tratamento 1l do mrcc: io + io · 2019-04-24 · curso imuno-oncologia em tumores urológicos...

Curso Imuno-oncologia em tumores urológicos

Tratamento 1L do mRCC: IO + IO

Lucas V. dos Santos

Coordenador do Programa de Filantropia em Oncologia

Beneficência Portuguesa de São Paulo1

Conflitos de Interesse

Honorários por consultoria: nada a declarar

Apoio educacional: BMS, MSD, Merck Serono

Pesquisa clinica: BMS, MSD, Roche, Pfizer, Astra Zeneca, Exelixis

Ações e opções: nada a declarar

2

O embate

3

IO-IO IO-VEGFi

Votação

Considerando-se seus conhecimentos atuais, para um paciente FIT com RCC metastático, IMDC intermediário, sem comorbidades ou contra-indicações às terapias, qual seria a sua primeira opção: Ipi-Nivo ou Anti-PD-1-VEGFi?

4

Desejos e Necessidades

1. Cured of disease, preferably with limited toxicity during/after therapy and the ability to stop therapy

2. To live longer

3a. Disease control

3b. Quality of life maintained

3c. Free of therapy

3d. Reduced costs

5

Classificação de risco

6Heng DY, et al. J Clin Oncol 2009; 27:5749

Clinical• KPS < 80% (P < .0001)• Time from diagnosis to tx < 1 yr (P

= .01)

Laboratory• Hemoglobin < LLN (P < .0001)• Calcium > ULN (P = .0006)• Neutrophil count > ULN (P <

.0001)• Platelet count > ULN (P = .01)

Mos Since Therapy Initiation

Prob

abili

ty o

f OS

Favorable: 0 risk factors; intermediate: 1-2 risk factors; poor: 3+ risk factors

0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

No. of Events/No. at RiskFavorableIntermediatePoor

11/13361/30194/152

16/11050/18219/36

4/6217/82

1/3

2/222/180/1

0/30/30/0

FavorableIntermediatePoor

mRCC – baixo risco

7Rini B et al. Lancet Oncol. 2016;17:1317.

Median absolute change in tumor burden during surveillance: 1.3 cm

‒ Relative change: 31%

‒ Median growth rate: 0.09 cm/mo

23/43 (53%) patients with PD immediately started systematic therapy after progression and 20/43 (47%) continued on surveillance

‒ Median additional surveillance period for these patients: 15.8 mos36

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Perc

ent

Mos

0 6 12 18 24 30 42 48 54 60

Time to progressionObservation timeOS 38.6 mos

14.9 mos9.4 mos

mRCC – 15-year evolution

8.

Study/Author Year N Setting Experimental arm

Best OS (months)

Flanigan et al 2001 120 1st lineINF-α +

Nephrectomy

11.1

Motzer et al 2002 463 1st line INF-α 13.0

McDermott et al 2005 192 1st line HD IL-2 17.5

Motzer at al 2007 750 1st line Sunitinib 26.4

AVOREN 2007 649 1st line IFN + BEV 23.3

INTORACT 2013 791 1st line TEM + BEV 25.8

COMPARZ 2013 1,110 1st line Pazopanib 29.3

Motzer et al. 2014 168 1st / 2nd

line Nivolumab 25.5

RECORD-3 2014 471Sequential1st and 2nd

lineEVE SU 32.0

Racional bloqueio PD-1/CTLA-4

9Adapted from Ribas. NEJM. 2012;366:2517

CM 214: Ipi-Nivo vs Sun

10Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126

Phase 3, randomized, open-label trial of nivolumab combined with ipilimumab vs sunitinib monotherapy in treatment-naïve patients with advanced or metastatic clear cell RCC1

N=1,070

Start Date: October 2014Estimated Trial Completion Date: TBDEstimated Primary Completion Date: June 2019Status: Ongoing, not recruitingStudy Director: Bristol-Myers Squibb

R1:1

Sunitinib50 mg PO qd for 4 weeks

(6-week cycles)

Nivolumab3 mg/kg IV q3w for 4 doses, then q2w

Key Inclusion Criteriaa

• Advanced/metastatic clear cell RCC• No prior systemic therapy for RCC• Prior adjuvant/neoadjuvant therapy

allowed if the agent did not target the VEGF pathway, and recurrence occurred ≥6 months after last dose

