-025: Exploratory Analysis of Subgroup OS by Subgroup Nivolumab, n/n Everolimus, n/n Overall 183/ /411 MSKCC Favorable 45/145 52/148 Intermediate 101/ /203 Poor 37/64 47/60 Prior antiangiogenic regimens Region Age, yrs Sex 1 128/ / /116 57/114 US/Canada 66/174 87/172 Western Europe 78/140 84/141 Rest of the world 39/96 44/98 < / / to < 75 53/119 77/ /34 20/40 Female 48/95 56/107 Male 135/ /304 Motzer R, et al. N Engl J Med. 2015;373: Favors nivolumab

48 Potential Benefit of Nivolumab Treatment Beyond Progression in Advanced RCC: Subgroup Analysis of CheckMate 025

49 CheckMate 025: Phase III Çalışma Pts with advanced RCC with clear-cell component, KPS 70%, 1-2 previous antiangiogenic agents, progression 6 mos before enrollment (N = 803) Primary endpoint: OS Secondary endpoints: ORR, safety Tasarımı Nivolumab 3 mg/kg IV Q2W (n = 406) Everolimus 10 mg PO QD (n = 397) Progressed (n = 316) Did not progress (n = 90) Progressed (n = 320) Did not progress (n = 77) Treated beyond progression (n = 153) Treated briefly beyond progression (n = 18) Not treated beyond progression (n = 145) Treated beyond progression (n = 65) Treated briefly beyond progression (n = 111) Not treated beyond progression (n = 144) Subgroup analyses: efficacy, safety from baseline to first progression and after first progression Escudier BJ, et al. ASCO Abstract 4509.

50 CheckMate 025 Subgrup Analizi: Escudier BJ, et al. ASCO Abstract Hasta Özellikleri Disease Characteristics at First Progression TBP (n = 153) NTBP (n = 145) Median age, yrs (range) 62 (29-85) 63 (23-85) Male, % Quality of life score (FKSI-DRS),* median (range) 31.0 ( ) 27.0 ( ) KPS: 90/70 or 80/< 70, % 73/27/1 48/50/2 Change in KPS: deterioration/improvement, % 17/16 27/8 Target lesion status at progression, % Increase in target lesions Appearance of new lesions Both of above Site of new lesions : lung/node/bone/liver, % 14/10/5/5 12/10/14/8 Change in tumor burden, % Bulky to small Small to bulky *TBP, n = 135; NTBP, n = % increase in smallest SOD of target lesions. Based on all pts treated and not treated beyond progression. Bulky: 13 cm; small: < 13 cm

51 CheckMate 025 Subgrup Analizi: OS Nivolumab appears to improve OS in pts treated beyond progression Median OS, Mos (95% CI) Probabililty of OS TBP NTBP TBP 28.1 (23.2-NE) 15.0 ( ) HR: 0.41 (95% CI: ) NTBP Pts at Risk, n Mos TBP NTBP Escudier BJ, et al. ASCO Abstract 4509.

52 CheckMate 025 Subgrup Analizi: Tümör Yükündeki Azalma Postprogression nivolumab achieved reduced tumor burden in ~ 50% of evaluable pts (n = 142) In 14% (20/142), tumor burden reduced 30%; by contrast, 0/52 pts had tumor burden reduced 30% in the everolimus arm post progression Best Reduction From First Progression in Target Lesion (%) Best Reduction in Target Lesions With Nivolumab Asterisks represent responders before first progression. Square symbols represent % change truncated to 100% Pts Escudier BJ, et al. ASCO Abstract 4509.

53

54

55

56

57

58 Metastatik RCC İmmünoterapi Gelecek

59 Atezolizumab: Metastatik RCC de Preliminary ORR Pt Subgroup ORR, n (%) No previous VEGFR TKI (n = 24) 3 (13) Previous VEGFR TKI (n = 38) 6 (16) Fuhrman grade 4 and/or sarcomatoid histology 4 (22) (n = 18) Fuhrman grade 4 (n = 16) 4 (25) Sarcomatoid histology (n = 6) 2 (33) MSKCC poor risk (n = 20) 5 (25) MSKCC intermediate/favorable risk (n = 42) 4 (10) McDermott DF, et al. J Clin Oncol. 2016

60 Phase Ib: 1. Basamak Tedavide Atezolizumab + Bev Atezolizumab 20 mg/kg + Bev 15 mg/kg q3w Safety Treatment-related grade 3 AEs occurred in 3% of pts (1 case of neutropenia) No grade 4 AEs or deaths were attributed to atezolizumab Efficacy (n = 10) ORR: 40% IC 1 (2 pts), 1 pt each IC 0 or IC unknown SD 24 wks: 50% Change in SLD From Baseline (%) IC 3 IC 3: 10% PD-L1+ IC 2: 5% to < 10% PD-L1+ IC 1: 1% to < 5% PD-L1+ IC 0: < 1% PD-L1+. IC 1 IC 0 IC 1 IC 0 IC 0 IC Days on Study IC 1 IC Lieu C, et al. ESMO Abstract 1049O.

