Presentación de PowerPoint · Treatment-naïve NSCLC Non-squamous Squamous No Targetable Alterations PD-L1

INMUNOTERAPIA EN CANCER DE PULMON Tratamiento de Primera Línea

Noemí Reguart, MD, PhDH. Clínic de Barcelona

Desafio Oncologico: mas alla del genoma

X Desafío Oncológico (Valencia, 03 y 04 diciembre)

Disclosure Information

❑ Consultant or Advisory Role: Merck Sharp and Dohme, Roche, Boehringer Ingelheim, Pfizer, Takeda, Novartis, Astra-Zeneca, Lilly

❑ Research Funding: Pfizer, Novartis

❑ Speaking: Merck Sharp and Dohme, Roche, Boehringer Ingelheim, Pfizer, Takeda, Novartis, Astra-Zeneca

❑ Other: Institutional financial interests: those related to clinical trials and patient recruitment

FIGURE 2. Stage IV NSCLC (no targetable alterations)

PS 0-1 PS 2 PS 3-4

1st

line

PD-L1< 50%PD-L1≥ 50%

SCC and non-SCC

Pembrolizumab (I,A)(*)

CT, chemotherapy; SCC, squamous; BSC, best supportive care(*) combination of immunotherapy + CT may be considered#

# Not EMA approved

non-SCC

Platinum+Pemetrexed (II,A)Taxol+CBDCA+Bevacizumab (I,A)Paclitaxel+CBDCA+Bev+Atezolizumab# (I,A)Platinum+Pemetrexed+Pembrolizumab (I,A)Platinum+Pemetrexed+Atezolizumab# (I,B)

Platinum based-CT (I,A)Platinum+Taxane+Pembrolizumab# (I,A)Platinum+Taxane+Atezolizumab# (I,B)

SCCSingle agent CT (I,B)Carboplatin-based

CT (II,A)

BSC (II,B)

SEOM: Current linical Practice Guidelines

Magem M, CTO 2018

Chemo/I-O Chemo/I-O I-O

IO (alone/combination) is a new standard of care in 1L

Martínez et al. Clin Cancer Res January 14 2019

Nonsquamous, Ch alone vs Ch-IO

Squamous, Ch alone vs Ch-IO

Sq and nonsq, Ch alone vs IO alone

First Line IO, IO-IO, NO chemo

1. KN-024, Reck M WCLC 2019, NEJM 2016; 2. IMpower110 Spigel D et al. Oral presentation at ESMO 2019; 3. KN 042, Mok ELCC 2019, Lancet 2019; 4. CM 227,

Peters, ESMO 2019, NEJM 2019

CM-2274

KN-042 (≥1%)

KN-024 (≥50%) IMpower 110 (TC3 & IC3)

Median follow-up 29 months

Median follow-up 43 months

Median follow-up 12.8 months

First Line IO plus Chemo: by histology, PD-L1 all comer

1. KN-189: Gadgeel S.M, ASCO 2019. Gandhi NEJM 2018 ; 2. IMPower 150 Socinski. MA. ASCO 2018, NEJM 2018; 3. KN-407 Paz Ares ESMO 2019, NEJM 2018;

4. IMpower 132 Papadimitrakopoulou V.A., WCLC 2018; 5. IMpower 130, Capuzzo ESMO 2018, West H. Lancet 2019; 6. IMpower 131 Jotte R, WCLC 2019

IMpower 131* (arm B, C)

KN-407

Non-Sq NSCLC Sq NSCLC

platinum (cis/carbo)-pemetrex CBCDA-taxol-beva

platinum (cis/carbo)-pemetrex CBCDA-nabpac CBCDA-nabpac

CBCDA-taxol/nabpac

The ‘quatriplets’ come into play: I-O plus I-O plus Chemo

Press Release 28 Oct 2019

Press Release 22 Oct 2019

PD-L1 expression enriches for IO responses

Hellmann, Lancet Oncol 2017

TPS < 1% TPS 1-49% TPS ≥50%

IHC Images from Teixidó C, Reguart N

CM 057 KN-010 CM 012

H. Borghaei, NEJM 2015 Roy S Herbst , Lancet 2016

OS by PD-L1 status difficult to interpret across trials

TC or TC & IC?

Defining subgroups based on Predictive BiomarkersDriver oncogenes and PD-L1 TPS expression

Camidge R, Nat Rev Clin Oncol 2019

Categorical versus continuous variables No PD-L1 level either guarantees or excludesI-O benefit!!

