Cáncer Renal; Cara a Cara: Tratamiento de 2a línea/ A ...€¦ · Hospital Universitario Central...

Cáncer Renal; Cara a Cara: Tratamiento de 2a línea/ A favor Inmunoncología

Hospital Universitario Central de Asturias Servicio de Oncología Médica Emilio Esteban González

Inmunoterapia – Carcinoma Renal

XD Liu et al. Cancer Immunol Res 2015

Mecanismos de Acción Agentes en segunda línea de tratamiento

aMitochondrial VEGFR-3 IC50 is 20 nM.

1. Axitinib EPAR assessment report; 2. Sorafenib EPAR; 3. Everolimus EPAR public assessment; 4. Wang C, et al. Cancer Immunol Res 2014; 2:846–

56; 5. Cabozantinib FDA; 6. You W-K, et al. Cancer Res 2011;71:4758–68; 7. Lenvatinib EPAR [All accessed April 2017].

Axitinib1 Sorafenib2 Everolimus3 Nivolumab4 Cabozantinib

5,6 Lenvatinib7

MoA VEGFR-TKI VEGFR-TKI mTOR inhibitor

PD-1 inhibitor

VEGFR-TKI VEGFR-TKI

Selectivity (IC50, <10 nM)

VEGFR-1 VEGFR-2 VEGFR-3 PDGFRα PDGFRβ

KIT

CRAF FKBP-12 PD-L1 PD-L2

VEGFR-2 VEGFR-3

MET RET AXL KIT

TRKB

VEGFR-1 VEGFR-2 VEGFR-3

RET

Potency (IC50, nM) VEGFR-1 VEGFR-2 VEGFR-3 MET AXL FGFR2

0.09–0.12 0.2 ± 0.06 0.1–0.29

– – –

–

90 –a

– – –

– – – – – –

– – – – – –

12.2

0.035 6.0 1.3 7.0 –

4.7 3.0 2.3 – –

27

ESTUDIO CheckMate 025 Patients previously treated with anti-angiogenic therapy

Primary endpoints: OS

Secondary endpoints: PFS, ORR, duration of objective response, duration of OS in PD-L1-

positive versus negative subgroups, safety, disease-related symptom progression rate

Eligibility

Advanced or mRCC with clear cell component

Received 1 or 2 prior anti-angiogenic therapy

Progression on or after most recent therapy (within 6 months of study enrolment)

Karnofsky PS ≥70

Nivolumab

3 mg/kg IV every 2 weeks

Everolimus

10 mg po daily

RANDOM I

SA T I ON

N=822

1:1

Treatment until

disease progression

or unacceptable

toxicity

clinicaltrials.gov (NCT01668784)

IV, intravenous; po, per os [oral administration]; PD-L1, programmed death ligand 1; PS, performance status

Study completion: Feb 2016

Motzer RJ et al. N Engl J Med 2015; 373:1803–1813.

Nivolumab (n=410) Everolimus (n=411)

Median age, years (range) 62 (23–88) 62 (18–86)

Male gender 77% 74%

MSKCC risk group

Favorable

Intermediate

Poor

35%

49%

16%

36%

49%

15%

Previous nephrectomy 89% 87%

Previous antiangiogenic regimens for RCC

1

2

72%

28%

72%

28%

Previous systemic therapy for mRCC

Sunitinib

Pazopanib

Axitinib

60%

29%

12%

59%

32%

12%

Patients with quantifiable PD-L1 expression

≥1%

<1%

90%

25%

75%

94%

23%

77%

CARACTERISTICAS PACIENTES

7

SUPERVIVENCIA GLOBAL (SG) Median OS, months (95% CI)

Nivolumab 25.0 (21.8–NE)

Everolimus 19.6 (17.6–23.1)

HR (98.5% CI): 0.73 (0.57–0.93)

P = 0.0018

0 3 6 12 9 15

Months

18 21 24 27 30 33

No. of patients at risk Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0

411 366 324 287 265 241 187 115 61 20 2 0 Everolimus

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Surv

ival

(P

rob

abili

ty)

Nivolumab

Everolimus

Minimum follow-up was 14 months.

NE, not estimable.

