Pieter de Mulder Lecture

Transcription

1 Pieter de Mulder Lecture From cytokines to targeted therapies to immunotherapy: 30 years of progress in advanced RCC Cora N. Sternberg Department of Medical Oncology San Camillo & Forlanini Hospitals Rome, Italy

2 Pieter de Mulder Born: May 28th 1949 and Died April 7th 2007

3 Phase II Trials prior to modern therapies for RCC at MSKCC Sternberg CN, Yagoda A, Casper E, Scoppetuolo M, Scher HI. Phase II trial of elliptinium in advanced renal cell carcinoma and carcinoma of the breast. Anticancer Res Jul- Aug;5(4): Sternberg CN, Yagoda A, Scher H, Bosl G, Dershaw D, Rosado K, Houston C, Rosenbluth R, Vinciguerra V, Boselli B. Phase II trial of trimetrexate in patients with advanced renal cell carcinoma. Clinical Community Oncology Program. Eur J Cancer Clin Oncol Apr;25(4): Sternberg CN, Yagoda A, Scher HI, Hollander P. Phase II trial of N-methylformamide for advanced renal cell carcinoma. Cancer Treat Rep May;70(5): Sternberg CN, Yagoda A. N-methylformamide-induced hypophosphatemia.cancer Treat Rep Mar;69(3): Sternberg CN, Vogelzang NJ. Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers. Crit Rev Oncol Hematol Jun 27;46 Suppl:S

4 Probability of Continuing Response High-Dose IV Bolus IL-2 Therapy: (n=255; 7 clinical trials) Complete Response (n=17) FDA Approval % RR with durable responses in a small % of patients Overall Response (n=43) Partial Response (n=26) (10 Years) Duration (m onths) MDR - 54 months But: Significant toxicity and cost! Application limited to selected patients treated at a few centers 6 PR with response durations of 43+ to 85+ mos. Median survival 15.8 mos Fyfe GA et al, J Clin Oncol 1995 Mar;13(3): Fyfe GA et al, J Clin Oncol 1996 Aug;14(8):2410-1

5 Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in advanced RCC September 1987 until March 1989 Interleukin-2 administered 3 X 10 6 U/m 2 /day CI (or 9 mu, international unit) on days 1-5, 13-17, 21-24, and (18 doses per cycle). Patients on the LAK treatment arm underwent leukapheresis after 1 st IL- 2 infusion on days 8-10 and LAK cell reinfusion on days Lower dose but given by continuous infusion (CI) rather than by bolus as is current regimen Lam TM et al., Cancer 1995 Sep 1;76(5):824-32

6 Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in advanced RCC (n=71) No differences between treatment arms with regard to response (p = 0.61) Law TM et al., Cancer 1995 Sep 1;76(5):824-32

7 Multicenter US Randomized Trial (n=71)

8 Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in advanced RCC (n=71) Lesser toxicity but inpatient ICU administration Median survival 13 mos ( 95% CI 9-18 mos); p= alive and free of disease at 63+, 69+ and 75+ mos: 2 with CR and 1 SD treated with IL-2+IFN α and surgery Law TM et al., Cancer 1995 Sep 1;76(5):824-32

9 Kidney cancer is not a single disease Proximal nephron Distal nephron Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma Incidence (%) 1 75% 5% 10% 5% 5% Hereditary mutations 1 VHL MET FH BHD BHD Sporadic mutations 2 VHL (89%) MET (13%) TBD TBD TBD FLCN, folliculin; BHD, Birt-Hogg-Dubé; FH, fumarate hydratase; MET, mesenchymal epithelial transition factor; VHL, von Hippel-Lindau. 1. Pfaffenroth, et al. Expert Opin Biol Ther. 2008;8(6): Linehan WM, et al. Semin Cancer Biol. 2013;23(1):46-55.

