How does histology alter treatment? Cora N. Sternberg, MD, FACP Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy

Size: px

Start display at page:

Download "How does histology alter treatment? Cora N. Sternberg, MD, FACP Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy"

Cory Hardy
6 years ago
Views:

2 How does histology alter treatment? Cora N. Sternberg, MD, FACP Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy

3 Targeting VHL/HIF in Clear Cell RCC VHL Bevacizumab (Antibody) HIF mtor VEGF PDGF TGF-α Temsirolimus Everolimus VEGFR PDGFR EGFR Pazopanib Axitinib Sunitinib Sorafenib

4 Kidney Cancer is Not a Single Disease Clear Cell Papillary Type 1 Chromophobe Hybrid Oncocytoma Papillary Type 2 TFE3 Angiomyolipoma Oncocytic Clear/Chromophobe Linehan M, Genome Res 22: 2012

5 Kidney Cancer is Not a Single Disease Clear Cell Papillary Type 1 VHL Met Chromophobe Hybrid FLCN Oncocytoma Papillary Type 2 FH fumarate hydratse TFE3 Angiomyolipoma Oncocytic Clear/Chromophobe TFE3, TFEB, MITF TSC1, TSC2 SDHB, SDHC, SDHD PTEN succinate dehydogenase Linehan M, Genome Res 22: 2012

6 Kidney Cancer is a Metabolic Disease Genes associated with non ccrcc: - MET, FLCN,FH, SDH,TFE3, TFEB, MITF, TSC1,TSC2, and PTEN All associated with abnormalities of the cell s ability to sense oxygen, iron, nutrients or energy Linehan M et al, Semin Oncol 40:

Hereditary Type 1 (HPRC): familial syndrome: Germline mutation of the c-met gene 90% chance of developing RCC, risk up to 1,100 tumors/kidney Active surveillance of

7 Hereditary Type 1 (HPRC): familial syndrome: Germline mutation of the c-met gene 90% chance of developing RCC, risk up to 1,100 tumors/kidney Active surveillance of small tumors, surgery when 3 cm Sporadic tumors: 13% c-met mutations Often less likely to metastasize than clear cell RCC Surgery is the standard of care Papillary Type 1 RCC

8 Type 1 papillary kidney cancer. Hereditary papillary RCC (HPRC) bilateral kidney cancer Autosomal dominant

Papillary Type 2 RCC Made up of a number of different non type-1 papillary RCCs Hereditary Leiomyomatosis (HLRCC): germline mutation of the fumarate hydratase

9 Papillary Type 2 RCC Made up of a number of different non type-1 papillary RCCs Hereditary Leiomyomatosis (HLRCC): germline mutation of the fumarate hydratase (FH) gene Aggressive: no active surveillance-wide resection Warburg effect (aerobic glycolisis): VEGF and EGFR blockade Sporadic tumors: not well characterized

10 Type 2 papillary kidney cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) uterine leiomyomas (fibroids) cutaneous leiomyomas Papillary type 2 kidney cancer Autosomal dominant

11 4% of all RCC Inherited syndome: Birt- Hogg-Dubé Germline mutation of the FLCN gene in > 95% of families Generally indolent unless associated with sarcomatoid Active surveillance until 3 cm-surgery Chromophobe RCC

12 Chromophobe kidney cancer. Birt-Hogg-Dube (BHD) - mutation of the FLCN gene

13 Collecting Duct Carcinoma-Bellini Tumor < 2% of cases Highly aggressive from collecting ducts in renal medulla Respond transiently to TCC chemotherapy regimens Role of targeted therapy unclear

14 Collecting Duct RC: Bellini Tumor Phase II Study: n=23 Gemcitabine + Cisplatin (or Carbo) ORR: 26% including one patient with CR Median PFS 7.1 months Median OS: 10.5 months Oudard S et al., J Urol 2007

15 Renal Medullary Carcinoma Young patients with African descent and sickle cell trait or Hb SC disease Extremely lethal disease Transient response to TCC chemotherapy regimens Overexpression of DNA topo II (ADM and etoposide) No support for VEGF or mtor inhibitors

6% of RCC in adults Aggressive with early nodal metastases VEGF vs met antagonist?