Resultados a dos años (SG)

8

Nivolumab

Ove

rall

Su

rviv

al

(Pro

ba

bil

ity)

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12 18

Months

24 30 36 42

Everolimus

Median OS,

months (95% CI)

Nivolumab 26.0 (22.2–29.6)

Everolimus 19.7 (17.6–22.3)

HR (95% CI) 0.73 (0.61–0.88)

P = 0.0006

3 9 15 21 27 33 39

No. at risk

Nivolumab

Everolimus 410 359 305 251 204 129 38 0

411 325 268 214 162 103 32 0

390 337 276 225 171 80 5

367 289 247 183 130 61 5

52%

76%

67%

42%

• Minimum follow-up was 26 months at the database lock on May 11, 2016 (Figure 2)

• Median OS benefit was observed with nivolumab versus everolimus in patients with

Memorial Sloan Kettering Cancer Center intermediate risk (21.9 vs 18.4 months, respectively)

and poor risk (15.3 vs 7.9 months) Adapted from poster presented by Plimack ER et al at the 15th International Kidney Cancer Symposium; November 4–5, 2016; Miami, FL, USA.

SG DEPENDIENDO DE LA EXPRESIÓN PD-L1

PD-L1 <1% (n = 76%)

Median OS, months (95% CI)

Nivolumab 21.8 (16.5–28.1)

Everolimus 18.8 (11.9–19.9)

No. of patients at risk

Nivolumab 94 86 79 73 66 58 45 31 18 4 1 0

Everolimus 87 77 68 59 52 47 40 19 9 4 1 0

0.0

0 3 6 12 9 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Surv

ival

(P

rob

abili

ty)

Nivolumab

Everolimus

PD-L1 ≥1% (n = 24%)

10



Everolimus 21.2 (17.7–26.2)

276 265 245 233 210 189 145 94 48 22 2 0

299 267 238 214 200 182 137 92 51 16 1 0

Nivolumab

0 3 6 12 9 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

Everolimus

HR (95% CI): 0.79 (0.53–1.17)

HR (95% CI): 0.77 (0.60–0.97)

PD-L1 <5% (n=671) PD-L1 ≥5% (n=85)

Months 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3 6 9 12 15 18 21 24 27 30 33 Months

0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3 6 9 12 15 18 21 24 27 30 33 Number of patients at risk

Nivolumab 44 41 38 36 33 28 22 16 9 1 1 0

Everolimus 41 38 31 27 23 21 17 6 3 2 1 0

Number of patients at risk

Nivolumab 326 310 286 270 243 219 168 109 57 25 2 0

Everolimus 345 306 275 246 229 208 160 105 57 18 1 0



Everolimus 18.1 (10.3–NE)



Everolimus 20.0 (17.7–24.7)

Nivolumab

Everolimus

Nivolumab

Everolimus

SG DEPENDIENDO DE LA EXPRESIÓN PD-L1

Líneas de tratamiento Posterior

12

Nivolumab N = 410

Everolimus N = 411

Subsequent systemic therapya, % Everolimus Axitinib Pazopanib Sunitinib Sorafenib Bevacizumab Cabozantinib Nivolumab

61 31 29 11 9 7 6 5 2

67 6

39 16 10 10 6 2 6

Median time from randomization to subsequent therapy, months (95% CI)

12.4 (10.3–13.2)

8.0 (7.0–9.6)

aSubsequent therapy received by ≥5% of patients

Adapted from poster presented by Plimack ER et al at the 15th International Kidney Cancer Symposium; November 4–5, 2016; Miami, FL, USA.

13

RESPUESTAS OBJETIVAS (ORR)

Nivolumab

N = 410

Everolimus

N = 411

Objective response rate, % 25 5

Odds ratio (95% CI)

P value

5.98 (3.68–9.72)

<0.0001

Best overall response, %

Complete response

Partial response

Stable disease

Progressive disease

Not evaluated

1

24

34

35

6

1

5

55

28

12

Median time to response,

months (range) 3.5 (1.4–24.8) 3.7 (1.5–11.2)

Median duration of response,

months (range)* 12.0 (0–27.6) 12.0 (0–22.2)

Ongoing response, n/N (%) 49/103 (48) 10/22 (45)

SUPERVIVENCIA LIBRE DE PROGRESIÓN (PFS)

No. of patients at risk Nivolumab 410 230 145 116 81 66 48 29 11 4 0 Everolimus 411 227 129 97 61 47 25 16 3 0 0

0 3 6 12 9 15

Months

18 21 24 27 30

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0 P

rogr

ess

ion

-Fre

e S

urv

ival

(P

rob

abili

ty)

