esmo summit russia 2019 · esmo summit russia 2019 current standards and practice changing studies...
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ESMO SUMMIT RUSSIA 2019
Current standards and practice changing
studies in metastatic NSCLC without
actionable mutations
Fedor Moiseenko
Head of chemotherapy department
St. Petersburg City Cancer Center
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CONFLICT OF INTEREST DISCLOSURE
◆ Personal financial interests: honoraria and advisory role Astra Zeneca, Takeda,
Sanofi, Pfizer, Biocad, Novartis, MSD, Merck, Roche, BMS, Boehringer
Ingelheim, Lilly
◆ Institutional financial interests: Biocad, Novartis
◆ Non-financial interests: educational activities provided by Pfizer, Astra Zeneca,
MSD, BMS, Roche
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D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018
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Schiller JH, et al. N Engl J Med. 2002;346:92-98.
ECOG 1594: EQUALITY OF COMBINATIONS IN
UNSELECTED NSCLC
1.0
0.8
0.6
0.4
0.2
0
%
Months
0 5 10 15 20 25 30
Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel
mPFS: 3,1 – 4,2 monOS: 7,4 – 8,1 mon
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DURATION OF CHEMO IN NSCLC
Author Design N OS (mon) Р
Smith MVP x 3 155 6 0,2
MVP x 6 153 7
Socinski Pac/Carbo x 4 114 6,6 0,63
Pac/Carbo -> PD 116 8,5
Von Plessen Carbo/Vin x 4 150 2,3 0,75
Carbo/Vin x 6 147 2,6
Park Cisp-doublet 158 14,9 0,461
Cisp-doublet 156 15,9
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CDDP VS CARBO COMBINATIONS
de Castria TB et al. The Cochrane Library 2013.
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PEMETREXED COMBINATIONS BETTER IN
NSQCLC
Treat J., et al // Lung Cancer, 2012
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BEV + CT ↑OS & PFS
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2ND LINE: DOCETAXEL > BSC
Frances A. Shepherd et al // J Clin Oncol, 2000
7 mon vs 4,6 mon
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2ND LINE: PEMETREXED = DOCETAXEL
Nasser Hanna et al // J Clin Oncol, 2004
PFS: 2.9 vs 2.9 monHematologic toxicity
Docetaxel > pemetrexed
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2ND LINE +: ERLOTINIB > BSC
Shepherd, et al. // N Engl J Med, 2005
% s
urv
ivin
g
Erlotinib (n=246)
Adenocarcinoma
`Placebo (n=119)Placebo (n=78)
Erlotinib (n=144)
SqCLC
Months Months
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30 0 5 10 15 20 25
1.00
0.75
0.50
0.25
0
% s
urv
ivin
g
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D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018
ESMO CLINICAL PRACTICE GUIDELINES
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Martin Reck, et al. // N Engl J Med, 2016
1ST LINE IMMUNOTHERAPYKEYNOTE-024: pembro vs CT in PD-L1>50%
● NSCLC stage IV (Adeno + Sqaumous)
● Untreated
