Coordinación científica: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla,
Santander
Organizado por: Fundación para el progreso
de la oncología en Cantabria
Adyuvancia en cancer renal: Más dudas que certezas?
Guillermo de Velasco
Hospital 12 de Octubre
ADJUVANT KIDNEY CANCER INTO CONTEXT
Estimated cancer incidence in Spain 2015 (REDECAN)
Estimated mortality by tumor type (10 more frequent) in Spain 2014 (Instituto
de Salud Carlos III. Área de Epidemiología Ambiental y Cáncer. Centro Nacional de Epidemiología)
ADJUVANT KIDNEY CANCER INTO CONTEXT
5 year survival rate for stage III is 53% vs stage IV is 15%
50% of patients are diagnosed in stage I
30% of patients are diagnosed in stage II and III
Probability of recurrence in stage III is 40%
VALIDATED MODELS FOR RELAPSE RISK IN KIDNEY CANCER
The University of California Los Angeles Integrated Staging System (UISS)
The stage, size, grade, and necrosis (SSIGN) score
Frank, I., et al. J Urol 2002
Zisman, A., et al. J Clin Oncol 2001
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CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
ECOG-ACRIN E2805
Sunitinib Sorafenib Placebo
Age (years) 56 (49-64) 55 (48-63) 57 (49-64)
ECOG 0/ECOG 1 510 (79%)/137 (21%) 511 (79%)/138 (21%) 508 (79%)/139 (21%)
Type of nephrectomy
Radical
Partial
614 (95%)
33 (5%)
605 (93%)
44 (7%)
617 (95%)
29 (4%)
Clear cell
Papillary
Chromophobe
Mixed
Unclassified
Sarcomatoid features
513 (79%)
39 (6%)
40 (6%)
31 (5%)
23 (4%)
51 (8%)
519 (80%)
52 (8%)
43 (7%)
21 (3%)
14 (2%)
58 (9%)
509 (79%)
59 (9%)
28 (4%)
31 (5%)
19 (3%)
61 (10%)
UCLA (UISS) Int-high
UCLA (UISS) Very high
323 (50%)
324 (50%)
324 (50%)
325 (50%)
326 (50%)
321 (50%)
AJCC stage
I
II
III
IV
57 (9%)
159 (25%)
422 (65%)
9 (1%)
61 (9%)
167 (26%)
409 (63%)
12 (2%)
64 (10%)
154 (24%)
424 (66%)
4 (1%)
ECOG-ACRIN E2805
Haas NB, et al. Lancet 2016; 387: 2008–16
mDFS= 70 months (Su) vs 73.4m (So) vs 79.6 m (P)
PRIMARY ENDPOINT: DISEASE FREE SURVIVAL
All groups did better than predicted at the time of study design; mOS has not yet been reached in any group
5-year DFS rate:
54.3% (Su) vs 54.0% (So) vs 56.4% (P)
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CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
NEGATIVE
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CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
CLI
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IN A
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VA
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CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
NEGATIVE
POSITIVE
ASSURE and S-TRAC in perspective
Variable ASSURE S-TRAC
Study Conduct Central Scans Review No Yes (eligibility and efficacy)
Patient
Characteristics
ccRCC 79.1% 99.0%
ECOG PS 0 81.8% 73.8%
RCC Stage I-II 33.4% 0%
Dose
administered
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 intensity
Full Dose: 40.2% Reduced Dose 44.5%
(first 3 cycles) 88.4%
CLI
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CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
CLI
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AL
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IALS
IN A
DJU
VA
NT
TR
EA
TM
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T O
F R
CC
CLINICAL TRIALS
ESTIMATED ENROLLMENT
PATIENT CHARACTERISTICS
TREATMENT PRIMARY ENDPOINT
CURRENT STATUS
ASSURE* (NCT00326898)
Double-blind
1923 Clear cell or nonclear cell: - pT1b, G3-4 N0 M0 - pT2-4, any grade N0 M0 - pT any grade and N+ vascular invasion
Placebo vs Sunitinib (50mg 4weeks on and 2 weeks off) vs Sorafenib (400mg/12h) for 1 year.
DFS Data presented
S-TRAC* (NCT00375674)
Double-blind
720 Clear cell predominant:
- T3N0/x M0, G 2, ECOG
PS1 - pT any grade N1-2 M0 o T4N0/x M0, any grade and ECOG PS
Placebo vs Sunitinib (50mg 4 weeks on y 2 weeks off) for 1 year.
DFS Data presented
SORCE* (NCT00492258)
Open-label
1656 Clear cell or nonclear cell: - Leibovich intermediate or high risk (score 3-11)
Placebo for 3 years vs Sorafenib 400mg/12h for 1 year then placebo for 2 years vs Sorafenib 400mg/12h for 3 years
DFS Completed
PROTECT* (NCT01235962)
Double-blind
1500 Clear cell or clear cell predominant: - pT2, G3-4 NO - pT3-4, any grade N0 - pT any and any grade, N1
Pazopanib 800mg/24h vs placebo for 1 year
DFS Ongoing, not recruiting
EVEREST* SWOG 9031
(NCT01120249) Double-blind
1170 Clear cell or nonclear cell; - Intermediate-high risk or very high risk.
Placebo vs Everolimus 10mg/24h for 54 weeks
RFS Recruiting
ARISER* (NCT00087022)
Double-blind
864 Clear cell: - T3a-4 N0/NX M0 - Any pT N+ M0 - T1b-T2 N0/NX M0 G≥ 3
Placebo vs Girentuximab (WX-G250) weekly for 24 weeks
DFS, OS Data presented
ATLAS* (NCT01599754)
Double-blind
700 Clear cell: - T2-4 N0/NX M0 - Any pT N+ M0
Placebo vs Axitinib 5mg/12h for 3 years
DFS Ongoing, not recruiting
WO39210 IMmotion010 Double-blind
673 Clear cell or sarcomatoid component: - Leibovich score > 6 - Metastasectomy
Placebo vs Atezolizumab 1200 mg/3w for 16 cycles or 12 months
DFS Recruitment not yet opened
MK3475 PN 564*
Double-blind
1000 Clear cell or sarcomatoid component: - pT2 G4 or sarcomatoid, N0 - pT3 or pT4 andy G, N0 - Any pT, any G, N1 - M1 NED
Placebo vs Pembrolizumab 200 mg/3w
DFS Recruitment not yet opened
Premises for Adjuvant treatment
Good treatment
Acceptable toxicity
Good endpoint
No strong correlation between 5-year DFS and 5-year OS
rates
ONGOING ADJUVANT STUDIES IN RCC
• Targeted therapy trials:
- SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 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
In order to give individualized recommendations, specialists need to ask the patient which benefits and disadvantages he or she considers to be important.
PROS CONS
ADJUVANT TREATMENT IN RENAL CELL CARCINOMA
Toxicity Hospital visits Health system costs Benefit in OS to be defined
Benefit in oncological outcome Delay in treatment recurrence Medical surveillance Benefit in OS to be defined
UNMEET QUESTIONS
PROGNOSTIC GROPUS: To optimize the patients’ selection and identify those that could benefit from this therapeutic strategy (gene-assay, N+, positive margins, metastasectomy) DOSE INTENSITY AND TREATMENT DURATION TOXICITY MANAGEMENT THE ROLE OF VEGF DRIVEN ANGIOGENESIS IN ADJUVANT TREATMENT ADJUVANT TREATMENT VS EFFICIENT FOLLOW UP
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