Nivolumab

Everolimus

Median PFS, months (95% CI)

Nivolumab 4.6 (3.7–5.4)

Everolimus 4.4 (3.7–5.5)

HR (95% CI): 0.88 (0.75–1.03)

P = 0.1135

In a post-hoc analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for nivolumab vs 11.7 months for everolimus (HR (95% CI): 0.64 (0.47–0.88)) 15

EFECTOS ADVERSOS

16

Treatment-related AEs in >15% of patients in either arm


AE, % Nivolumab (n = 406)

Everolimus (n = 397)

Any Grade Grade 3/4 Any Grade Grade 3/4

Treatment-related AEs 79 19 88 37

Fatigue 33 2 34 3

Nausea 14 < 1 17 1

Pruritus 14 0 10 0

Diarrhea 12 1 21 1

Decreased appetite 12 < 1 21 1

Rash 10 < 1 20 1

Cough 9 0 19 0

Anemia 8 2 24 8

Dyspnea 7 1 13 < 1

Edema peripheral 4 0 14 < 1

Pneumonitis 4 1 15 3

Mucosal inflammation 3 0 19 3

Dysgeusia 3 0 13 0

Hyperglycemia 2 1 12 4

Stomatitis 2 0 29 4

Hypertriglyceridemia 1 0 16 5

Epistaxis 1 0 10 0

EECTOS ADVERSOS

aTime to resolution is based on the time of onset of the AE (not at the start of treatment). + indicates a censored value

GI = gastrointestinal; NR = not reached

17

• The median time to onset of treatment-related select AEs with nivolumab was 7.3–17.4 weeks,

depending on AE category (Figure 3)

• The majority of treatment-related select AEs with nivolumab resolved (63%–89%, depending

on AE category), with the exception of endocrine AEs (37%) (Figure 3)

Time to onset and resolution of treatment-related select Aes

0 50 100 150 200

Weeks

Median time to onset (range)

7.3 (2.0–71.1)

Hepatic (n = 45; 11%)

Skin (n = 107; 26%)

GI (n = 56; 14%)

Renal (n = 28; 7%)

Endocrine (n = 41; 10%)

Pulmonary (n = 18; 4%)

8.4 (0.1–100.1)

10.1 (0.1–122.1)

10.6 (4.0–79.1)

16.4 (2.1–112.3)

17.4 (1.9–73.0)

0 5 0 1 0 0 1 5 0 2 0 0

W e e k s

M e d i a n t i m e t o r e s o l u t i o n a ( r a n g e )

H e p a t i c ( n = 3 7 / 4 4 ; 8 4 % )

S k i n ( n = 8 3 / 1 0 6 ; 78 % )

G I ( n = 4 7 / 5 6 ; 8 4 % )

R e na l ( n = 1 7 / 2 7 ; 6 3 % )

E n do c r i n e ( n = 1 5 / 4 1 ; 3 7 % )

P u l mo n a r y ( n = 1 6 / 1 8 ; 8 9 % )

8 . 0 ( 1 . 6 – 1 2 7 . 1 + )

1 6 . 0 ( 0 . 1 – 1 5 6 .6 + )

7 . 8 6 ( 0 . 1 – 1 3 2 . 1 + )

2 6 . 1 4 ( 0 . 6 – 1 0 9 . 1 + )

N R ( 1 . 9 – 1 4 1 . 9 + )

5 . 5 7 ( 1 . 3 – 9 6 . 1 + )


18

CALIDAD DE VIDA (QoL) CON FKSI-DRS

Questionnaire completion rate: ≥80% during the first year of follow-up.

Mean

Ch

an

ge F

rom

Baselin

e

Nivolumab

Everolimus

4 0 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

W eek

-6

0

-4

-2

2

4

6

No. of patients at risk Nivolumab 362 334 302 267 236 208 186 164 159 144 132 1 19 1 12 97 90 89 81 72 63 59 53 44 43 31 30 26 20 Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9

Wo

rse

B

ett

er

▪ Mean change from baseline in the nivolumab group increased over time

and differed significantly from the everolimus group at each assessment

through week 76 (P<0.05)

DROGAS CON DIFERENTE

TOXICIDAD

aOutcomes from different clinical trials

should not be

directly compared because of differences

in trial design and patient populations.