● EGFR, ALK wt
● ECOG 0−1
● TPS PD-L1 (>50%)
● No steroids
Pembrolizumab2 mg/kg
q3w(up to 35 cycles or PD)
4-6 cyclesPlatinum doublet:
TCPem + cis/carboGem + cis/carbo
● Primary
– PFS
● Secondary
– OS
– ORR
РАНДОМИЗАЦИЯ
b
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J.C. Soria presented at ESMO, 2016
1ST LINE IMMUNOTHERAPYSelection of patients with TPS PD-L1 >50%
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Martin Reck, et al. // N Engl J Med, 2016
1ST LINE IMMUNOTHERAPYKEYNOTE-024: pembro > CT in PD-L1>50%
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Brahmer JR, et al. // J Clin Oncol. 2017;35(suppl): Abstract 9000.Brahmer JR, et al. // J Clin Oncol. 2019
1ST LINE IMMUNOTHERAPYKEYNOTE-024: pembro > CT in PD-L1>50%
25 months of FU & 60% crossover in control arm
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Presented by G. Lopez at ASCO Annual Meeting 2018
1ST LINE IMMUNOTHERAPY
KEYNOTE-042: pembro > CT in PD-L1 ≥ 1%
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D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018
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1ST LINE CHEMO-IMMUNOTHERAPY
Phase 3 trials in non-sqNSCLC
Regimen N PFS ОS
Nonsquamous NSCLC
KEYNOTE 189 Plat/Pem + Pembro
Plat/Pem 6165.6 vs 4.9 m
HR 0.52
p<0.00001
nr vs 11.3 m
HR 0.49
p<0.00001
IMPower 150 ТС + Atezo
ТС + Bev + Atezo
ТС + Bev
800
8.3 vs 6.8 m
HR 0.59
p<0.0001
19.2 vs 14.7 m
HR 0.78
p=0.016
IMPower 132 Plat/Pem + Atezo
Plat/Pem 5787.6 vs 5.2 m
HR 0.60
p < 0.0001
18.1 vs 13.6 m
HR: 0.81
p = 0.0797
Плоскоклеточный НМРЛ
IMPower 131 Плат/Пакли + Атезо
Плат/набПакли + Атезо
Плат/набПакли
684
6.3 vs 5.6 m
HR 0.71
p=0.001
14.0 vs 13.9
HR 0.96
p=0.69
KEYNOTE 407 Плат/(наб)Пакли + Пембро
Плат/(наб)Пакли 5596.4 vs 4.8 m
HR 0.56
P<0.001
15.9 vs 11.3
HR 0.64
p=0.0008
Все гистологические формы
CheckMate 227 ХТ + Ниво 363 5.6 vs 4.7 m
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1ST LINE CHEMO-IMMUNOTHERAPY
KEYNOTE-198 design
Pembro 200 mg +
Pemetrexed 500 mg/m2 +
Carbo AUC 5 or
Cis 75 mg/m2
Q3W 4 cycles
Placebo +
Pemetrexed 500 mg/m2 +
Carbo AUC 5 or
Cis 75 mg/m2
Q3W 4 cycles
• Non-sqCLC
• untreated
• FFPE for biomarker
analysis
• EGFRwt & ALKwt
• ECOG 0 – 1
• No pneumonitis, no
steroids
Stratification
• PD-L1 expression
(TPSa <1% vs ≥1%)
• CDDP vs. carbo
• Smoking status
R (2:1)
N = 410
N = 206
Pembro 200 mg
Q3W up to 31 cycles
+
Pemetrexed
500 mg/m2 Q3W
Placebo
Q3W up to 31 cycles
+
Pemetrexed
500 mg/m2 Q3W
Pembro 200 mg
Q3W up to 35 cycles
PDb
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1ST LINE CHEMO-IMMUNOTHERAPY
KEYNOTE-189: pembro + CT ↑OS & ↑PFS2
S. Gadgeel et al. // ASCO Annual Meeting 2019 (#9013)
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1ST LINE CHEMO-IMMUNOTHERAPY
KEYNOTE-189: pembro + CT ↑OS
irrespectively to PD-L1 expression
Gandhi L, et al. AACR 2018, Abstract CT075.