16 Xp11.2 Translocation RCC MiT Family RCC: TFE3,TFB and MITF Children and young adults ( 20-45%) of RCC 1-1.6% of RCC in adults Aggressive with early nodal metastases VEGF vs met antagonist? Fusion of TFE3 gene to various partners PRCC in t(x;1) (p11.2;q21) SFPQ in t(x;1)(p11.2;p34) ASPSCR1 in t(x;17)(p11.2;q25) NONO in inv(x)(p11.2;q12) CLTC in t(x;17)(p11;q23)

17 First case with TFE3 kidney cancer 21 year old female with locally advanced kidney cancer Surgery 4/21/87 Died 1/08/88 11 cm T3A Cell line of her tumor, karyotypic analysis: the 1/X translocation Unpublished, Courtesy of M. Linehan

18 MiT family of transcription factors TFE3, TFEB, MITF

19 Unclassified RCC Aggressive tumor Heterogeneous group of tumors not fitting into any subtype Role of targeted therapy undefined

20 International mrcc database consortium prognostic model 1 st line VEGF or mtor targeted therapies n = 2,215 (1,963 ccrcc and 252 nccrcc) nccrcc patients: Younger (p<0.0001) Low Hgb (p = 0.014) Elevated neutrophils (p = ) Significantly worse outcomes OS 22.3 vs mos (p<0.0001) TTF 7.8 vs. 4.2 mos (p<0.0001) nccrcc treated with targeted therapies have a significantly worse outcome than ccrcc patients Kroeger et al ASCO GU 2013, JCO (31): suppl 6; abstract 396

21 Retrospective Study and EAPs with Sunitinb and Sorafenib in nccrcc First Author (Year) Tyrosine Kinase Inhibitor Tumor Type N Respons e Rate (%) Median PFS Median OS Choueiri (2008) Sunitinib & Sorafenib Chromophobe (12) Papillary (41) 53 Overall 10 Chr 25 Pap 4.8 Overall = 8.6 mo Pap = 7.6 mo Chr = 10.6 mo Sunitinib 11.9 mo > Sorafenib 5.1 mo 19.6 mo Gore (2009) Sunitinib (Expanded Access) Non-clear cell RCC subtypes not specified 588/ 4371 Overall mo 13.4 mo Stadler (2010) Sorafenib (Expanded Access) Papillary (158) Chromophobe (30) Collecting duct (11) TFE translocation (2) RMC (1) 202/ 2504 Pap 3 Chr 5 24 wks 40 wks Choueiri, TK et al. JCO 26 (1): , Gore, ME et al. The Lancet Oncology 10 (8): , Stadler et al. Cancer 116(5): , 2010.

22 Phase II Trials with Sunitinib in nccrcc First Author (Year) Type of Study Tumor Type N Response Rate Media n PFS (mos) Median OS (mos) Ravaud (2009) Phase II Papillary Type I & II 27 Overall 15% Pap 1 20% Pap 2 13% 5.7 NR Molina (2010) Phase II Papillary (8) Unclassified (5) Others (10) 23 Overall 4% Pap 0% 5.5 (Pap = 5.6) NR Lee (2012) Phase II Papillary (21) Chromophobe (4) Others (4) 29 Overall 36% Pap 26% TTP = Tannir (2012) Phase II Papillary (27) Unclassified (8) Chromophobe (5) RMC (4) CDC (2) Others (4) 57 Overall 5% Pap 0% 2.7 (Pap = 1.5) 16.8 Ravaud et al. J Clin Oncol 27.15S (2009): 5146 Molina et al. Investigational New Drugs 30.1 (2012): Lee et al. Annals of Oncology 23.8 (2012): Tannir et al. European Urology 62 (6) (2012):

SUPAP: Phase II Trial of First-line Sunitinib in Papillary mrcc Eligibility criteria Age 18 years Locally advanced or metastatic, histologically confirmed type

unacceptable toxicity No prior systemic therapy for mrcc (including sunitinib) Primary end point: objective tumour response Secondary end points: safety, OS,

23 SUPAP: Phase II Trial of First-line Sunitinib in Papillary mrcc Eligibility criteria Age 18 years Locally advanced or metastatic, histologically confirmed type 1 or 2 papillary RCC Measurable disease by RECIST ECOG PS 1 N = 61 Type 1: n = 15 Non type 1: n = 46 Sunitinib 50 mg/d; 4 wk on/2 wk off Disease progression or unacceptable toxicity No prior systemic therapy for mrcc (including sunitinib) Primary end point: objective tumour response Secondary end points: safety, OS, PFS, time to response, duration of response Ravaud A and Escudier. Presented at: 37th ESMO Congress; 28 September 2 October 2012; Vienna, Austria: abstract 797PD.