10 Features of clear cell RCC biology Disruption of VHL gene 1 Activation of mtor signaling 1 Characterized by: Metabolic derangements 1 Molecularly distinct phenotypes 2 Marked inter- and intratumor heterogeneity 3 1. Pinthus JH, et al. Can Urol Assoc. 2011;5(4): Monzon FA, et al. Mod Pathol. 2011;24(11): Lopez JI. APMIS. 2016;124(3):

11 Adipose Adrenal Blood vessel Bone Bone marrow Breast Cervical CNS Colorectal Endometrium Oesophagus Gallbladder Head & neck Heart Kidney Liver Lung Lymphoid Muscle Myometrium Neuroendocrine Ovary Pancreas Pituitary Placenta Prostate Skin Small intestine Soft tissue Stomach Testis Thymus Thyroid Urinary WBC Hybridisation signal intensity for VEGF-A mrna Metastatic RCC is a VEGF-driven disease VEGF-A expression in ~5000 tissue specimens VEGF-A expression is 3.2-fold higher in kidney malignancies than in normal tissue 0 VEGF, vascular endothelial growth factor. Jubb AM, et al. J Clin Pathol 2004;57:

12 NGS Genomic alterations in clear cell RCC Frequently mutated genes identified in RCC samples by both Sato et al. 2 and The Cancer Genome Atlas 3 *Selective deep sequencing of frequently mutated tumor suppressors in additional samples in the study by Sato et al. (n = 240). 1. Hakimi AA, et al. Nat Genet 2013;45:849 50; 2. Sato X, et al. Nat Genet 2013;45:860 7; 3. The Cancer Genome Atlas Research Network. Nature 2013;499:43 9; Hakimi AA, et al. Nat Genet 2013;45:

13 Effects on survival of BAP1 and PBRM1 mutations in sporadic RCC: a retrospective analysis with independent validation Figure 1. Kaplan-Meier curves of overall survival HR=hazard ratio. (A) UTSW cohort and (B) TCGA cohort. Kapur P et al, Lancet Oncol Volume 14, Issue 2, 2013,

14 Intra-tumoural heterogeneity: A key challenge in the validation of genetic biomarkers Sites of core biopsies and regions harvested from nephrectomy and metastasectomy Gerlinger M, et al. N Eng J Med 2012;366:

15 Metastatic RCC is a VEGF-driven heterogeneous disease R2 R1 R3 R8 R5 R9 KDM5C MTOR VHL EV001 R4b SETD2 R4a SETD2 GL M1 M2a M2b SETD2 KDM5C R6 dom VHL PBRM1 EV005 R7 GL R2 R5 SF3B1 R3 R1 PIK3CA R4 PIK3CA R6 min R8 10 non-synonymous mutations Terminal branch Internal branch Trunk RMH004 PBRM1 ATM R10 VHL PTEN R4 GL R2 MSH6 VT PBRM1 ARID1A R3 SMARCA4 The trunk of the tumor harbors the ubiquitous founding driver mutations The sprouting branches carry heterogeneous mutations ccrcc, clear-cell RCC; VHL, von Hippel Lindau. 1. Gerlinger M, et al. Nat Genet 2014;46:225 36; 2. Yap TA, et al. Sci Transl Med 2012;4:127ps10.

16 From cytokines to targeted therapies: 30 years of progress in advanced RCC Cytokines IL-2 and IFN-α High-dose IL-2 FDA approval based on phase II data Bevacizumab Temsirolimus + IFN- Sorafenib Sunitinib Everolimus Pazopanib Axitinib VHL tumour suppressor gene isolated Chromatin remodelling gene mutations

17 From cytokines to targeted therapies: 30 years of progress in advanced RCC Cytokines IL-2 and IFN-α High-dose IL-2 FDA approval based on phase II data Bevacizumab + IFN- Temsirolimus Sorafenib Sunitinib Everolimus Pazopanib Axitinib Nivolumab Cabozantinib Lenvatinib + everolimus VHL tumour suppressor gene isolated Chromatin remodelling gene mutations

18 Proportion surviving OS, % Targeted therapies have improved OS in mrcc Before VEGF-targeted therapies (IFN-ɑ) VEGF-targeted therapies risk factor (n = 80) 1 or 2 risk factors (n = 269) 3, 4 or 5 risk factors (n = 88) Median survival 30 months 14 months 5 months Risk group No. factors Favourable 0 Intermediate 1-2 Poor 3-6 Median survival 43 months 23 months 8 months Time from start of IFN-α, years Time since start of treatment, months *Risk factors for survival included anaemia, thrombocytosis, neutrophilia, hypercalcaemia, KPS <80%, and <1 year from diagnosis to treatment. Motzer RJ et al. J Clin Oncol. 2002;20: Heng DY et al. Lancet Oncol 2013;14:

19 Pathways and Current Drugs in Metastatic Renal Cell Carcinoma VEGF and tyrosine kinase inhibitors PD-1 and mtor inhibitors BLOOD VESSEL Cabozantinib c-met T-cell receptor ANTIGEN-PRESENTING MHC CELL Neoantigen Lenvatinib FGFR VEGFR Endothelial cell PDGFR AXL T-CELL PD-1 Nivolumab Cell-signaling factor FGF VEGF Axitinib Pazopanib Sorafenib Sunitinib Bevacizumab PDGF PD-L1 and PD-L2 RENAL-CANCER CELL CYTOPLASM PI3K AKT Renal-cancer cell AXL c-met Cabozantinib Everolimus Temsirolimus mtor Mutated VHL HIF Activation of HIF target genes (e.g., VEGF) Protein synthesis Nucleotide synthesis Lipid synthesis Anabolic effects AKT, protein kinase B; FGFR, fibroblast growth factor receptor; HIF, hypoxia-inducible factor; MET, hepatocyte growth factor receptor; MHC, major histocompatibility complex; mtor, mammalian target of rapamycin; PD-1, programmed cell death protein 1; PDGF, platelet-derived growth factor; PD-L1/2, programmed cell death-ligand 1/2; PI3K, phosphatidylinositol-3-kinase; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; VHL, von Hippel Lindau. Chouieri TK and Motzer RJ. NEJM 2017;376:

20 Progression-free survival probability Sunitinib vs. IFN-α: progression-free survival in the treatmentnaїve population Median progression-free survival Sunitinib (n=375): 11.0 months IFN-α (n=375): 5.1 months HR: 0.54 (95% CI: ) p< % reduction in risk of progression or death with sunitinib vs IFN-α Time (months) Motzer RJ, et al. N Engl J Med 2007;356:

21 Italian Sunitinib Expanded Access Program: (n=521) Sternberg CN et al. Oncology 2015, vol 88,( 5) pp

22 Phase III Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma Subjects with advanced RCC (N = 435) Randomization 2:1 Stratification ECOG PS 0 vs 1 Prior nephrectomy Y vs. N Rx naïve vs 1 cytokine pre-treated Pazopanib 800 mg qd (n = 290) Placebo (n = 145) Option to receive pazopanib via an open-label study at progression (VEG107769) FebSternberg CN, et al. J Clin Oncol 2010;28:

23 Pazopanib vs placebo: progression-free survival in the treatment-naїve population Proportion progression-free Median progression-free survival Pazopanib (n=155): 11.1 months Placebo (n=78): 2.8 months HR: 0.40 (95% CI: ) p< % reduction in risk of progression or death with pazopanib vs placebo 0.0 Number at risk, n Pazopanib Placebo Time (month) In the treatment-naїve population, PFS was significantly greater with pazopanib vs placebo (p<0.001) Sternberg Sternberg CN, CN, et al. et J al. Clin J Clin Oncol Oncol 2010;28:

24 COMPARZ Study design (n=1110) Key Eligibility Criteria Advanced/metastatic RCC Clear-cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS 70 Adequate organ function Stratification factors KPS 70/80 vs. 90/100 Prior nephrectomy Baseline LDH >1.5 vs. 1.5 ULN Randomised 1:1 Open Label Pazopanib 800 mg qd Continuous dosing Sunitinib 50 mg qd 4 wk on/2 wk off Primary endpoint Secondary endpoints PFS OS Duration of response ORR Safety Time to response Health outcomes analysis Motzer R et al, N Eng J Med 2013 Aug 22;369(8):722-31

25 COMPARZ TRIAL: Pazopanib is non-inferior to sunitinib for efficacy PFS independent review Proportion progression free n Median PFS, months (95% CI) Pazopanib ( ) 0.6 Sunitinib ( ) HR=1.05 (95% CI ) Months Number at risk Pazopanib Sunitinib Motzer R et al, N Eng J Med 2013 Aug 22;369(8):722-31

