Renal Cell (RCC) and Bladder Carcinoma (TCC)

Transcription

1 Renal Cell (RCC) and Bladder Carcinoma (TCC) Prof. Dr. med. Viktor Grünwald Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

2 Disclosures Compensated lectures: BMS, Ipsen, Eisai, Novartis, Pfizer, Roche Advisory: Astac Zeneca, Bayer, BMS, Cerulean, Ipsen, Eisai, Novartis, Pfizer, Roche Research grants: Astra Zeneca, BMS, MSD, Pfizer, Novartis Stock shareholder : none

3 Checkpoint Blockade in GU Cancer Carinoma Status outcome Renal cell Phase III positive Urothelial Phase III positive Prostate Phase III negative Germ cell Basket study - Penile Basket study -

4 PD-L1 a negative predictor PCA RCC GCT Gevensleben et al. (2016). CCR, 22(8), Thompson et al. Proc Natl Acad Sci USA 2004;101: Cierna et al. (2016). Annals of Oncology, 27(2),

5 Don t be too advanced for the field: Sipuleucel-T in PCA HR 0,78 (0,61-0,98) P=0,03 Kantoff et al. (2010). NEJM, 363(5), Fong et al. (2014). JNCI Journal of the National Cancer Institute, 106(11)

6 PCA: Ipilimumab vs. Placebo Kantoff et al. (2010). NEJM, 363(5),

7 Mutational load of GU cancers varies MS Lawrence et al. Nature 2013

8 ...so does immune cell infiltration Mandal, R., Senbabaoglu, Y., Desrichard, A., Havel, J. J., Dalin, M. G., Riaz, N., et al. (2016). JCI Insight, 1(17), e

9 Immunotherapy not a one-size-fits-all approach hot tumor A B cold tumor Nonimmunogenic tumor microenvironment single agent CD8 T cell CD4 T cell Tumor cell with PD-L1 expression CD8 T cell with granzyme B CD8 T cell CD8 with CD45RO T cell expression with PD-L1 expression Combination therapies with agents that create immunogenic tumor microenvironment and immune checkpoint therapy combination Immunogenic tumor microenvironment Immune checkpoint ther apy and durable clinical benef t Durable clinical benef t Sharma & Allison. The future of immune checkpoint therapy. (2015). The future of immune checkpoint therapy. Cancer Immunology Immunotherapy, 1 7.

10 OS-benefit for Nivolumab in 2 nd line 2-year-Follow-up Motzer RJ et al. N Engl J Med, 2015; 373: Plimack et al. KCS 2016

11 ...but, only minor improvement in PFS 44% received treatment beyond progression for nivolumab, and 46% for everolimus Motzer et al. (2015). NEJM,

12 Geonomic profile differs by line in mrcc (ctdna analysis) Pal et al. (2017). European Urology.

13 What about combinations in RCC?

14 Immunogenic cell death the goal of combinations with RTX or CTX Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2017). Nature Reviews. Immunology, 17(2),

15 Immunotherapy a matter of combinations? Salama, A. K. S., & Moschos, S. J. (2016). Annals of Oncology, mdw534.

16 g the Balance Toward Anti-Cancer Immunity ombined VEGF/PD-L1 Blockade Anti-Cancer Immunity Bevacizumab Sunitinib Atezolizumab Atezolizumab death-ligand 1; VEGF, vascular endothelial growth factor. es. 2008; McDermott, J Clin Oncol. 2016; Wallin. Nat Commun McDermott D, et al. IMmotion150 bioma

17 Bevacizumab/Atezolizumab improved T-cell-migration Wallin et al. (2016). Nature Communications, 7,

18 IC3+ RCC Patient: PR with atezolizumab Herbst et al. (2014). Nature, 515(7528),

19 ATEZO-BEV: PFS (ITT) Atezolizumab + bevacizumab Atezolizumab Sunitinib Atezo: 6.1 mo (5.4, 13.6) Sunitinib: 8.4 mo (7.0, 14.0) Atezo + bev: 11.7 mo (8.4, 17.3) Atezo + bev vs sunitinib Atezo vs sunitinib Stratified HR (95% CI) 1.00 (0.69, 1.45) 1.19 (0.82, 1.71) P Value a Atezo, atezolizumab; Bev, bevacizumab. a P values are for descriptive purposes only and not adjusted for multiple comparisons. McDermott et al. ASCO GU 2017: 431