24 Is Temsirolimus the Treatment of Choice? Hudes G, N Engl J Med May 31;356(22):

25 mtor Inhibitors in nccrcc-everolimus Phase 2 trial: RAPTOR study First-line treatment for patients with previously untreated advanced papillary RCC Primary end point: PFS at 6 months Secondary end points: Disease control rate, objective response rate, median PFS, safety ClinicalTrials.gov: NCT

26 prcc (Type I and II histology) clinical trials ESMO-ECCO 2012 & 2013 Sunitinib SUPAP A. Ravaud N patients Everolimus RAPTOR B. Escudier PFS 5.6 mo 7.6 mo investigator 3.7 mo central review RR 12% NA OS Type I Non type I/Type II 12.5 mo 21 mo [ ] 28.0 mo 20.3 mo Type I vs type II enrolled 15 vs vs 58 ( 25 UKN) Ravaud A, ESMO 2012, abst 797PD, Escudier B, ECC 2013, Asterdam, September 2013

27 RECORD-3: First-line PFS by Predominant Histology* Clear Cell mrcc Non-Clear Cell mrcc Cumulative event-free probability (%) EVE SUN Everolimus (n/n = 156/205) 80 Sunitinib (n/n = 134/197) Time (months) Number of patients still at risk K-M Median PFS (mo) Everolimus Sunitinib Hazard Ratio = 1.39 Two-sided 95% CI [1.10, 1.75] Cumulative event-free probability (%) EVE SUN Everolimus (n/n = 24/31) 80 Sunitinib (n/n = 23/35) Time (months) Number of patients still at risk K-M Median PFS (mo) Everolimus Sunitinib Hazard Ratio = 1.54 Two-sided 95% CI [0.86, 2.75 ] *Post-hoc exploratory sub-group analysis Motzer RJ, J Clin Oncol 31, 2013 (suppl; abstr 4504)

28 mtori for Non-clear and Sarcomatoid RCC n= 85 patients 62 non-clear cell RCC 23 sarcomatoid ccrcc Response Rate by RECIST 1.1 Objective Response All Sarcomatoid Non-Clear ccrcc Cell No. of patients (%) 82 (100) 23 (100) 59 (100) PR, n (%) SD, n (%) PR or SD 6 months, n (%) PD, n (%) 6 (7) 40 (49) 20 (24) 36 (44) 3 (13) 7 (30) 4 (17) 13 (57) 3 (5) 33 (56) 14 (24) 23 (39) Voss MH et al, Ann Oncol Mar;25(3):663

29 mtori Therapy Duration for Non-Clear Cell RCC STAB PR STAB PR STAB Voss MH et al, Ann Oncol Mar;25(3):663

30 mtori for Non-clear and Sarcomatoid RCC Progression-Free Survival and Overall Survival All Patients Sarcomatoid ccrcc Non-Clear Cell No. of patients (%) 85 (100) 23 (27) 62 (73) Median PFS (95% CI), mo 2.9 ( ) 3.5 ( ) 2.8 ( ) Median OS (95% CI), mo 8.7 ( ) 8.2 ( ) 9.1 ( ) Voss MH et al, Ann Oncol Mar;25(3):663

31 mtori for Non-clear and Sarcomatoid RCC Progression-Free Survival OS by MSKCC risk group Overall Survival Voss MH et al, Ann Oncol Mar;25(3):663

Phase II Study of Everolimus vs Sunitinib: Mixed Sub-type nccrcc (ASPEN) Key inclusion criteria Papillary or chromophobe nccrcc KPS 60 Key exclusion criteria Collecting duct, medullary, small cell,

