Inmunoterapia en 1ª y 2ª línea del cáncer de pulmón

J.M. Sánchez TorresH.U. Princesa

Madrid

SEOM guidelines: Treatment algorithm

RR: 44.8% vs 27.8%, P= 0.001

DoR: NR vs. 6.3 m.

TTR: 2.2 m vs. 2.2 m

mOS: 30 mo. vs 14.2 mo., HR 0.63

OS at 12 months: 70.3% vs 54.8%

OS at 24 months: 51.5% vs 34.5%

Reck M, et al. NEJM 2016

Reck M, et al. J Clin Oncol 2019

PFS: 10.3 vs 6.0 mo.

Primary endpoint

Keynote 024: Pembrolizumab vs CT as first-line treatment for NSCLC with a PD-L1 TPS ≥50%

OS: 30.0 vs 14.2 mo.

Effective crossover 65%

Carbone DP, et al. N Engl J Med. 2017

CheckMate 026: Nivolumab vs CT as 1st-L for NSCLC

NivolumabChemotherapy

47 30 26 21 16 12 4 160 42 22 15 9 7 4 1

111 54 30 15 9 7 2 1 194 65 37 23 15 12 5 0 0

Nivolumabn = 47 n = 60

9.7(5.1, NR)

5.8(4.2, 8.5)

Chemotherapy

Median PFS, months(95% CI)

High TMB

PF

S (

%)

3 6 9 12 15 18 21

No. at RiskMonths

100

90

80

70

60

50

40

30

20

10

0

0

Nivolumab

Chemotherapy

0 3 6 9 12

Months

15 18 21 24

Nivolumab

Chemotherapy

100

90

80

70

60

50

40

30

20

10

0

n = 111 n = 94

4.1(2.8, 5.4)

6.9(5.5, 8.6)

HR = 1.82 (95% CI: 1.30, 2.55)

Nivolumab Chemotherapy

(95% CI)Median PFS, months

Low/medium TMB

HR = 0.62 (95% CI: 0.38, 1.00)

CheckMate 026: Nivolumab vs CT as 1st-L: PFS by TMB

Carbone DP, et al. N Engl J Med. 2017

CheckMate 227: Ph III of Ipilimumab plus Nivolumab vs Chemotherapy as 1st-L for NSCLC with high TMB (≥10 mut/Mb)

mPFS: 7.2 mo. vs 5.5 mo., HR 0.58

1-year PFS: 43% vs 13%

Response Rate: 45.3% vs 26.9%Ongoing response after 1 year: 68% vs 25%

Hellmann MD, et al. NEJM 2018

Primary endpoint:PFS in TMB ≥10 mut/Mb)

CheckMate 227: Ph III of Ipilimumab plus Nivolumab vs Chemotherapy as 1st-L for NSCLC with high TMB

Hellmann MD, et al. NEJM 2018

Keynote-189: Ph III Pembrolizumab or placebo plus pemetrexed-platinum as 1st-L for non-Sq NSCLC: OS

Ghandi L, et al. N Engl J Med 2018

mOS: NR vs 11.3 mo., HR 0.49,P<0.001

1-y OS: 69.2% vs 49.4%

RR: 47.6% vs 18.9%, P<0.0001

DoR: 11.2 mo. vs 7.8 mo.

Primary endpoints: PFS and OS

Subgroup analysis of PFS

mPFS: 8.8 mo. vs 4.9 mo., HR 0.52, P<0.001

1-year PFS: 34.1% vs 17.3%

Ongoing: 33.8% vs 17.8%

Effective crossover: 41.3% of ITT

(50% excluding pts still on therapy)

Keynote-189: Ph III Pembrolizumab or placebo plus pemetrexed-platinum as 1st-L for non-Sq NSCLC: PFS

Ghandi L, et al. N Engl J Med 2018

PFS: 8.8 mo. vs 4.9 mo

34.1%

17.3%

Primary endpoints: PFS and OS

IMpower150: Ph III Atezolizumab plus Bevacizumab plus PTX-carbovs Bevacizumab plus PTX-carbo as 1st-L for non-Sq NSCLC: PFS

