tratamento 1l do mrcc: io + io · 2019-04-24 · curso imuno-oncologia em tumores urológicos...
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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
11Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
12Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
13Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
Nivolumab + ipilimumab
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)
14Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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)
15Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
Favors NIVO + IPI Favors SUN
CM 214: OS by risk group (30mo FUp)
16Tannir NM et al ASCO GU 2019, abstr 547
CM 214: ORR I-P risk
17Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
18Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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)
19Tannir NM et al ASCO GU 2019, abstr 547
P<0.009
CM 214: ORR, PFS, OS ITT
20Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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)
21Tannir NM et al ASCO GU 2019, abstr 547
CM 214: OS ITT (30mo FUp)
22Tannir NM et al ASCO GU 2019, abstr 547
CM 214: Favorable risk
23Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
24Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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 NIVO + IPI Favors SUN
Favors SUN Favors NIVO + IPI
CM 214:AE
25Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
26Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
27Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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)
28Tannir NM et al ASCO GU 2019, abstr 547
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
30Tannir MN et al. ASCO GU 2019, abstr 581
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
31Tannir MN et al. ASCO GU 2019, abstr 581
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
32Tannir MN et al. ASCO GU 2019, abstr 581
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)
33Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
-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
35McDermott DF et al. ASCO GU 2019, abstr 564
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
36McDermott DF et al. ASCO GU 2019, abstr 564
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
Sunitinib 50 mg PO QD for 4 wks on, 2 wks off
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
Sunitinib 50 mg PO QD for 4 wks on, 2 wks off
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
Nivolumab + ipilimumab
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)
43Motzer RJ et al. N Engl J Med 2018. doi: 10.1056/NEJMoa1712126
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
49