• KPS ≥70%• Available FFPE archival or recent tumor

tissue sample• No prior treatment with VEGF pathway

agents or agents targeting T-cell co-stimulation or checkpoint pathways

• No current or history of CNS metastases

Ipilimumab1 mg/kg IV q3w for 4 doses

Until progression,bunacceptable

toxicity, withdrawal of

consent, or end of trial (up to

5 years)

PEP: i-p risk pts (ORR, PFS, OS) by RECIST 1.1/IRRCP (ORR) <0.001; P (PFS) < 0.009, power 80%

P (OS) <0.04 (HR 0.77), power 90%O´Brien and Fleming alpha spending function for interim analysis, OS

events 51% 75% 820 i-p risk pts

CROSSOVER ALLOWED

CM 214: Baseline characteristics


Characteristic

IMDC Intermediate/Poor Risk(N=847)

Intention to Treat(N=1,096)

Nivolumab + Ipilimumab N=425

Sunitinib N=422

Nivolumab + Ipilimumab N=550

Sunitinib N=546

Median age, years 62 61 62 62

Male, % 74 71 75 72 IMDC prognostic score %

Favorable (0) Intermediate (1–2) Poor (3–6)

07921

07921

236117

236116

Quantifiable tumor PD-L1 expression, %

<1% ≥1%

n=3847426

n=3927129

n=4997723

n=5037525

Number of sites with ≥1 target/non-target lesion, %a

1 ≥2

2179

2080

2278

2278

Most common site of metastasis, %

Lung Lymph node Boneb

Liver

69452221

70512321

69452018

68492220

P-A 31%A-A 22%

CM 214: Treatmentdiscontinuation


Nivolumab + Ipilimumab

N=547

SunitinibN=535

Treatment discontinuation, % 77 82Reasons for treatment discontinuation, %

Disease progressionStudy drug toxicityAE unrelated to study drugOtherLost to follow-up

422464

<1

551269

<1

The median (95% CI) duration of treatment for all treated patients was 7.9 months (6.5‒8.4) with NIVO + IPI and 7.8 months (6.4‒8.5) with SUN

CM 214: OS I-P risk


3 6 129 15Mos18 21 24 27 30 33

Patients at Risk, nNivolumab 425 399 372 348 332 318 300 241 119 44 2 0

422 387 352 315 288 253 225 179 89 34 3 0Sunitinib

20

40

60

80

100

OS

(%)

00

Nivolumab + ipilimumabSunitinib

425422

NR (28.2-NE)26.0 (22.1-NE)

Patients,n Median, Mos (95% CI)

HR for death: 0.63 (99.8% CI: 0.44-0.89;P < .001)

Nivolumab + ipilimumab

Sunitinib


Sunitinib

12-Mo OS (95% CI)

18-Mo OS (95% CI)

80 (76-84)72 (67-76)

75 (70-78)60 (55-65)

FDA Approval on 4/18/18

Nivolumab + ipilimumab as combination treatment of intermediate or poor risk, previously untreated RCC

CM 214: OS I-P risk (2)


0 1 2

SubgroupNIVO + IPI

No. of Deaths/Patient

s

SUNNo. of

Deaths/Patients Hazard Ratio (95% CI)

Overall 140/425 188/422 0.66 (0.53–0.82)Age, years

<65 ≥65 and <75≥75

77/26546/12517/35

118/25955/13315/30

0.53 (0.40–0.71)0.86 (0.58–1.27)0.97 (0.48–1.95)

SexMaleFemale

104/31436/111

130/30158/121

0.71 (0.55–0.92)0.52 (0.34–0.78)

RegionUSACanada/EuropeRest of the world

33/11251/14856/165

43/11068/14777/165

0.64 (0.40–1.00)0.70 (0.49–1.01)0.63 (0.45–0.89)

Baseline IMDC prognostic riskIntermediatePoor

87/31452/102

121/31766/97

0.66 (0.50–0.87)0.57 (0.39–0.82)

Prior nephrectomyYesNo

103/34137/84

127/31961/103

0.69 (0.53–0.89)0.63 (0.42–0.94)

Baseline PD-L1 expression<1%≥1%Not reported

93/28428/10019/41

114/27857/11417/30

0.73 (0.56–0.96)0.45 (0.29–0.71)0.75 (0.39–1.45)

Favors NIVO + IPI Favors SUN

CM 214: OS I-P risk (3)


SubgroupNIVO + IPI

No. of Deaths/Patient

s

SUNNo. of

Deaths/Patients Hazard Ratio (95% CI)

