Tratamiento adyuvante yneoadyuvante

del cáncer renal en 2017

Tratamiento adyuvante yneoadyuvante

del cáncer renal en 2017

Xavier Garcia del Muro SolansInstitut Català d’Oncologia Hospitalet. Barcelona

Pronóstico del CR mediante un sistema integradoen 468 pts CR localizado (N0M0):

UCLA Integrated Staging System (UISS)

Zisman A. JCO 2002

5-year OS: 83% 72% 44%

Tumor Stage, Size, Grade and Necrosis: the SSIGN score forpatients with clear cell renal cell carcinoma

Frank I. J Urol 2002Leibovich BC. Cancer 2003

Randomized phase III trials of adjuvant therapyafter nephrectomy for high-risk RCC

TreatmentTreatment OutcomeOutcome

RT vs.RT vs. observationobservation SurvivalSurvival (NS)(NS)MPA vs.MPA vs. observationobservation RelapseRelapse raterate (NS)(NS)TmTm cellscells + BCG vs.+ BCG vs. observationobservation DFS (NS)DFS (NS)INF vs.INF vs. observationobservation SurvivalSurvival (NS)(NS)HDHD--IL 2 vs.IL 2 vs. observationobservation DFSDFS (NS)(NS)INF + ILINF + IL--2 + 5FU vs2 + 5FU vs observationobservation OS (p=.02)OS (p=.02)TmTm cellcell vaccinevaccine vs.vs. observationobservation 5y PFS (p=.02)5y PFS (p=.02)HSPPCHSPPC--9696 VaccineVaccine vsvs observobserv.. RFS (NS)RFS (NS)ThalidomideThalidomide 3y RFS (p=.02)3y RFS (p=.02)G250 vsG250 vs observationobservation DFS (NS)DFS (NS)

TreatmentTreatment OutcomeOutcome

RT vs.RT vs. observationobservation SurvivalSurvival (NS)(NS)MPA vs.MPA vs. observationobservation RelapseRelapse raterate (NS)(NS)TmTm cellscells + BCG vs.+ BCG vs. observationobservation DFS (NS)DFS (NS)INF vs.INF vs. observationobservation SurvivalSurvival (NS)(NS)HDHD--IL 2 vs.IL 2 vs. observationobservation DFSDFS (NS)(NS)INF + ILINF + IL--2 + 5FU vs2 + 5FU vs observationobservation OS (p=.02)OS (p=.02)TmTm cellcell vaccinevaccine vs.vs. observationobservation 5y PFS (p=.02)5y PFS (p=.02)HSPPCHSPPC--9696 VaccineVaccine vsvs observobserv.. RFS (NS)RFS (NS)ThalidomideThalidomide 3y RFS (p=.02)3y RFS (p=.02)G250 vsG250 vs observationobservation DFS (NS)DFS (NS)

Adjuvant targeted therapy trials in RCC

Phase III Adjuvant sunitinibor sorafenib for high-risk,non-metastatic renal-cellcarcinoma (ECOG-ACRIN)

Haas NB. Lancet 2016

34Confidential. Internal Use Only.

ASSURE Compared Effect of Sunitinib orSorafenib Versus Placebo on DFS

Haas NB et al. Lancet. 2016;387:2008-2016.

34

Arm CPlacebo

Daily for 1 year

Arm ASunitinib

50 mg QD 4/2 for 1 year

Enrollment Criteria:Nonmetastatic RCCthat meets radiologiccriteria to be clinically³ T1b N any (resectable)M0 disease

NEPHRECTOMY

Arm BSorafenib

400 mg BID for 1 year

Stratification• UISS risk

– Intermediate highrisk

– Very high risk• Histologic subtype

– Clear cell– Nonclear cell

• Performance status• Surgery

– Type of approach

Primary Endpoint Disease-free survival (investigator assessed)

Secondary Endpoints Overall survival, disease-free survival for clear cell RCC, and safety

RAND

OMIZE

N=1943

1:1:1

Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma

Phase III trial of sunitinib versus placebo as adjuvant treatmentfor high-risk renal cell carcinoma after nephrectomy (S-TRAC)

Patient Disposition and Treatment

* Duration of treatment was defined as the period between first and last doses of the drugand included interruptions, cycle delays, and the scheduled 2-week off treatment.† Investigators had to select only one reason.

