Guillermo de Velasco Hospital 12 de Octubre

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

GOALS IN ADJUVANT TREATMENT

Delay DFS

Second chance of cure

Improve OS

Reduce toxicity

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%

Premises for Adjuvant treatment

Good treatment

Good endpoint

Able to Improve OS

Acceptable toxicity

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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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


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


Haas NB, et al. Lancet 2016; 387: 2008–16

ECOG-ACRIN E2805

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)

ECOG-ACRIN E2805

ECOG-ACRIN E2805

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CURRENT STATUS


Double-blind



DFS Data presented

S-TRAC* (NCT00375674)

Double-blind





DFS Data presented


Open-label



DFS Completed


Double-blind




EVEREST* SWOG 9031




RFS Recruiting


Double-blind





Double-blind








MK3475 PN 564*

Double-blind




NEGATIVE

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CURRENT STATUS


Double-blind



DFS Data presented

S-TRAC* (NCT00375674)

Double-blind





DFS Data presented


Open-label



DFS Completed


Double-blind




EVEREST* SWOG 9031




RFS Recruiting


Double-blind





Double-blind








MK3475 PN 564*

Double-blind




S-TRAC TRIAL

Ravaud A, et al. N Engl J Med 2016;375(23):2246-2254.

Ravaud A, et al. N Engl J Med 2016;375(23):2246-2254.

S-TRAC TRIAL

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CURRENT STATUS


Double-blind



DFS Data presented

S-TRAC* (NCT00375674)

Double-blind





DFS Data presented


Open-label



DFS Completed


Double-blind




EVEREST* SWOG 9031




RFS Recruiting


Double-blind





Double-blind








MK3475 PN 564*

Double-blind




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%

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CURRENT STATUS


Double-blind



DFS Data presented

S-TRAC* (NCT00375674)

Double-blind





DFS Data presented


Open-label



DFS Completed


Double-blind




EVEREST* SWOG 9031




RFS Recruiting


Double-blind





Double-blind








MK3475 PN 564*

Double-blind




Motzer R. ASCO 2017

PROTECT TRIAL

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CURRENT STATUS


Double-blind



DFS Data presented

S-TRAC* (NCT00375674)

Double-blind





DFS Data presented


Open-label



DFS Completed


Double-blind




EVEREST* SWOG 9031




RFS Recruiting


Double-blind





Double-blind








MK3475 PN 564*

Double-blind




- ATLAS: Axitinib 3 y. vs. Placebo.

Es por falta de poder estadístico?¿?

DFS

M Sun et al, Eur Urol 2018

OS

M Sun et al, Eur Urol 2018


Good treatment BETTER PATIENT SELECTION


Good treatment

Acceptable toxicity


Good treatment

Acceptable toxicity

Good endpoint

No strong correlation between 5-year DFS and 5-year OS

rates


Good treatment

Acceptable toxicity

Good endpoint

Improve OS

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

@H12O_GUCancer @g_develasco

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Guillermo de Velasco Hospital 12 de Octubre

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