32 Phase II Study of Everolimus vs Sunitinib: Mixed Sub-type nccrcc (ASPEN) Key inclusion criteria Papillary or chromophobe nccrcc KPS 60 Key exclusion criteria Collecting duct, medullary, small cell, oncocytoma, or lymphoma-type pathology Prior systemic therapy for mrcc Patients will be stratified by histology and Motzer risk criteria R A N D O M I Z E Target: n = 108 This study is ongoing, but not recruiting participants. Everolimus 10 mg QD on days 1 42 of each 42-day cycle Sunitinib 50 mg QD on days 1 28 of each 42-day cycle Primary end point: PFS Secondary end points: tolerability, QoL Treat until disease progression, unacceptable toxicity, or withdrawal of consent ClinicalTrials.gov identifier: NCT

33 Phase II Study of Everolimus vs Sunitinib: Mixed Sub-type nccrcc (MDACC) Key eligibility criteria Advanced nccrcc, including (but not limited to) chromophobe, papillary, collecting duct, translocation, sarcomatoid ( 20% component), and unclassified) ECOG PS 0-1 No prior systemic therapy R A N D O M I Z E Target: n = 108 Everolimus 10 mg QD Sunitinib 50 mg QD (4 wk on/2 wk off) Treat until disease progression, unacceptable toxicity, or discontinuation for any other reason This study is ongoing, but not recruiting participants. Primary end point: PFS ClinicalTrials.gov identifier: NCT

34 Foretinib: Dual VEGFR and MET Inhibitor Met Receptor Foretinib Activating Mutation No Proliferation

35 Foretinib (MET/VEGFR-2 Inhibitor) Intermittent dosing (n=37) Daily dosing (n=37) TOTAL (N=74) Overall Response Rate n (%) 5 (13.5) 5 (13.5) 10 (13.5%) PFS 9.6 mos 9.1 mos 11.6 mos Median OS Not reached Not reached Not reached 1 year OS (%) Evaluable: 10 germline MET mutations: 5 PR (50%); 5 somatic MET mutations: 1 PR (20%); 2 MET amplification: 0 PR; 18 gain chromosome 7: 1 PR (5%) Choueiri TK et al. JCO 31.2 (2013):

36 Tumor Shrinkage in 50 out of 68 patients Germline Mutations Best percentage change from baseline * MET aberration (MET amplification, trisomy 7 or somatic mutation; excluding germline mutations) Tested, but no germline mutation or MET aberrations Confirmed PR=13.5% (all cohort) * ** ** **** * Choueiri TK et al. JCO 31.2 (2013):

37 MET a Potential Target Across All Papillary Renal Cell Carcinomas Copy number alterations (gain) in 46% of type II prcc and in 81% of type I prcc Significant correlation between DNA copy number alterations and mrna expression level 11 somatic mutations of MET gene in 51 type I prcc (21.6%), and 4 new mutations. Supports investigating MET inhibitors in prcc in correlation with MET activation status Albiges et al, Clin Cancer Res;

38 Erlotinib in Papillary RCC SWOG phase II trial 52 patients enrolled (7 ineligible) ORR 11% (5/45; 95% CI, 3%-24%) Disease control rate 64% Freedom from treatment failure at 6 months 29% (95% CI, 17% to 42%) Median OS 27 mo (95% CI: 13-36) Gordon MS et al. JCO (2009):

39 Selected Ongoing Phase II Trials Pazopanib in papillary RCC (NCT ) Axitinib in nccrcc after temsirolimus (NCT ) Bevacizumab plus everolimus in nccrcc (NCT ) Bevacizumab plus erlotinib in papillary RCC (HLRCC & sporadic) (NCT ) Tivantinib (ARQ 197) with or without erlotinib in papillary RCC (NCT ) Modified courtesy of B. Rini

40 How does histology alter treatment? Non ccrcc: - distinct tumor entities - different genetic abnormalities - different phenotypes - different biology Further work needs to be done to understand the pathogensis No established standard of care An aggressive surgical approach justified in selected patients

41 How does histology alter treatment? VEGF TKIs and mtori safety and efficacy in EAP trials and prospective phase II trials A role for c-met inhibitors in patients with germline mutation of c-met Role of EGFR inhibition is being explored All patients with metastatic nccrcc should be referred for enrollment on clinical trials

42 Thank you for your attention

Have Results of Recent Randomized Trials Changed the Role of mtor Inhibitors?

Have Results of Recent Randomized Trials Changed the Role of mtor Inhibitors? Bernard Escudier Institut Gustave Roussy Villejuif, France EIKCS Lyon April 2015 What is the current role of mtor inhibitors?