Overall 140/425 188/422 0.66 (0.53–0.82)

Bone metastasesYesNo

40/84100/341

50/89138/333

0.71 (0.47–1.08)

0.64 (0.49–0.82)

Liver metastasesYesNo

40/88100/337

54/89134/333

0.64 (0.42–0.96)

0.66 (0.51–0.85)

Lung metastasesYesNo

98/29442/131

141/29647/126

0.61 (0.47–0.78)

0.81 (0.53–1.22)

Lymph-node metastasesYes No

75/19065/235

99/21689/206

0.79 (0.59–1.07)

0.55 (0.40–0.76)

0 1 2


CM 214: OS by risk group (30mo FUp)

16Tannir NM et al ASCO GU 2019, abstr 547

CM 214: ORR I-P risk


OutcomeN=847

NIVO + IPIN=425

SUNN=422

Confirmed ORRa % (95% CI)

42 (37–47) 27 (22–31)

P<0.001Confirmed BOR,a %

CRPRSDPDUnable to determine/NR

9b

323120

8

1b

254517

12

CM 214: PFS I-P risk


0 3 6 9 12 15 18 21 24 27 30

Prog

ress

ion-

Free

Sur

viva

l (Pr

obab

ility

)

425 304 233 187 163 149 118 46 17 3 0422 282 191 139 107 86 57 33 11 1 0

No. of at patients at riskNIVO + IPI

SUN

Months

1.00.90.80.70.60.50.40.30.20.10.0

Median PFS, Months (95% CI)NIVO + IPI 11.6 (8.7–15.5)

SUN 8.4 (7.0–10.8)

HR (99.1% CI), 0.82 (0.64–1.05)P=0.03a

CM 214: PFS i-p risk (30mo FUp)


P<0.009

CM 214: ORR, PFS, OS ITT


OutcomePatient (N = 1096*)

Nivo + Ipi(n = 550)

Sunitinib(n = 546)

Confirmed ORR,† % (95% CI)

39(35-43)

32(28-36)

P = .0191

PFS,‡ median mos(95% CI)

12.4(9.9-16.5)

12.3(9.8-15.2)

HR: 0.98 (99.1%: 0.79-1.23)P = .8498

OS, median mos(95% CI)

NR (NE-NE) 32.9 (NE-NE)

HR: 0.68 (99.8%: 0.49-0.95)P = .0001

*23% of patients in the nivo + ipi arm and 25% of patients in the sunitinib arm had tumor PD-L1 expression ≥ 1%. †IRRC assessed by RECIST v1.1. ‡IRRC assessed.

SunNivo + Ipi

0

0.2

0.4

0.6

0.8

1.0

Mos

Prob

abili

ty o

f OS

Median OS, Mos (95% CI)Nivo + ipi NR (NE-NE)Sun 32.9 (NE-NE)

3 6 129 15 18 21 24 27 30 330

HR: 0.68 (99.8% CI: 0.49-0.95;P = .0003)

Patients at Risk, n550546

523506

492471

464432

443402

426363

404334

339283

197173

7166

46

00

CM 214: ORR in risk subgroups(30mo FUp)


CM 214: OS ITT (30mo FUp)


CM 214: Favorable risk


Outcome N=249a

NIVO + IPIN=125

SUNN=124

OS,b median, months (95% CI)NR 32.9 (NE–NE)

HR (99.8% CI), 1.45 (0.51–4.12)P=0.27

OS, 12-month rate, % (95% CI) 94 (87–97) 96 (90–98)

OS, 18-month rate, % (95% CI) 88 (80–92) 93 (87–97)

Confirmed ORR,c % (95% CI)29 (21–38) 52 (43–61)

P<0.001

Confirmed CR, % 11 6

PFS,d median, months (95% CI)

15.3 (9.7–20.3) 25.1 (20.9–NE)

HR (99.1% CI), 2.18 (1.29–3.68)P<0.001

CM 214:Dako 28-8 PharmDx test


Subgroup1,2NIVO + IPI1,2

No. of PatientsSUN1,2

No. of PatientsORR Difference

(95% CI)P-value2

ORRBaseline PD-L1 expression

≥1%<1%

100284

114278

<0.00010.0252

Hazard Ratio(95% CI)