26 PISCES: Study Design R 1:1 n = 169 Period 1 Pazopanib 800 mg OD Sunitinib 50 mg 4/2 a Period 2 Sunitinib 50 mg 4/2 a Pazopanib 800 mg OD Patient preference of further treatment 10 weeks 2-week 10 weeks washout Double-blind phase End of study Time (weeks) Stratification factors: ECOG PS (0 vs 1) Metastatic sites (1 vs 2) a 4 weeks on treatment 2 weeks matching placebo 4 weeks on treatment. ECOG PS, Eastern Cooperative Oncology Group performance status Escudier B et al, J Clin Oncol May 10;32(14):

27 Phase 3 METEOR study: PFS and Response in All 658 Patients Progression-Free Survival per IRC Median Cabozantinib (N=330) 7.4 mo Everolimus (N=328) 3.9 mo HR 0.51 (95% CI ), p< Objective Response Rate Cabozantinib (N=330), % Everolimus (N=328), % 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 4 7 Cut-off for PFS and ORR: May 22, Confirmed responses per RECIST version 1.1. All responses were partial responses. Choueiri TK et al, Lancet Oncol, 2016 Jul;17(7):917-27

28 Phase 3 METEOR study: Overall Survival Median OS mo (95% CI) No. of Deaths Cabozantinib (N=330) 21.4 (18.7-NE) 140 Everolimus (N=328) 16.5 ( ) 180 Hazard ratio 0.66 (95% CI ), P= % reduction in the risk of death NE, Not estimable Cut-off: Dec 31, 2015 No. at Risk Cabozantinib Everolimus Choueiri TK et al, Lancet Oncol, 2016 Jul;17(7):917-27

29 Immune response to cancer Cancer immunity cycle Cancer cells may express tumor-specific antigens due to the presence of mutations These antigens may induce an immune response Upregulation of PD-L1 in the tumor microenvironment enables cancers to evade T- cell mediated killing Inhibition of the PD-L1/PD-1 and PD-L1/B7.1 interaction may restore antitumor T-cell activity Chen DS, Mellman I. Immunity 2013;39:1 10.

30 Nivolumab Phase 3 Checkmate-025 study: progression-free survival and antitumor activity Progression-free survival PFS per investigator Antitumour activity per investigator No. of Patients Median PFS mo (95% CI) No. of Events Nivolumab ( ) 318 Everolimus ( ) 322 Nivolumab N = 410 Everolimus N = 411 Objective response rate, % 25 5 Odds ratio (95% CI) p value 5.98 ( ) < HR = 0.88 (95% CI , p = 0.11) Best overall response, % Complete response Partial response Stable disease Progressive disease Not evaluated No. of patients at risk Nivolumab Everolimus Months Median time to response, months (range) Median duration of response, months (range) 3.5 ( ) 3.7 ( ) 12.0 ( ) 12.0 ( ) Motzer RJ, et al. N Engl J Med 2015;373:

31 Overall Survival (Probability) Nivolumab Phase 3 Checkmate-025 study: Overall Survival % reduction in the risk of death No. of Patients No. of patients at risk Months Nivolumab Everolimus Median Overall Survival mo (95% CI) Nivolumab (21.8 NE) Everoimus ( ) HR = 0.73 (98.5% CI , p=0.0018) Minimum follow-up was 14 months Motzer RJ, et al. N Engl J Med 2015;373:

32 Overall survival (probability) Checkmate-025 study: Updated Overall Survival % 76% 52% Median OS, months (95% CI) Nivolumab 26.0 ( ) Everolimus 19.7 ( ) HR (95% CI) 0.73 ( ) P= % Nivolumab Everolimus No. at risk Nivolumab Everolimus Months Minimum follow-up was 26 months at the database lock on May 11, 2016 Plimack E, et al. IKCS, 2016

