Systemic treatment for non-clear cell

histology

Alessandra Mosca

Medical Oncology«Maggiore della Carità» University HospitalUniversity of East Piedmont “A. Avogadro”

Novara

De Vita VT el al, 2005

Sporadic/hereditary(Sporadic)/hereditary (hereditary leiomyomatosis)

(+) (-)

HIF, VEGF

Linehan et al, Annu Rev Med 2010

clear cell

Histology

clear cell

124 pts (20%) non-clear cell

clear cell

clear cell

clear cell

clear cell

Axitinib vs Sorafenib 723 2nd line PFS 6.7 vs 4.7 mo (p<0.0001) clear cell8Rini BI et al, Lancet 2011

REGIMEN NR of PTS EFFICACY (MEDIAN)/ACTIVITY

Temsirolimus vs IFN vs Tem+IFN (phase III) Hudes, NEJM 2007Dutcher JP, Med Oncol 2009

124 non-clear

55 papillary PFS 7.0 vs 1.8 mo (Tems vs IFN)OS 11.6 vs 4.3 mo (Tems vs IFN)

Sunitinib or Sorafenib (retrospective) Choueiri TK, JCO 2008

41 papillary PFS 11.9 (Sunitinib) vs 5.1 mo (Sorafenib)

Sunitinib (phase II)Ravaud A, JCO 2009, abstr 5146

5 papillary type I23 papillary type II

No response1 PRPFS/OS ongoing

Sunitinib (EAP)Gore ME, Lancet Oncol 2009

588 non-clear OS 9.4 (non-clear) vs 13.4 (clear) mo

Erlotinib [EGFR inhibitor] (phase II)Gordon MS, JCO 2009

45 papillary 64% SD+PROS 27 mo

Sunitinib (phase II)Plimack ER, JCO 2010, abstr 4604

23 papillary PFS 1.6 mo, OS 10.6 mo

Sorafenib (EAP)Stadler WM, Cancer 2010

202 non-clear:107 papillary20 chromophobe

84% SD+PR; 16% PD 90% SD+PR; 10% PDPFS 11.5 mo; OS 12.5 mo

Gemcitabine + Cisplatin or Carboplatin (phase II)Oudard S, J Urol 2007

23 mets collecting duct RCC 26% PR (5) + CR (1)PFS 7.1 mo, OS 10.5 mo

CLINICAL TRIALS CONSIDERING NON-CLEAR CELL RCC

REGIMEN NR of PTS EFFICACY (MEDIAN)/ACTIVITY

Bortezomib (phase II)NCI, Los Angeleshttp://clinicaltrials.gov/NCT00276614

3 mets non-clear -Start Date: April 2006-Estimated Study Completion: July 2009

Everolimus (RAPTOR-phase II)http://clinicaltrials.gov/NCT00688753

60 advanced papillary -study start:July 2009-estimated primary completion: July 2011

Temsirolimus vs Sunitinib (phase II) Central European Societyhttp://clinicaltrials.gov/NCT00979966

108 advanced or mets non-clear

-Start Date: July 2009-Estimated Study Completion: July 2011

Sunitinib (phase II)IC Humanitas (MI)http://clinicaltrials.gov/NCT01034878

55 mets non-clear -Start Date: Dec 2009-Estimated Study Completion: Nov 2011

Sunitinib (phase II)Asan Medical Centerhttp://clinicaltrials.gov/NCT01219751

35 advanced non-clear -Start Date: June 2008-Estimated Study Completion: September 2011

NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC:

COMPLETED -I-

REGIMEN NR of PTS EFFICACY (MEDIAN)/ACTIVITY

Gemcitabine + Irinotecan (phase II) NCI, Clevelandhttp://clinicaltrials.gov/NCT00401128

30 mRCC (clear and non-clear) -2ary endpoint: % response of clear vs non-clear-Start Date: May 2004

Pemetrexed + Gemcitabine (phase II) MDACC (Houston)http://clinicaltrials.gov/NCT00491075

16 advanced non-clear -Start Date: Dec 2005-Estimated Study Completion: Sep 2011

Capecitabine (phase II)Kidney Cancer Research Bureauhttp://clinicaltrials.gov/NCT01182142

51 mets non-clear -Start Date: Sept 2007-Estimated Study Completion: August 2010

NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC:

COMPLETED -II-

REGIMEN Estimated NR of PTS EFFICACY (MEDIAN)/ACTIVITY

Everolimus (phase II)Seoul National University Hospitalhttp://clinicaltrials.gov/NCT00830895

48 mets non-clear -study start:January 2009-estimated primary completion: March 2012

Sunitinib (phase II)MDACC (Houston)http://clinicaltrials.gov/NCT00465179

60 advanced non-clear -Start Date: March 2010-Estimated Study Completion: March 2013

Everolimus vs Sunitinib (phase II) MDACC (Houston)http://clinicaltrials.gov/NCT01185366

108 advanced non-clear -Start Date: August 2010-Estimated Study Completion: August 2013

Everolimus vs Sunitinib (phase II) Duke Universityhttp://clinicaltrials.gov/NCT01108445

108 mets non-clear -Start Date: September 2010-Estimated Study Completion: September 2014

Everolimus + Bevacizumab (phase II) MSKCChttp://clinicaltrials.gov/NCT01399918

34 advanced non-clear -Study start: July 2011-Estimated study completion: July 2013

Erlotinib + Bevacizumab (phase II)http://clinicaltrials.gov/NCT01130519

40 papillary (sporadic/hereditary)

-Study start: May 2010-Estimated study completion: March 2017

Tivozanib (phase II)AVEO Pharmaceuticalshttp://clinicaltrials.gov/NCT01297244

100 advanced RCC (clear and non-clear)

-Start Date: January 2011-Estimated Study Completion: June 2012

NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC:

ONGOING

UP DATE FROM

894/2076 (43%) pts

ineligible

for clinical trials

Adapted from Heng D et al, ASCO GU 2012

Adapted from Heng D et al, ASCO GU 2012

Adapted from Heng D et al, ASCO GU 2012

Adapted from Heng D et al, ASCO GU 2012

Non-clear cell histology

remains

a significant and independent

risk factor

for cancer specific death

for mRCC pts treated by TT

25 non-clear cell 132 clear celltreated with TT:

median survival15.4 mo (non-clear) vs35 mo (clear)p=0.007

37 pts -> intermittent schedule

37 pts -> daily schedule

Adverse events:

-Hypertension 50%

-Pulmonary embolism 11%

-Fatigue 6.8%

-Diarrhea 6.8%

Adapted from Choueiri TK et al, ASCO GU 2012

67/74 pts evaluable for both MET mutation and response to Foretinib:

5/10 (50%) pts with germline MET mutation: PR

5/10 (50%) pts with germline MET mutation: SD

5/57 (9%) pts without germline MET mutation: PR

1/5 (20%) pts with somatic MET mutation: PR

Sporadic papillary RCC

is different from

hereditary papillary RCC?

Adapted from Cho D, ASCO GU 2012

CONCLUSIONS -I-

Adapted from Cho D, ASCO GU 2012

CONCLUSIONS -II-

CONCLUSIONS -III-

Multidisciplinary approach to

RCC patients

(Pathologist, Urologist, Oncologist,

Radiologist, Statistician, Nurse, …)