PFSBaseline PD-L1 expression

≥1%<1%

100284

114278

0.00030.9670

OSBaseline PD-L1 expression

≥1%<1%

100284

114278

<0.0010.0249

0 1 2

–50 0 50


Favors SUN Favors NIVO + IPI

CM 214:AE


FatiguePruritusDiarrheaRashNauseaIncreased lipase levelHypothyroidismDecreased appetiteAstheniaVomitingAnemiaDysgeusiaStomatitisDyspepsiaMucosal inflammationHypertensionPPE syndromeThrombocytopenia

36.9

N+I, %(N = 547)

S, %(N = 535)

28.226.5

21.619.9

16.515.5

13.713.2

10.86.25.7

4.22.72.42.20.90.4 17.8

49.39.2

52.012.5

37.810.8

25.024.9

17.020.6

15.533.5

27.917.9

28.440.4

43.2

60 40 20 0 20 40 60

CM 214:AE leading todiscontinuation


NIVO + IPI (N=547), %Any Grade Grade 1 Grade 2 Grade 3 Grade 4

Any treatment-related AE1 22 2 4 12 4Increased ALT 3 0 0 2 1Increased AST 2 <1 <1 1 <1Diarrhea 3 <1 1 2 0Hypophysitis 1 0 <1 1 <1Arthralgia 1 <1 <1 <1 0

SUN (N=535), %Any Grade Grade 1 Grade 2 Grade 3 Grade 4

Any treatment-related AE1 12 1 3 6 1Diarrhea 1 <1 0 <1 0Fatigue 1 <1 1 1 0Increased ALT 1 <1 0 1 0Increased AST 1 0 <1 <1 0Palmar-plantar erythrodysesthesia syndrome 1 <1 <1 0 0Skin ulcer 1 <1 <1 0 0Thrombocytopenia 1 <1 <1 <1 0

Treatment-related deaths occurred in 1% (n=8)c of patients in the NIVO + IPI arm and in 1% (n=4)d of patients in the SUN arm2

CM 214:time to onset of selectedAEs


Skin(n = 48)

Endocrine(n = 178)

GI(n = 154)

Hepatic(n = 101)

Renal(n = 48)

Pulmonary(n = 34)

300 60

Time to Onset from Treatment Initiation, Weeks90 11010 40 70 10020 50 80 120

CM 214: AEs over time (30mo FUp)


CM 214: Discont(d) due to AE

29Tannir MN et al. ASCO GU 2019, abstr 581

Event NIVO+IPI (N = 547)

Any grade, n (%)a Grade 3–4, n (%)Any event 136 (24.9) 96 (17.6)

Increased ALTb 15 (2.7) 15 (2.7)Diarrhea 15 (2.7) 10 (1.8)Increased ASTb 14 (2.6) 12 (2.2)Pneumonitis 12 (2.2) 6 (1.1)Colitis 8 (1.5) 8 (1.5)Hypophysitis 7 (1.3) 6 (1.1)Arthralgia 7 (1.3) 3 (0.5)Adrenal insufficiency 6 (1.1) 6 (1.1)

CM 214: Doses of discont(d) dueto AE


25

20

15

10

5

00 5 10 15 20 25 30 35

No. of NIVO doses received40 45 50

No.o

fpat

ient

s

CM 214: ORR according todiscontinuation due to AE


All patients who discontinueddue to treatment-relatedAEs ITT patientsNIVO+IPI SUN NIVO+IPI SUN

Outcome (N = 135)a (N = 64) (N = 550) (N = 546)ORR, %(95% CI)

46.7(38.0–55.4)

32.8(21.6–45.7)

41.3(37.1–45.5)

34.1(30.1–38.2)

P value Not calculated 0.0154BOR, n (%)

Complete responsePartial response Stable disease Progressive disease Unable to determine

Never treatedDeath prior to assessment Early d/c due to toxicity Other

16 (11.9)47 (34.8)39 (28.9)21 (15.6)12 (8.9)

–2 (1.5)8 (5.9)2 (1.5)

2 (3.1)19 (29.7)31 (48.4)

012 (18.8)

–4 (6.3)8 (12.5)

0

58 (10.5)169 (30.7)165 (30.0)121 (22.0)37 (6.7)3 (0.5)12 (2.2)8 (1.5)14 (2.5)

10 (1.8)176 (32.2)222 (40.7)86 (15.8)52 (9.5)11 (2.0)16 (2.9)8 (1.5)17 (3.1)

