esmo summit russia 2019 · esmo summit russia 2019 current standards and practice changing studies...

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

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

D. Planchard et al. // Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018

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

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

CDDP VS CARBO COMBINATIONS

de Castria TB et al. The Cochrane Library 2013.

PEMETREXED COMBINATIONS BETTER IN

NSQCLC

Treat J., et al // Lung Cancer, 2012

BEV + CT ↑OS & PFS

2ND LINE: DOCETAXEL > BSC

Frances A. Shepherd et al // J Clin Oncol, 2000

7 mon vs 4,6 mon

2ND LINE: PEMETREXED = DOCETAXEL

Nasser Hanna et al // J Clin Oncol, 2004

PFS: 2.9 vs 2.9 monHematologic toxicity

Docetaxel > pemetrexed

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


ESMO CLINICAL PRACTICE GUIDELINES

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

J.C. Soria presented at ESMO, 2016

1ST LINE IMMUNOTHERAPYSelection of patients with TPS PD-L1 >50%

Martin Reck, et al. // N Engl J Med, 2016

1ST LINE IMMUNOTHERAPYKEYNOTE-024: pembro > CT in PD-L1>50%

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

Presented by G. Lopez at ASCO Annual Meeting 2018

1ST LINE IMMUNOTHERAPY

KEYNOTE-042: pembro > CT in PD-L1 ≥ 1%

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


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


KEYNOTE-189: pembro + CT ↑OS & ↑PFS2

S. Gadgeel et al. // ASCO Annual Meeting 2019 (#9013)


KEYNOTE-189: pembro + CT ↑OS

irrespectively to PD-L1 expression

Gandhi L, et al. AACR 2018, Abstract CT075.

ИММУНОХИМИОТЕРАПИЯ 1-ая ЛИНИЯ НМРЛ

IMpower150

Leena Gandhi et al. // N Engl J Med (2018)


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)


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


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


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


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


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



Paz-Arez et al. // ASCO Annual Meeting (2018)

1ST LINE IO-IO

CheckMate 227: Nivo + Ipi vs CT

M.D. Hellman at al., Presented at AACR 2018, abstr. CT077

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%

1ST LINE

TMB and PD-L1

E.Castellanos et al., Presented at ASCO 2019, abstr. CT077

1ST LINE

David F. Heigener et al. // Clin Can Res 2019

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

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

esmo summit russia 2019 · esmo summit russia 2019 current standards and practice changing studies...

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