Dosing InformationSunitinib

n=306Placebon=304

Treatment duration*, median (range), months 12.39 (0.13–14.9) 12.42 (0.03–13.7)

Treatment completion, % 55.6 69.4Treatment discontinuation, % 44.4 30.6Reasons for discontinuation†, %

Adverse events 27.5 5.3Disease progression/relapse 7.2 19.4Other 9.8 5.6

Dose reductions, n (%) 45.8 4.9Dose interruptions, n (%) 54.2 27.6Relative dose intensity, median (range) 88.4 (15–106.2) 99.7 (10–105.7)

9

Ravaud A. NEJM 2016

Disease-Free Survival By BlindedIndependent Central Review

* Two-sided P value from log-rank test stratified by UISS high-risk group.

5-yearDFS rate:59.3%

51.3%

3-yearDFS rate:64.9%

59.5%

Prop

ortio

nD

isea

se-F

ree

Disease-Free Survival (years)

10

P=0.030*

Ravaud A. NEJM 2016

Disease-Free Survival By BlindedIndependent Central Review

* Two-sided P value from log-rank test stratified by UISS high-risk group.

5-yearDFS rate:59.3%

51.3%

3-yearDFS rate:64.9%

59.5%

Prop

ortio

nD

isea

se-F

ree

Disease-Free Survival (years)

10

P=0.030*

ASSURE and S-TRAC in perspective

Variable ASSURE S-TRACStudy Conduct Central Scans Review No Yes (eligibility and efficacy)

PatientCharacteristics

ccRCC 79.1% 99.0%

ECOG PS 0 81.8% 73.8%

RCC Stage I-II 33.4% 0%

Doseadministered

Starting Dose levels 2(50 mg and 37.5 mg)

1(50 mg)

50mg 4/2 as starting dose 69.6% 100%

Minimum Dose Reduction 25 mg 37.5 mg

Relative Dose intensityFull Dose: 40.2%

Reduced Dose 44.5%(first 3 cycles)

88.4%

ASSURE and S-TRAC in perspective

Variable ASSURE S-TRACStudy Conduct Central Scans Review No Yes (eligibility and efficacy)

PatientCharacteristics

ccRCC 79.1% 99.0%

ECOG PS 0 81.8% 73.8%

RCC Stage I-II 33.4% 0%

Doseadministered

Starting Dose levels 2(50 mg and 37.5 mg)

1(50 mg)

50mg 4/2 as starting dose 69.6% 100%

Minimum Dose Reduction 25 mg 37.5 mg

Relative Dose intensityFull Dose: 40.2%

Reduced Dose 44.5%(first 3 cycles)

88.4%

• DFS and OS for 1069high-risk patients who hadccRCC histology and pT3,pT4, or N+ disease ofASSURE randomized trial.

• Outcome analyses bydose quartiles of thesepatients receiving sunitinibor sorafenib were alsoperformed

• CONCLUSIONS: Neitherprognostic category of thetumor nor dose intensity oftherapy altered the lack ofdifference in DFS or OS inthis population of patientswith high-risk ccRCC

• DFS and OS for 1069high-risk patients who hadccRCC histology and pT3,pT4, or N+ disease ofASSURE randomized trial.