61 1.Basamak Tedavide PD-1 + VEGF Pathway Blokajı: Devam Eden Çalışmalar Study Nivolumab Phase (Number of Pts) NCT I (175) Pembrolizumab Treatment Nivo + Sun; Nivo + Paz; Nivo + Ipi at 3 different dose combinations* Status Closed to accrual NCT I/II (228) Pem±Paz Recruiting NCT Ib (60) Pem + Axi Recruiting NCT Ib/II (61) Pem + Bev Recruiting Atezolizumab NCT (IMmotion150) NCT (IMmotion151) Avelumab II (305) Atezo± Bev vs Sun Closed to accrual III (830) Atezo + Bev vs Sun Recruiting NCT Ib (55) Avel + Axi Recruiting *Previous systemic therapy for metastatic disease allowed for SUN and PAZ combination arms. Clinicaltrials.gov.

62 CheckMate-016: Phase I: 1.Basamak Tedavide Nivolumab +İpilimumab mrcc; no previous systemic therapy other than cytokine therapy for mrcc or 1 prior adjuvant/neoadjuvant therapy with recurrence 6 mos after last treatment Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV q3w x 4 doses (n = 47) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV q3w x 4 doses (n = 47) (N = 100) Nivolumab 3 mg/kg + Ipilimumab 3 mg/kg IV q3w x 4 doses (n = 6) Nivolumab 3 mg/kg IV q2w Primary endpoint: Safety Secondary endpoints: ORR, DoR, PFS, OS Hammers H, et al. ASCO Abstract 4516.

63 CheckMate-016: Cevap Oranları Tumor Response, n (%) Nivo 3 mg/kg + Ipi 1 mg/kg (n = 47) Nivo 1 mg/kg + Ipi 3 mg/kg (n = 47) Nivo 3 mg/kg + Ipi 3 mg/kg (n = 6) ORR 18 (38.3) 19 (40.4) 0 CR 4 (8.5) 1 (2.1) 0 PR 14 (29.8) 18 (38.3) 0 SD 17 (36.2) 17 (36.2) 5 (83.3) Median duration of response: Nivolumab 3 mg/kg + ipilimumab 1 mg/kg: 67.7 wks (range: ) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg: 81.1 wks (range: ) Hammers H, et al. ASCO Abstract 4516.

64 CheckMate-214: Nivo + Ipi vs Sunitinib 1.Basamak Tedavide Advanced/metastatic clear-cell RCC with no prior systemic therapy (N 1070) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV q3w for 4 doses, followed by Nivolumab 3 mg/kg IV q2w Sunitinib 50 mg PO QD 4 wks on/2 wks off Primary endpoint: PFS, OS Secondary endpoints: ORR, safety ClinicalTrials.gov. NCT

65 AŞI ve Anti-VEGF Kombinasyonu

66 Median PFS: 11.1 ay Median OS: 30.2 ay Faz- III ADAPT çalışması devam ediyor (NCT )

67 339 tedavi almamış metastatik RCC, IMA901+sunitinib vs. sunitinib 33 aylık takip süresinde genel sağkalımlar iki kolda da benzer bulunmuş Rini et al. Lancet Oncol; 2016: 17:

68 Pratikte RCC Tedavisinde İmmünoterapiyi Optimize Etme Stratejisi Inflamed tumors (TIL+, PD-L1+) PD-1/PD-L1 monotherapy Tolerant tumors (TIL+, PD-L1-) PD-1/PD-L1 combination therapy Anti-VEGF Cytokines IDO inhibitors Other checkpoint inhibitors Noninflamed tumors (TIL-, PD-L1-) PD-1/PD-L1 combination therapy Vaccines Engineered T cells

69 Metastatik RCC de Güncel Tedavi İyi ya da orta risk grubu 1.Basamak Tedavi *Pazopanib veya *Sunitinib, bevacizumab + IFN* (veya diğer TKI, HD IL-2, or temsirolimus) 2. Basamak Tedavi *Kabozantinib, *Nivolumumab *axitinib (after TKI), Lenvatinib-everolimus (veya diğer TKI, temsirolimus, ya da bevacizumab) Axitinib, sorafenib, sunitinib, veya pazopanib (sitokin sonrası) (veya temsirolimus or bevacizumab) Kötü risk gurubu Temsirolimus Veya sunitinib veya pazopanib Standart yok (clinical trial, supportive care) *Category 1 NCCN. Clinical practice guidelines in oncology: kidney cancer. v

70 Sonuçlar HD-IL-2 seçilmiş hastalarda, tecrübeli merkezlerde halen bir seçenek (uzun yanıt süresi) Metastatik RCC tedavisinde tek ajan olarak PD-1 pathway blokajı etkilidir Nivolumab anti-anjiojenik tedavi sonrası ilerleme olan hastalarda everolimusa karşı sağkalım üstünlüğü göstermiştir Nivolumab ile QoL daki düzelme daha kısa sürede ve anlamlı QoL avantajı Özellikle iyi prognozlu seçilmiş hastalarda progresyon sonrası da nivolumab tedavisine devam edilmesi yarar sağlamaktadır

71 Sonuçlar Nivo alan hastaların 1/3 ü uzun dönem takipte 4-5 yıl yaşamaktadır (faz I-II) Bu katkı, risk grubu ve performans skorundan bağımsızdır Diğer PD-1 ve PD-L1 blokajı yapan ajanlar ile de çalışmalar devam etmektedir Kombinasyon çalışmaları (anti-pd-1/pd-l1+anti-ctla ya da anti-vegf) devam etmekte ve ümit vaad edici görünüyor (maliyet analizi? Toksisite?) Aşı çalışmaları devam ediyor

72 TEŞEKKÜR EDERİM