CM 214: OS according todiscontinuation due to AE


0 3 6 9 12 15 18 21 24

Months

NIVO+IPI NR (NE)SUN NR (18.2–NE) HR (95% CI), 0.70 (0.42–1.15)

27 30 33 36 39 42 45

1.0

0

0.3

0.5

0.7

0.9

0.2

0.1

0.4

0.6

0.8

A. All patients who discontinueddue to treatment-related AEsa

No. at risk

NIVO+IPI 135SUN 64

12958

12155

11950

11548

11443

10937

101 9835 35

9135

8532

7625

5018

1410

21

00

Median OS (95% CI), months

12-month OS probability (95% CI), %NIVO+IPI 87 (80–91)SUN 79 (67–87)

24-month OS probability (95% CI), %

NIVO+IPISUN

74 (66–81)61 (47–72)

30-month OS probability (95% CI), %

NIVO+IPISUN

69 (60–76)59 (46–70)

0 3 6 9 12 15 18 21 24

Months

NIVO+IPI NR (NE)SUN 37.9 (32.2–NE) HR (95% CI), 0.71 (0.59–0.86)

27 30 33 36 39 42 45

1.0

0

0.3

0.5

0.7

0.9

0.2

0.1

0.4

0.6

0.8

B. ITT patients

No. at risk

NIVO+IPI 550SUN 546

523 492507 472

464435

443404

425367

410345

389 371325 310

351295

327275

271232

161145

5855

45

00

Median OS (95% CI), months

12-month OS probability (95% CI), % NIVO+IPISUN

83 (80–86)78 (74–81)

24-month OS probability (95% CI), % NIVO+IPI 71 (67–74)SUN 61 (56–65)

30-month OS probability (95% CI), %NIVO+IPI 64 (60–68)SUN 56 (52–60)

Ove

rall

surv

ival

(pro

babi

lity)

Ove

rall

surv

ival

(pro

babi

lity)

CM 214:QOL (Kidney CancerSymptom index – i-p risk pts)


-10-9-8-7-6-5-4-3-2-10123456789

10

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

NIVO+IPI

SUNMea

n C

hang

eFr

om B

asel

ine

FKSI

-19

Sco

re (S

E)

33

Wor

seB

ette

r

Weeks425 347 281 239 212 180 166 152 143 139 125 108 76 44

422 371 284 221 184 147 127 113 104 93 80 64 43 26

No. of patients at riskNIVO + IPI

SUN

Mean change from baseline was significantly greater with NIVO + IPI than with SUN at each assessment

during the first 6 months (P<0.001)

CM 214:QOL – Treatment-freesurvival as a new outcome

34McDermott DF et al. ASCO GU 2019, abstr 564

6 12 18 24 30Months since randomization

Time-to-Event Endpoints

0

100

60

40

20

036

Patie

nts

(%)

80Death

Survival after initiationof subsequent therapy

TFS

Time on I-O protocol therapy

Overall survival:From randomization until death,or censored at date last know n alive

Time to subsequent therapyinitiation or death:From randomization until subsequent systemic anticancer therapy initiationor death, w hichever occurred f irst,or censored at date last know n aliveand free of subsequent therapy

Time to I-O protocol therapy cessation:From randomization until cessationof I-O protocol therapy (or censoredat date last know n alive on I-Oprotocol therapy)

CM 214:QOL – TFS in ITT


NIVO+IPI(N = 463)

SUN(N = 477)

Median (95% CI) TFS, months 3.0 (2.5–3.7) 1.3 (1.1–1.5)

TFS, months TFS rate (95% CI),%

NIVO+IPI SUN

18 23 (19–28) 7 (5–10)

24 21 (18–26) 7 (5–10)

1.00

0.75

0.50

0.25

Prop

ortio

nal

ive

and

free

ofsu

bseq

uent

syst

emic

ant

ican

cer

ther

apy

NIVO+IPI

SUN0.00

0 6 12 18 24 30 36Time since discontinuation of protocol therapy (months)

No. at riskNIVO+IPI SUN

463477

14856

11133

7519

5812

374

111


CM 214:QOL – TFS in favorablerisk pts NIVO+IPI

(N = 111)SUN

(N = 94)

Median (95% CI) TFS, months 6.3 (4.1–15.1) 1.1 (1.0–1.6)

TFS, months TFS rate (95% CI),%

NIVO+IPI SUN

18 32 (24–43) 13 (7–23)

24 29 (21–40) 13 (7–23)

0 6 12 18 24 30Time since discontinuation of protocol therapy (months)

36

1.00

0.50

NIVO+IPI0.25

SUN

0.00

0.75

Prop

ortio

nal

ive

and

free

ofsu

bseq

uent

syst

emic

ant

ican

cer

ther

apy

No. at riskNIVO+IPI 111 50 42 29 24 15 6SUN 94 14 10 6 4 2 1

37.