33 Treatment beyond progression Tumor Burden change post-pd A total of 142/153 pts treated with nivolumab beyond PD had tumor measurements pre- and post-pd ~50% 14% 50% had a reduction in tumor burden post-progression and 14% (n = 20) had a 30% reduction in tumor burden Escudier B et al. Poster presentation at ASCO

34 First line combination trials: closed PD-1 + CTLA-4 inhibition PD-L1 + VEGF inhibition Personalized immunotherapy + VEGFR inhibition Checkmate214 1 Phase III IMmotion151 2 Phase III ADAPT 3 Phase III Sunitinib 50 mg/day 4/2 Sunitinib 50 mg/day 4/2 Sunitinib R n=1071 R n=830 Nivolumab + ipilimumab Atezolizumab + bevacizumab 3mg/kg IV + 1mg/kg IV every 3 weeks X4 then Nivolumab 3mg/kg IV every 2 weeks 1200 mg IV + 15 mg/kg IV every 3 weeks R n=450 AGS sunitinib 8 injections in first year followed by quarterly boosters + sunitinib Co-Primary endpoint: PFS, OS Co-Primary endpoint: PFS, OS Primary endpoint: OS 1. NCT NCT NCT

35 First line combination ongoing trials PD-L1 + VEGFR TK inhibition Javelin renal Phase III Sunitinib 50 mg/day 4/2 Combination VEGFR + mtor/pd-1 inhibition Lenvatinib + everolimus or pembrolizumab 2 Phase III Sunitinib 50 mg/day 4/2 PD-1 + VEGFR TK inhibition KEYNOTE Phase III Sunitinib 50 mg/day 4/2 R n=583 Avelumab + axitinib 10mg/kg IV every 2 weeks + 5mg PO BD n=735 R Lenvatinib + pembro 20 mg/day mg (IV) every 3 weeks Lenvatinib + everolimus 18 mg/day + 5 mg/day R n=840 Axitinib + pembro 5 mg BID mg (IV) every 3 weeks Primary endpoint: PFS Primary endpoint: PFS Co-Primary endpoint: PFS, OS 1. NCT NCT NCT

36 The immuno-oncology landscape Classes of immuno-oncology therapeutics DIVERSITY OF APPROACHES ADOPTIVE T-CELL THERAPY 1 CANCER VACCINES 1 T-CELL ACTIVATORS 2 ONCOLYTIC VIRAL THERAPY 3 IMMUNE MODULATORS 4-6 IMMUNE CHECKPOINT INHIBITORS 1,7 Autologous T-cell therapy CAR T-cells Antigenspecific vaccines Cell-based vaccines OX40/ CD134 CD40 4-1BB/ 4-1BBL IMLYGIC (talimogene laherparepvec) IDO Cytokines CSF-1 Mabs IMiDs CTLA-4 PD-1/PD-L1 TIM3 LAG3 1. Domagala-Kulawik J. Transl Lung Cancer Res 2015;4:177 90; 2. Linch SN et al. Front Oncol 2015;5:34; 3. Kaufman HL et al. J Immunother Cancer 2016;4: Holmgaard RB et al. Cell Rep 2015;13:412 24; 5. Ryder M et al. PLoS One 2013; 8:e54302; 6. Wang Y et al. J Natl Cancer Inst 2015;108(3); 7. Jiang T, Zhou C. Transl Lung Cancer Res 2015;4:

37 THIRD LINE SECOND LINE FIRST LINE ESMO RCC guidelines update 2016 Treatment group Good or intermediate risk Standard recommendation Sunitinib, Bevacizumab + IFN, Pazopanib Poor risk Temsirolimus Post-TKIs Cabozantinib, Nivolumab Options: Axitinib, Everolimus, Sorafenib Post two TKIs Post TKI/ Nivolumab Post TKI / Cabozantinib Post TKI and mtor Cabozantinib, Nivolumab Option: Everolimus Cabozantinib Options: Axitinib, Everolimus Nivolumab Options: Everolimus, Axitinib Sorafenib, Nivolumab, Cabozantinib Options: Other TKI or re-challenge Escudier B et al. Ann Oncol Sep;27(suppl 5):v58-v68

38 From cytokines to targeted therapies to immunotherapy: 30 years of progress in advanced RCC We have made great progress!

39