20 Dual Checkpoint Blockade a future was of treatment? IPI3 + NIVO1 IPI1 + NIVO3 ORR 40% 40% PD 17% 17% PFS 6,6 Mo. 9,1 Mo. Hammers et al. ASCO 2015 #4516. Hammers et al. ESMO 2016: 1062P

21 Efficacy of dual checkpoint inhibition in mrcc Hammers et al. ESMO 2016: 1962P

22 VEGF inhibition triggers PD-L1 expression Liu et al. Cancer Immunol Res; 3(9); 1 12.

23 Change in baseline (%) SU+NIVO pretreated (n=13) SU+NIVO Rx-naive (n=15) Time since first dose (weeks) 1 st occurrence of new lesion PAZ+NIVO pretreated (n=19) ORR: 52% (n=17/33) PFS: 49 wks. Amin et al. ASCO 21014: #5010 ORR: 45% (n=9/20) PFS: 31 wks

24 Do we have proper marker for patient selection?

25 Checkmate-025: PD-L1 is not predictive for nivolumab Motzer RJ et al. N Engl J Med, 2015; 373:

26

27 iptome Map of Angiogenesis and Immune-Associated n RCC Tumors PD-L1 IHC genesis (e.g., CD34, KDR, VEGFA) mmune, entation (e.g. CD8A, IFNG, PSMB8) Myeloid mmation (e.g. IL6, PTGS2, IL8) Res. 2012; Herbst, Nature 2014; Powles, SITC 2015; Fehrenbacher, Lancet McDermott D, et al. IMmotion150 bioma

28 b Demonstrated Improved PFS in Angiogenesis High S ogenesis Low Subset Sunitinib Atezolizumab + Bevacizumab Atezolizu High (n = 44) Low (n = 45) High (n = 45) Low (n = 43) Sunitinib HR 95% CI Atezolizumab + Bevacizumab HR 95% CI Atezoliz H is w) 0.31 (0.18, 0.55) Angiogenesis (High vs Low) 0.90 (0.54, 1.51) Angiogenesis (High vs Low) 0.7 signature: VEGFA, KDR, ESM1, PECAM1, ANGPTL4, CD34. median expression, Angiogenesis Low: < median expression. McDermott D, et al. IMmotion150 bioma

29 umab and Bevacizumab Demonstrated Improved PFS tinib in the T-Effector High Subset T-effector Low T-effector High Atezo + bev (n = 46) Atezo (n = 40) Sunitinib (n = 46) Atezo + be Atezo (n = Sunitinib (n HR (95% CI) T-effector Low T-effector High Atezo + bev vs sunitinib 1.41 (0.84, 2.36) 0.55 (0.32, 0.95) Atezo vs sunitinib 1.33 (0.76, 2.33) 0.85 (0.50, 1.43) ature: CD8A, EOMES, PRF1, IFNG, CD274. edian expression, T-effector Low: < median expression. McDermott D, et al. IMmotion150 bioma

30 iptome Map of Angiogenesis and Immune-Associated n RCC Tumors on PD-L1 IHC T-effector High Subpopulati T-effector High Myeloid Inflammation Low T-effector Hi Myeloid Inflamma PD-L1 IHC IC0 IC1 IC2 IC3 Res. 2012; Herbst, Nature 2014; Powles, SITC 2015; Fehrenbacher, Lancet McDermott D, et al. IMmotion150 bioma