IO-anti-VEGF

Treatment-naive advanced or metastatic RCC with clear-cell and/or

sarcomatoid histology; KPS ≥ 70; tumor tissue available for PD-L1 staining

(N = 915)

Atezolizumab 1200 mg IV +Bevacizumab 15 mg/kg IV Q3W

Sunitinib 50 mg PO QD for 4 wks on, 2 wks off

IMmotion151[1]

JAVELIN Renal 101[2]

Treatment-naive advanced RCC with a clear-cell component;

ECOG PS 0 or 1; tumor tissue for PD-L1 staining

(N = 886)

Avelumab 10 mg/kg IV Q2W +Axitinib 5 mg PO BID in 6-wk cycles


Patients with treatment-naive advanced clear-cell RCC; KPS ≥ 70%;

tumor tissue for PD-L1 staining(N = 861)

Pembrolizumab 200 mg IV Q3W +Axitinib 5 mg PO BID


KEYNOTE-426[3]

1o EP: PFS in PD-L1+ pts; OS in ITT pts

1o EP: PFS and OS in PD-L1+ pts

1o EP: PFS and OS in ITT

38.

IO-anti-VEGF (Summary)

Control Comparator(s) PFS (HR) OS (HR)Sunitinib Nivolumab/ipilimumab[1] No* (0.85) Yes (0.68)Sunitinib Bevacizumab + atezolizumab[2] Yes (0.83) No (0.81)Sunitinib Axitinib + avelumab[3] Yes (0.69) No (0.78)Sunitinib Axitinib + pembrolizumab[4] Yes (0.69) Yes (0.53)

Sunitinib Lenvatinib + everolimus vs lenvatinib/pembro Pending Pending

Sunitinib Cabozantinib/nivolumab Pending Pending

1. Motzer. NEJM. 2018;378:1277. 2. Motzer. Genitourinary Cancers Symposium 2018. Abstr 578.3. Motzer. ESMO 2018. Abstract LBA6. 4. Powels. Genitourinary Cancers Symposium 2019. Abstr 543.

39.

IO-anti-VEGF (Response Rate)

1. Motzer. NEJM. 2018;378:1277 and Tannir NM et al ASCO GU 2019, abstr 547 2. Motzer. Genitourinary Cancers Symposium 2018. Abstr 578.3. Motzer. ESMO 2018. Abstract LBA6. 4. Powles T et al. ASCO GU 2019; Abstr 543. . 5. Rini BI et al N Engl J Med 2019; 380:1116

Regimen Study Efficacy Population IRC-Assessed CR Rate

CR Rate in Selected Patients PR Rate Remission

Rate


CheckMate 214[1]

ITT 10.5%* PD-L1 ≥ 1%: 16%Sarcomatoid: 18%

30.7% ?

Atezolizumab + bevacizumab

IMmotion151[2] ITT 5.0% PD-L1 ≥ 1%: 9% 31% ?

Avelumab + axitinib

JAVELIN Renal 101[3]

ITT 3.0% PD-L1+: 4% 48% ?

Pembrolizumab + axitinib

Phase I[4] All patients 5.8% -- 53.5% ?

Pembrolizumab monotherapy

KEYNOTE-427[5] Cohort A (ccRCC) 2.7% PD-L1 CPS ≥ 1: 6.5% 35.5% ?

TKIs < 5% ? 30% to 40%

~ 0

40.

IO-anti-VEGF (PFS/PD)

1. Motzer. NEJM. 2018;378:1277. 2. Motzer. Genitourinary Cancers Symposium 2018. Abstr 578. 3. Motzer. ESMO 2018. Abstract LBA6. 4. Powels. Genitourinary Cancers Symposium 2019. Abstr 543. 5. McDermott. ASCO 2018. Abstr 4500.