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ИММУНОХИМИОТЕРАПИЯ 1-ая ЛИНИЯ НМРЛ
IMpower150
Leena Gandhi et al. // N Engl J Med (2018)
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1ST LINE CHEMO-IMMUNOTHERAPY
IMpower150: atezo + bev + TC ↑OS all PD-L1
Socinski M et al. ASCO Annual Meeting 2018, Abstract 9002; Socinski M et al. N Engl J Med. 2018 ;378(24):2288-2301
No. at Risk
Atezo+Bev+CP 121 107 105 100 93 87 79 63 52 39 32 23 11 6
Bev+CP 105 100 91 86 78 68 60 46 39 30 23 13 10 1 1
PD-L1-NegativeTC0 and IC0
PD-L1-LowTC1/2 or IC1/2
PD-L1-HighTC3 or IC3
100
Ove
rall
Surv
ival
, %
No. at Risk
Atezo+Bev+CP 167 157 145 135 125 115 103 82 61 50 29 17 8 4
Bev+CP 172 160 145 134 123 115 106 79 54 39 29 17 10 6 1 1 1
Time (months)
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 34
14.1 mo 17.1 mo
HRa, 0.82(95% CI: 0.62, 1.08)
HRa, 0.80(95% CI: 0.55, 1.15)
HRa, 0.70(95% CI: 0.43, 1.13)
100
Ove
rall
Surv
ival
(%
)
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32
16.4 mo 20.3 mo
34
100
Ove
rall
Surv
ival
, %
No. at Risk
Atezo+Bev+CP 71 64 64 61 56 54 53 43 34 30 23 17 15 6 2 2
Bev+CP 65 60 56 53 50 36 33 28 23 19 14 10 9 6 1
Time (months)
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 34
15.0 mo 25.2 mo
Atezo+Bev+CP
Bev+CP
Time (months)
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1ST LINE CHEMO-IMMUNOTHERAPY
IMpower150: atezo + bev + TC ↑OS in EGFR & ALK mut
Socinski, et al. ASCO 2018 (Abs 9002); Kowanetz, et al. AACR 2018 (Abs CT076)
OS benefit in EGFR/ALK+ patients was observed despite lower PD-L1 expression in these patients
NE17.5 mo
EGFR/ALK+
Bev + atezo + CP* vs Bev + CP
17.5 mo 21.2 mo
00
2 14 22 30
20
40
60
80
100
Time (months)
Ove
rall
surv
ival
(%
)
Bev + atezo + CP
Bev + CP
HR†=0.54(95% CI: 0.29–1.03)
0
0
2 14 20 26
20
40
60
80
100
Time (months)
Ove
rall
surv
ival
(%
)
Atezo + CP
Bev + CP
HR†=0.82(95% CI: 0.49–1.37)
EGFR/ALK+
Atezo + CP vs Bev + CP
4 6 8 10 12 16 18 20 24 26 28 4 6 8 10 12 16 18 22 24 28 30
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1ST LINE CHEMO-IMMUNOTHERAPY
IMpower150: atezo + bev + TC ↑OS in EGFR & ALK mut
Socinski, et al. ASCO 2018 (Abs 9002); Kowanetz, et al. AACR 2018 (Abs CT076)
13.2 mo9.1 mo
Liver metastases
Bev + atezo + CP vs Bev + CP
9.1 mo7.0 mo
OS benefit in patients with liver metastases was observed despite lower PD-L1 expression in these patients
00
2 14 22 30
20
40
60
80
100
Time (months)
Ove
rall
surv
ival
(%
)
Bev + atezo + CPBev + CP
HR*=0.54 (95% CI: 0.33–0.88)
0
0
2 14 20 26
20
40
60
80
100
Time (months)
Ove
rall
surv
ival
(%
)
Atezo + CPBev + CP
HR*=0.85(95% CI: 0.53–1.36)
Liver metastases
Atezo + CP vs Bev + CP
4 6 8 10 12 16 18 20 24 26 28 4 6 8 10 12 16 18 22 24 28 30
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1ST LINE CHEMO-IMMUNOTHERAPY
IMpower132: atezo + pem + carbo/cis
Socinski M et al. ASCO Annual Meeting 2018, Abstract 9002; Socinski M et al. N Engl J Med. 2018 ;378(24):2288-2301
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1ST LINE CHEMO-IMMUNOTHERAPY