31 n of Bevacizumab to Atezolizumab is Associated With ed Benefit in T-effector High /Myeloid Inflammation High Su on T-effector High Myeloid Low T-effector High Myeloid Hig Atezo + bev (n = 23) Atezo (n = 23) Sunitinib (n = 19) Atez Atez Suni nature: CD8A, EOMES, PRF1, IFNG, CD274. ession, Low: < median expression. McDermott D, et al. IMmotion150 biomar

32 orrelates With PFS in Gene Expression Subgro Angiogenesis Signature T-effector Signature % % h 44 10% Low n = 41 nitinib 12% 14% 9% 12% High Low n = 43 n = 42 Atezo 20% 5% High n = 44 29% 12% Low n = 42 Atezo + bev 24% 25% 2% High n = 41 5% Low n = 44 Sunitinib 20% 11% 5% 10% High Low n = 45 n = 40 Atezo 33% 17% High n = 42 16% Low n = 4 Atezo + b ssed ORR. McDermott D, et al. IMmotion150 biom

33 What about response?

34 Depth of remission is prognostic in RCC (TKI-era) Survival Probability Median OS (m) 100% to 60% (n=283) % to 30% (n=547) % to 0% (n=1155) % to +20% (n=390) % (n=156) 7.33 No post-baseline scan (n=218) Time (Months) Grünwald V et al. ESMO 2013, Amsterdam, #2702; EUR UROL 2015

35 CM025: OS according to best response at 4 mo. Motzer et al. ASCO 2016

36 QoL-responders gain OS-benefit HR-QoL responders (2 pts..): NIVO (55%) > EVE (37%) Faster with NIVO (4.7 mo. vs. NR) Cella et al. ASCO 2016 #4549

37 Conclusion RCC GU-cancers are immunogenic Nivolumab has improved 2 nd line treatment in RCC Depth of remission is prognostic with targeted therapies in RCC Combinations may improve efficacy Gene signatures may guide future choice of therapy

38 Urothelial Carcinoma

39 Systemic therapy in TCC 1 st Linie - Cisplatin/Gemcitabine - (DD-MVAC) 1 st Linie: frail - Carboplatin/Gemcitabine - Gemcitabine - Taxane 2 nd Linie - Vinflunine - Taxane - (Ifosfamide) Bellmunt et al. ESMO Guidelines Working Group. (2014, September). Annals of Oncology.

40 VICTOR: UK-real world retrospective Data for vinflunine Hussain et al. (2017), International Journal of Oncology, 50(3),

41 Chemotherapy in mtcc 1 st line 2 nd line ORR: 44% OS: 12,7 Mo. PFS: 7,6 Mo. ORR: 9% PFS: 3 Mo. Bellmunt et al. (2012). JCO, 30(10), Bellmunt et al. (2009). JCO, 27(27),

42 Long-term survival with CTX PCG 1 n=312 GC 1 n=314 GC 2 n=203 MVAC 2 n=202 MVAC 3 n=129 DD-MVAC 3 n=134 PFS (mo.) y-PFS rate % 18% y-PFS rate % 11% - - OS (mo.) y-OS rate % 31% y-OS rate 17%* 16%* 13% 15% 10% 14% 1 Bellmunt et al. (2012). JCO, 30(10), van der Maase et al. (2005). JCO, 23(21), Sternberg et al. (2001). JCO, 19(10),

43 Inflammatory TCC association with better OS PD-L1+ TIMC analysed 23 mo. 12 mo. TIMC: tumor infiltrating monocytic cells Bellmunt et al. (2015). Annals of Oncology, mdv009. doi: /annonc/mdv009

44 Checkpoint inhibitors in mtcc Durvalumab Avelumab PD-L1 PD-1 Nivolumab C h a n g e F r o m B a s e l i n e, % Pembrolizumab 52% experienced a decrease in target lesions 20% increase 30% decrease Massard et al. (2016). JCO, 34(26), JCO Apolo et al. (2017). JCO, Balar et al. ESMO Sharma et al. ASCO 2016: 4501.