• Outcome analyses bydose quartiles of thesepatients receiving sunitinibor sorafenib were alsoperformed

• CONCLUSIONS: Neitherprognostic category of thetumor nor dose intensity oftherapy altered the lack ofdifference in DFS or OS inthis population of patientswith high-risk ccRCC

Randomized phase III trial of adjuvant pazopanib vs placebo afternephrectomy in patients with locally advanced RCC (PROTECT)

Motzer R. ASCO 2017

Motzer R. ASCO 2017

Sternberg C. ASCO 2017

ONGOING ADJUVANT STUDIES IN RCC

• Targeted therapy trials:- SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 pts

- ATLAS: Axitinib 3 y. vs. Placebo. 142 pts

- EVEREST: Everolimus vs placebo. 1218 pts

• Immune Checkponit Inhibitors trials:- PROSPER: Perioperative Nivolumab vs. surgery alone

- Immotion 10: Atezolizumab vs. placebo

- KEYNOTE 564: Pembrolizumab vs. placebo

• Targeted therapy trials:- SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 pts

- ATLAS: Axitinib 3 y. vs. Placebo. 142 pts

- EVEREST: Everolimus vs placebo. 1218 pts

• Immune Checkponit Inhibitors trials:- PROSPER: Perioperative Nivolumab vs. surgery alone

- Immotion 10: Atezolizumab vs. placebo

- KEYNOTE 564: Pembrolizumab vs. placebo

NEOADYUVANCIA EN CANCER DE RIÑÓN

OUTCOMES AND POTENTIAL BENEFITSOF NEOADJUVANT THERAPY IN RCC

• Tumor downsizing

Aprox. 30% pts have RR. 75-85% stabilization o shrinkage

• Reducing tumor complexity (RENAL score)

55% reduction in nephrometry score

• Facilitate radical to partial nephectomyReduction of tumor volume and complexity. PN safe

• Regression of tumor thrombus level and facilitate surg.Aprox. 25% of reduction. Surgery safe

• Making unresectable tumors resectableIt makes resection possible in Tm considered unrectable

•

• Tumor downsizing

Aprox. 30% pts have RR. 75-85% stabilization o shrinkage

• Reducing tumor complexity (RENAL score)

55% reduction in nephrometry score

• Facilitate radical to partial nephectomyReduction of tumor volume and complexity. PN safe

• Regression of tumor thrombus level and facilitate surg.Aprox. 25% of reduction. Surgery safe

• Making unresectable tumors resectableIt makes resection possible in Tm considered unrectable

•

• Prospective study of preoperative Sorafenib in 30 ptscandidates to nephrectomy, to assess toxicities, surgicalcomplications and tumor responses

• 17 pts had localized and 13 metastatic disease• 2 PR and 26 SD• All pts were able to proceed with nephrectomy and nocomplications related to sorafenib were observed

• Prospective study of preoperative Sorafenib in 30 ptscandidates to nephrectomy, to assess toxicities, surgicalcomplications and tumor responses

• 17 pts had localized and 13 metastatic disease• 2 PR and 26 SD• All pts were able to proceed with nephrectomy and nocomplications related to sorafenib were observed

CONCLUSIONS

• Adjuvant therapy trials in RCC have conflicting results. However,some data suggest that appropriate selection of patients (high-risk,clear cell) and optimal doses might be relevant factors associatedwith benefit

• At present, available data do not justify the systematic use ofadjuvant therapy. However, adjuvant sunitinib for one year couldbe an option to consider in patients with very high-risk disease

• Neoadjuvant therapy before surgery for localized renal cell canceris feasible and might be especially useful in selected patients withlarge unresectable masses, high-level venous tumor thrombusinvolvement, and patients with large masses and indications fornephron sparing surgery. Nevertheless, this approach is stillinvestigational and should be carefully used in selected patients

CONCLUSIONS

• Adjuvant therapy trials in RCC have conflicting results. However,some data suggest that appropriate selection of patients (high-risk,clear cell) and optimal doses might be relevant factors associatedwith benefit

• At present, available data do not justify the systematic use ofadjuvant therapy. However, adjuvant sunitinib for one year couldbe an option to consider in patients with very high-risk disease

• Neoadjuvant therapy before surgery for localized renal cell canceris feasible and might be especially useful in selected patients withlarge unresectable masses, high-level venous tumor thrombusinvolvement, and patients with large masses and indications fornephron sparing surgery. Nevertheless, this approach is stillinvestigational and should be carefully used in selected patients