Socinski MA, et al. N Engl J Med 2018

Landmark PFS, %

Arm B:

atezo + bev + CP

Arm C:

bev + CP

6-month 66% 56%

12-month 38% 20%

18-month 27% 8%

HR, 0.62 (95% CI: 0.52, 0.74)

P < 0.0001b

Median follow-up: ~20 mo

Median, 8.3 mo(95% CI: 7.7, 9.8)

Median, 6.8 mo(95% CI: 6.0, 7.1)

Primary endpoint: PFS

PFS in the ITT-WT

IMpower150: Ph III Atezolizumab plus Bevacizumab plus PTX-carbovs Bevacizumab plus PTX-carbo as 1st-L for non-Sq NSCLC: OS

Socinski MA, et al. N Engl J Med 2018

Landmark OS, %

Arm B:

atezo + bev + CP

Arm C:

bev + CP

12-month 67% 61%

18-month 53% 41%

24-month 43% 34%

HR, 0.78 (95% CI: 0.64, 0.96)

P = 0.0164Median follow-up: ~20 mo

Median, 14.7 mo(95% CI: 13.3, 16.9)

Median, 19.2 mo(95% CI: 17.0, 23.8)

OS in the ITT-WT

IMpower132: Ph III Atezolizumab plus Pemetrexed-platinum vs Pemetrexed-platinum as 1st-L for non-Sq NSCLC: PFS, RR and DoR

Papadimitrakopoulou, VA, et al. WCLC 2018

5.2 mo(95% CI: 4.3, 5.6)

7.6 mo(95% CI: 6.6, 8.5)

HR 0.60 (95% CI: 0.49, 0.72)

P < 0.0001Minimum follow-up, 11.7 mo

Median follow-up, 14.8 mo

APP PP

ORR, % 47% 32%

CR 2% 1%

PR 45% 32%

Median DOR, mo 10.1 7.2

Ongoing response,

%42% 30%

APP PP

6-mo PFS 59.1% 40.9%

12-mo PFS 33.7% 17.0%

APP, atezolizumab + carboplatin/cisplatin + pemetrexed; CR, complete response; DOR, duration of response; HR, hazard ratio; IRF, independent review facility; ORR, objective response rate; PP, carboplatin/cisplatin + pemetrexed; PR, partial response. IRF-assessed median PFS was 7.2 mo with APP and 6.6 mo with PP (stratified HR: 0.758 [95% CI: 0.623, 0.923] P = 0.055)Data cutoff: May 22, 2018.

PD-L1 high PD-L1 low PD-L1 negative

mPFS (mo.) 10.8 vs 6.5 6.2 vs 5.7 8.5 vs 4.9

1-y PFS 46% vs 25% 27% vs 20% 35% vs 8%

HR 0.46 (0.22-0.96) 0.80 (0.56-1.16) 0.45 (0.31-0.64)

Interim OS analysis:18.1 mo. vs 13.6 mo.

HR 0.81 (0.64-1.03)

Primary endpoints: PFS and OS

Keynote-407: Ph III Carboplatin-PTX/nab-PTX with orwithout pembrolizumab for metastatic Sq NSCLC: PFS

Paz-Ares L, et al. N Engl J Med 2018

mPFS: 6.4 mo. vs 4.8 mo., HR 0.56, P<0.001

RR: 57.9% vs 38.4%

DoR: 7.7 mo. vs 4.8mo.

mPFS acording to PD-L1 expression:

- <1%: 6.3 mo. vs 5.3 mo., HR 0.68

- 1-49: 7.2 mo. vs 5.2 mo., HR 0.56

- ≥50%: 8.0 mo. vs 4.2 mo., HR 0.37

Primary endpoints: PFS and OS

Keynote-407: Ph III Carboplatin-PTX/nab-PTX with orwithout pembrolizumab for metastatic Sq NSCLC: OS

Paz-Ares L, et al. N Engl J Med 2018

mOS: 15.9 mo. vs 11.3 mo., HR 0.64, P<0.001

1-year OS: 65.2% vs 48.3%

Ongoing: 43.5% vs 25.7%

Effective crossover: 42.8%

1-year OS according to PD-L1 expression:

- <1%: 64.2% vs 43.3%, HR 0.61 (0.38-0.98)

- 1-49: 65.9% vs 50.0%, HR 0.57 (0.36-0.90)