IMpower132: atezo + pem + carbo/cis
↑ PFS
(Р < 0.0001)
Interim OS analysis
+ 4,5 mon (р = 0.0797)
V.A. Papadimitrakopoulou et al. // WLCC 2018
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D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018
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1ST LINE CHEMO-IMMUNOTHERAPY
Phase 3 trials in sqNSCLC
Regimen N PFS ОS
Плоскоклеточный НМРЛ
IMPower 131 Плат/Пакли + Атезо
Плат/набПакли + Атезо
Плат/набПакли
684
6.3 vs 5.6 m
HR 0.71
p=0.001
14.0 vs 13.9
HR 0.96
p=0.69
KEYNOTE 407 Плат/(наб)Пакли + Пембро
Плат/(наб)Пакли 5596.4 vs 4.8 m
HR 0.56
P<0.001
15.9 vs 11.3
HR 0.64
p=0.0008
Все гистологические формы
CheckMate 227 ХТ + Ниво
ХТ
363
(PD-L1 <1%)
5.6 vs 4.7 m
HR 0.74
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1ST LINE CHEMO-IMMUNOTHERAPY
KEYNOTE-407: pembro + CT ↑OS & ↑PFS2
Paz-Arez et al. // ASCO Annual Meeting (2018)
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1ST LINE CHEMO-IMMUNOTHERAPY
KEYNOTE-407: pembro + CT ↑OS & ↑PFS2
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1ST LINE IO-IO
CheckMate 227: Nivo + Ipi vs CT
M.D. Hellman at al., Presented at AACR 2018, abstr. CT077
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D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018
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2ND LINE IMMUNOTHERAPY
CHECKMATE 017/057
18%
SD
CR/PR
PD
62%
38%
26%
35%
7%22%12%
8%
Months from 6-month landmark analysis
SD
CR/PR
PD
58%
81
%
63
%61%
35%
24%
40%
13%8%
70 5765 52 44 42 3739 24 7 0 0
66 3853 29 23 18 1315 10 2 0 0
144 5587 32 17 10 510 3 0 0 0
CR/PR
(n = 34)
SD
(n = 102)
PD
(n = 128)
Median OS
(95% CI), mo
17.1
(11.1, 28.7)
8.0
(6.6, 10.4)
4.8
(3.4, 5.9)
HR vs PD (95% CI)0.43
(0.29, 0.65)
0.80
(0.61, 1.04)–
CR/PR
(n = 70)
SD
(n = 66)
PD
(n = 144)
Median OS
(95% CI), mo
NR
(25.6, NR)
16.1
(10.2, 23.5)
9.1
(6.2, 11.4)
HR vs PD (95% CI)0.18
(0.12, 0.27)
0.52
(0.37, 0.71)–
Nivolumab Docetaxel
Months from 6-month landmark analysis
34 2130 15 13 10 79 4 0 0 0
102 3563 24 17 11 47 2 0 0 0
128 2852 18 15 13 810 5 1 0 0
OS
(%
)
100
0
40
60
80
20
0 126 18 24 30 4236 48 54 60 66
OS
(%
)
0
40
60
80
20
0 1
2
6 18 24 30 4
2
36 48 54 60 66
No. at risk
CR/PR
SD
PD
No. at risk
CR/PR
SD
PD
100
58%
19%
4%
12%2%5%
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1ST LINE
TMB and PD-L1
E.Castellanos et al., Presented at ASCO 2019, abstr. CT077
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1ST LINE
David F. Heigener et al. // Clin Can Res 2019
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David F. Heigener et al. // Clin Can Res 2019
Пембролизумаб(2Л PD-L1+)
Пембролизумаб(1Л PD-L1≥50%)
Ниволумаб(2Л)
Атезолизумаб(2Л)
Пембролизумаб+ Плат/Пем 1Л
Атезолизумаб + Бевацизумаб + ТС 1Л
При неплоскоклеточном НМРЛ
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COST!!!
Прибавка к текущим расходам на противоопухолевые препараты:
1st line (PD-L1 ≥50%) - + 20%2nd line w|o selection - + 31,1%2nd line (PD-L1 ≥1%) - + 13,4%
Aguiar P. et al. Immunotherapy, 2018