1. Choueiri TK, et al. Lancet Oncol 2016;17:917–27. 2. Escudier B, et al. NEJM

2007;356:125–34. 3. Motzer RJ, et al. J Clin Oncol 2009; 27:3584–90 4. Motzer RJ,

et al. Cancer 2010;116:4256–65. 5. Rini BL, et al. Lancet 2011;378:1931–9. 6.

Motzer R, et al. NEJM 2015;373:1803–13. 7. Sternberg CN, et al. J Clin Oncol 2010;

28:1061–8; 8. Hutson TE, et al. J Clin Oncol 2014;32:760–7; 9. Nivolumab EPAR

[Accessed April 2017].

mTOR

TKI

ANOREXIA MUCOSAL INFLAMMATION

RASH STOMATITIS

VOMITING FATIGUE

DIARRHOEA NAUSEA

WEIGHT LOSS DECREASED APPETITE

CONSTIPATION

COUGH DYSPNOEA

ALOPECIA DRY SKIN

DYSGEUSIA DYSPEPSIA

DYSPHONIA HAIR DISCOLOURATION

HAND–FOOT SYNDROME HYPERTENSION

SKIN DISCOLOURATION HYPOTHYROIDISM

ANAEMIA

ASTHENIA

HYPERTRIGLYCERIDEMIA

INFECTIONS

PERIPHERAL OEDEMA

PRURITIS

PYREXIA

BACK PAIN I

O

Efectos secundarios y seguridad

Data do not constitute substantial evidence because they represent cross-study comparisons of trials conducted using different methodologies. a23 weeks; b141 days. NA, not available.

1. Motzer RJ, et al. Lancet Oncol 2013;14:552–62; 2. Axitinib EPAR;

[Accessed April 2017]; 3. Escudier et al. NEJM 2007;356:125–34; 4. Sorafenib EPAR [Accessed

April 2017]; 5. Motzer RJ, et al. Cancer 2010;116:4256–65; 6. Motzer RJ, et al. NEJM 2015;373:1803–13; 7. Nivolumab EPAR [Accessed April 2017]; 8.

Choueiri TK, et al. NEJM 2015;373:1814–23;

9. Choueiri TK, et al. Lancet Oncol 2016;17:917–27.

AXIS (N=723)1,2

TARGET (N=903)3,4

RECORD-1 (N=416)5

CheckMate-025 (N=821)6,7

METEOR (N=658)8

HOPE 205 (N=153)9

Experimental arm Axitinib Sorafenib Everolimus Nivolumab Cabozantinib Lenvatinib + everolimus

Median treatment duration, months

8.2 5.3a 4.7b 5.5 8.3 7.6

Any dose reduction, %

34 13 7 NA 62 71

Discontinued due to AEs, %

4 10 13 8.6 12 24

All causality AEs Grade 3/4, %

65.7 64.3 NA 53 71 71

Guidelines ESMO 2016

Escudier B, et al. ESMO 2016

Guidelines NCCN 2017 (USA): NCCN v2.2017

AXINIVO study design (Phase II)

Eligibility criteria

• Clear-cell mRCC

• Failure of prior first-line regimen containing an anti-angiogenic

• Measurable disease (RECIST v1.0) and non-measurable lesion that could be followed by the investigator

• ECOG PS ≤1

N=224

Strata: MSKCC risk

criteria

RANDOM I S A T I ON

1:1

Axitinib 5 mg BID

Nivolumab 3 mg/kg IV

every 2 weeks

Nivolumab 3 mg/kg IV

every 2 weeks

Axitinib 5 mg BID

Crossover upon

progression

Final OS

analysis

after the 3-

year follow-

up period

RESULTADOS DEL RAPID CARACTERIZACIÓN MOLECULAR

Nivolumab como representante de inmunoterapia moduladora anti

PD-1 ha demostrado mejorar la SG y QoL en 2 ª y 3ª línea frente a

Everolimus (vía m-TOR)

Nivolumab es una alternativa sólida al tratamiento anti-angiogénico

por su mecanismo de acción y perfil de toxicidad diferente

Precisar el valor de PD-L1 en tumor/células inmunológicas infiltrantes

o perfiles moleculares son imprescindibles para mejorar la estrategia

terapéutica actual

CONCLUSIONES

Cáncer Renal; Cara a Cara: Tratamiento de 2a línea/ A ...€¦ · Hospital Universitario Central...

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