- ≥50%: 63.4% vs 51.0%, HR 0.64 (0.37-1.10)

Primary endpoints: PFS and OS

IMpower131: Ph III Atezolizumab plus Carboplatin-PTX/nab-PTX vs Carboplatin-nab-PTX as 1st-L for Sq NSCLC

Minimum follow-up, 9.8 mo

Median follow-up, 17.1 mo

Time (months)

12.0%

24.7%

12-month PFS

Arm B:

Atezo + CnP

Arm C:

CnP

Median PFS

(95% CI), mo

6.3

(5.7, 7.1)

5.6

(5.5, 5.7)

HRa (95% CI)

P value

0.71 (0.60, 0.85)

0.0001

ITT PD-L1 +(TC1/2/3 or

IC1/2/3)

PD-L1 high(TC3 or IC3)

PD-L1 low(TC1/2 or IC1/2)

PD-L1-(TC0 and IC0)

mPFS (mo.) 6.3 vs 5.6 7.0 vs 5.6 10.1 vs 5.5 6.0 vs 5.6 5.7 vs 5.6

1-year PFS 24.7% vs 12% 48% vs 20% 20% vs 9% 20% vs 12%

HR 0.71 (0.60-0.85)

0.61 (0.48-0.77)

0.44 (0.27-0.71)

0.70 (0.53-0.92)

0.81 (0.64-1.03)

Jotte R, et al. ASCO 2018

Primary endpoints: PFS and OS

1.Brahmer, et al. N Engl J Med 2015; 2.Borghaei, et al. N Engl J Med 2015; 3.Herbst, et al. Lancet 2015; 4.Barlesi, et al. ESMO 2016

Inmunoterapia en tratamiento de 2ª línea

CheckMate 017 & 057: Nivolumab as 2nd-L treatment: Long-term survivors: Survival at 4 years

Brahmer J, et al. AACR 2019

Nivolumab Docetaxel

mOS (mo.) 11.1 (9.2-13.1) 8.1 (7.2-9.2)

4-y survival 14% 5%

PD-L1 <1% Nivolumab Docetaxel

mOS (mo.) 9.7 (7.6-13.3) 7.8 (6.7-10.5)

4-y survival 9% 4%

PD-L1 >1% Nivolumab Docetaxel

mOS (mo.) 13.4 (16.0-17.7) 8.5 (7.0-9.3)

4-y survival 20% 4%

Keynote-010: Pembrolizumab as 2nd-L treatment: Long-term survivors

Herbst RS, et al. ESMO 2018

mOS: 16.9 mo. vs 8.2 mo.

HR: 0.53

3-year OS: DoR: 35% vs 13%

mOS: 11.8 mo. vs 8.4 mo.

HR: 0.69

3-year OS: DoR: 23% vs 11%

OAK: Atezolizumab as 2nd-L treatment: Long-term survivors

ITT Non-Sq Sq PD-L1+ PD-L1 high PD-L1-

2-year OS 31% vs 21% 35% vs 24% 20% vs 12% 32% vs 24% 43% vs 17% 30 vs 18%

Satouchi M, et al. WCLC 2017

IMpower133: Atezolizumab or placebo plus carboplatin-etoposide as 1st-L for ES SCLC

Horn L, et al. NEJM 2018

mOS: 12.3 mo. vs 10.3 mo., HR 0.701-y OS: 51.7% vs 38.2%

mPFS: 5.2 mo. vs 4.3 mo., HR 0.771-y PFS: 12.6% vs 5.4%

Conclusiones• Inmunoterapia: Revolución y realidad en el tratamiento del cáncer

de pulmón

• Elevada eficacia, potencial beneficio prolongado, mejoría en QoL y síntomas, y favorable perfil de seguridad: Tto estándar en 2ª línea

• Uso de biomarcadores, combinación con QT o con otras inmunoterapias: Superior eficacia frente a QT en 1ª línea

• Cuestión clave: Selección de pacientes y optimización de la terapia:– Características de los pacientes

– Histología

– Biomarcadores: PD-L1, TMB

– Estrategia y secuencia de tratamientos: Manejo individual

– Optima evaluación de la eficacia

– Retratamiento con inmunoterapia? Cuando? Todos?

– Duración de tratamiento