Regimen Study Median PFS, Mos Primary PD Rate, %

Nivolumab + ipilimumabCheckMate 214

(intermediate/poor risk)[1]

11.6 20

Atezolizumab + bevacizumab IMmotion151 (ITT)[2] 11.2 18

Axitinib + avelumab JAVELIN Renal 101 (ITT)[3] 13.8 12

Axitinib + pembrolizumab KEYNOTE-426 (ITT)[4] 15.1 10.9

Pembrolizumab monotherapy KEYNOTE-427[5] 8.7 28.2

TKIs 9-12 20

41.

IO-anti-VEGF (Toxicity)

Powles T et al. ASCO GU 2019; Abstr 543.

Treatment-Related AEs in ≥ 20% of Either Arm

42.

IO-anti-VEGF (Toxicity)

Motzer. ESMO 2018. Abstract LBA6.

Event, %Avelumab + Axitinib (n = 434) Sunitinib (n = 439)

All Grades Grade 3 / 4 All Grades Grade 3 / 4

TRAEs of any grade in ≥ 20% of pts or grade 3-4 in ≥ 3% of pts Diarrhea Hypertension Fatigue Hand-foot syndrome Dysphonia Nausea Hypothyroidism Stomatitis Decreased appetite Dysgeusia Increased alanine aminotransferase Thrombocytopenia Anemia Neutropenia

955448363327252422201313321

51 / 45 / 0

24 / 03 / 06 / 01 / 01 / 0

< 1 / 02 / 02 / 00 / 04 / 1

< 1 / 0< 1 / 0< 1 / 0

96453236343

341323263210181718

48 / 73 / 0

15 / 04 / 04 / 00 / 01 / 0

< 1 / 01 / 01 / 00 / 02 / 05 / 1

5 / < 17 / 1

TRAEs leading to discontinuation* 4 8

TRAEs leading to death† 1 < 1

IO-IO (Toxicity)


FatiguePruritusDiarrheaRashNauseaIncreased lipase levelHypothyroidismDecreased appetiteAstheniaVomitingAnemiaDysgeusiaStomatitisDyspepsiaMucosal inflammationHypertensionPPE syndromeThrombocytopenia

36.9

N+I, %(N = 547)

S, %(N = 535)

28.226.5

21.619.9

16.515.5

13.713.2

10.86.25.7

4.22.72.42.20.90.4 17.8

49.39.2

52.012.5

37.810.8

25.024.9

17.020.6

15.533.5

27.917.9

28.440.4

43.2

60 40 20 0 20 40 60

Conclusões (1)

Ipi-Nivo aprovado pelo FDA/ANVISA para IDMC intermediário-alto risco

Baseado em ganho de OS

Pem-Axi ainda sem aprovação pelo FDA/ANVISA

Ganho de OS

Ave-Axi ainda sem aprovação pelo FDA/ANVISA

Sem ganho de OS

Ipi-Nivo com benefício consistente em histologia sarcomatóide

44

Conclusões (2)

Ipi-Nivo com maior taxa de PD primária

Pem-Axi com maior taxa de resposta, mas Ipi-Nivo com maior taxa de resposta completa (cura?)

Dados de seguimento mais prolongado ainda necessário

Ipi-Nivo parece trazer menor toxicidade

Ipi-Nivo com maior taxa de descontinuação por EA

Porém EAs são manejáveis

Não parece haver detrimento da eficácia para os descontinuados

Ipi-Nivo é a única combinação com dados de qualidade de vida, e com dados robustos de sobrevivência livre de tratamento

45

Conclusões (3)

IO é diferente de TKI pela habilidade de induzir Sobrevida livre de tratamento

Combinações que melhoram SLP e SG sem melhorar a SLT talvez sacrifiquemo potencial de IO, aumenta a toxicidade e o custo

Estudos devem utilizer desfechos melhores para IO

Emerging end points in IO trials

Landmark OS

CR rate

Time to initiation of subsequent therapy

Treatment-free survival

Overall quality of life/overall value

46

Desejos e Necessidades1. Cured of disease, preferably with limited toxicity during/after therapy and

the ability to stop therapy

2. To live longer

3a. Disease control

3b. Quality of life maintained

3c. Free of therapy

3d. Reduced costs

47

Ipi-Nivo probably better (including favorable risk pts)

No answer to date

IO-anti-VEGF probably better (high tumor burden?)Ipi-Nivo only with QoL data

Ipi-Nivo only with data, Ipi-Nivo probably betterIpi-Nivo better

[email protected]

48

mailto:[email protected]

tratamento 1l do mrcc: io + io · 2019-04-24 · curso imuno-oncologia em tumores urológicos...

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