45 Activity of PD-(L)1i in mtcc ATEZO 1 ATEZO 2 NIVO 3 NIVO 4 PEMBRO 5 AVELU 6 DURVA 7 N Line CDDP unfit CDDP unfit 2. or CDDP unfit 2. or CDDP unfit CR (%) PR (%) OS (mo.) FDA license 1 Balar et al. ASCO 2016 # Dreicer et al.asco 2016 # Sharma et al. ASCO 2016 # Galsky et al. ESMO 2016 LBA31. 5 Balar et al. ESMO 2016 LBA32. 6 Patel ESMO 2016: Massard et al. (2016). JCO, 34(26), JCO

46 1 st Linie TCC: Atezolizumab (IMvigor210): CDDP-unfit 57% Bellmunt et al. ESMO 2016, 782PD

47 1 st line CDDP-unfit: chemotherapy approx. 38% OS: 8.1 vs. 9.3 mo. phase II : Vinflunine-doublet (GEM or CARBO) ORR: 44 vs. 29% PFS: 5.9 vs. 6.1 mo. OS: 12.8 vs mo. (P=0.86) De Santis et al. (2012). JCO, 30(2), De Santis et al. (2015). Annals of Oncology, mdv609.

48 IMvigor210: platinum-failure Atezolizumab OS; Mo. (95% CI) IC0/1 n=210 6,7 (5,4-8,0) IC2/3 n=100 11,9 (9,0-NE) Alle Pts. N=310 7,9 (6,7-9,3) 12-Mo. OS 31% 50% 37% approx.. 38% Loriot et al. ESMO 2016: 783P

49 Nivolumab (Platinum-failure) Overall Survival (Probability) No. at Risk All treated patients PD-L1 <1% PD-L1 1% Median OS, Months (95% CI) a All treated 8.74 (6.05 NR) PD-L1 <1% 5.95 ( ) PD-L1 1% (8.74 NR) PD-L1 <1% PD-L1 1% approx.. 40% All treated patients Months a Similar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached Galsky et al. ESMO 2016: LBA31

50 OS in 2 nd line with chemotherapy 27% Vinflunine 22% BSC Bellmunt et al. (2009). JCO, 27(27), Bellmunt et al. (2013). Annals of Oncology, 24(6),

51 Atezolizumab: similar outcome by line of Rx Perez-Garcia et al. ASCO GU 2017: 323

52

53 2 nd line TCC KN45 (OS) CTX Dealers choice: Docetaxel Paclitaxel Vinflunine Bellmunt et al. (2017). NEJM, 376(11),

54 PFS: Pembrolizumab vs. CTX Bellmunt et al. (2017). NEJM, 376(11),

55 KN45: adverse events Bellmunt et al. (2017). NEJM, 376(11),

56 KN-45: better HR-QoL with PD-1i Bellmunt et al. ASCO GU 2017: 282

57 DOR: longer with pembrolizumab Bellmunt et al. (2017). NEJM, 376(11),

58 What about enrichment?

59 Durvalumab (mixed cohort) ORR: 20% PFS: 2.2 mo. OS: 14.1 mo. Previous therapy: 91% Powles et al. ASCO GU 2017: 286

60 Massard et al. (2016). JCO, 34(26), JCO Durvalumab in mtcc

61 Avelumab in mtcc (mixed cohort) Apolo et al. (2017). JCO,

62 1 st line chemotherapy: 1-year-OS rate approx.60% van der Maase et al. (2005). JCO, 23(21),

63 Treatment effect or independent prognostic factor? Rosenberg et al. Lancet 2016

64 Treatment failure occurs despite enrichment for IC2/3+ TCC 50% Response to atezolizumab shown in IC2/3+ patients according to RECIST defined responses Rosenberg et al. Lancet 2016

65 Are we missing something?

66 Risks of immunotherapy: hyperprogression Champiat et al. (2016). CCR

67 Conclusion TCC Chemotherapy-efficacy is limited PD-(L)1 inhibitors are active irrespective of prior therapy Petter outcome in PD-L1+ TCC Phase III data indicate survival benefit (pembrolizumab) But, atezolizumab without improvement...