70%PD-L1

positive

30%PD-L1

negative 3% responders PD-L1 negative

17% responders PD-L1 positive

Treatment-naïve NSCLC

SquamousNon-squamous

No Targetable

Alterations

PD-L1 <1% PD-L1 ≥50%PD-L1 1%–49% PD-L1 <1% PD-L1 ≥50%PD-L1 1%–49%

KEYNOTE-4077

KEYNOTE-0423

IMpower1102 IMpower1102

IMpower 150*/1304/1325

*In patients with EGFR-mutant or ALK-positive NSCLC, atezolizumab, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated in the EU after failure of appropriatetargeted therapies.1 1. Reck et al. WCLC 2019. 2. Spigel D et al. ESMO 2019. 3. Mok et al. ELCC 2019. 4. Roche [press release]. September 6, 2019. 5. Barlesi F et al. Oralpresentation at ESMO 2018. LBA54. 6 Gadgeel S et al. Oral presentation at ASCO 2019. 7 Paz-Ares L et al. Oral presentation at ASCO 2018. 8 BMS [press release]. October 22, 2019.9. Peters S et al. ESMO 2019; 10 Cappuzzo F et al. WCLC 2019, Socinsky et al ESMO 2019

CheckMate 2279 CheckMate 2279

KEYNOTE-0241

KEYNOTE-1896

KEYNOTE-0241

KEYNOTE-0423

First Line Phase III I-O trials design based on PD-L1 TPS

IMpower13110

I-O

Mono

I-O I-O

I-O

Chemo

First-Line Therapy in PD-L1≥50%

Pembrolizumab monotherapy

undisputed first choice?

1



No Targetable

Alterations


KEYNOTE-4077

KEYNOTE-0423


IMpower 150*/1304/1325

*In patients with EGFR-mutant or ALK-positive NSCLC, atezolizumab, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated in the EU after failure of appropriatetargeted therapies.1 1. Reck et al. WCLC 2019. 2. Spigel D et al. ESMO 2019. 3. Mok et al. ELCC 2019. 4. Roche [press release]. September 6, 2019. 5. Barlesi F et al. Oralpresentation at ESMO 2018. LBA54. 6 Gadgeel S et al. Oral presentation at ASCO 2019. 7 Paz-Ares L et al. Oral presentation at ASCO 2018. 8 BMS [press release]. October 22,2019. 9. Peters S et al. ESMO 2019; 10 Cappuzzo F et al. WCLC 2019, Socinsky et al ESMO 2019


KEYNOTE-0241

KEYNOTE-1896

KEYNOTE-0241

KEYNOTE-0423


IMpower13110

I-O

Mono

I-O I-O

I-O

Chemo

I-O monotherapy in PD-L1≥50%

KEYNOTE-024

OS in PD-L1≥50%,WT NSQ-SQ1

KEYNOTE-042

OS in PD-L1≥50%, WT NSQ-SQ2

1- Reck et al. WCLC 2019; OA 14.012. Mok TSK et al. Oral presentation at ELCC 2019. 102O.

3. Spigel D et al. Oral presentation at ESMO 2019. LBA78. .

IMpower110

OS in TC3/IC3, WT NSQ-SQ3

20

Overall Survival

26.3 mo14.2 mo 20.0 mo12.2 mo 20.2 mo13.1 mo

Outcomes to 1st L pembrolizumab in patients with very high PD-L1 expression

Aguilar, Annals of Oncology 2019

n= 187

Edward B. Garon; ASCO 2019 (suppl; abstr LBA9015)

TPS ≥ 50% mOS 35.4 mo

5y 29.6%

Among Patients Who Received

≥2y of Pembrolizumab (11%)

5y OS 78.6%

Long Term Outcomes (5y)

Treatment Naive Patients

PD-L1 ≥50% and 1%–49%

I-O MONOTHERAPY IN PD-L1≥50%

Reck M, WCLC 2019

38/154 (24%) completed 35 cycles

ORR 82%

DoR ≥24 mo 25/38 (81%)

Long-Term responders and durable benefit with

pembrolizumab

1. Kurata T et al. JSMO Annual Meeting 2019. Kyoto, Japan. 2. Paz-Ares L et al. Oral presentation at ASCO 2018. 105.

3. Socinski MA et al. Oral presentation at ASCO 2018. 90024. Jotte, Oral presentation at WCLC 2019

.

I-O plus Chemo in PD-L1≥50%

23.6%

14.1%

67%

52%

23.4 mo10.2 mo22.0 mo10.7 mo

PFS2 after first line with Pembro mono or chemo-combo in PD-L1≥50%

KEYNOTE-189:

PFS2 in TPS≥ 50%platinum (cis/carbo)-pemetrexed (x4) +/- pembro

Gadgeel S et al. Oral presentation at ASCO 2019

KEYNOTE-024:

PFS2 in TPS≥ 50%platinum (cis/carbo)-pemetrexed (x4) +/- pembro

Brahmer JR, ASCO 2017

crossover64%

crossover50%

CheckMate 227 Part 1 Study Designa

N = 1189

PD-L1expression

< 1%

N = 550

NIVO + (low-dose) IPIb

n = 396

Chemoc

n = 397

NIVOd

n = 396

NIVO + (low-dose) IPIb

n = 187

Chemoc

n = 186

NIVOe + chemoc

n = 177

R1:1:1Key Eligibility Criteria

• Stage IV or recurrent NSCLC• No prior systemic therapy• No sensitizing EGFR mutations or

known ALK alterations• No untreated CNS metastases • ECOG PS 0–1

Stratified by SQ vs NSQR

1:1:1

Database lock: July 2, 2019; minimum follow-up for primary endpoint: 29.3 monthsaNCT02477826; bNIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W); cNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤ 4 cycles, with optional pemetrexed maintenance following chemo or NIVO + pemetrexedmaintenance following NIVO + chemo; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤ 4 cycles; dNIVO (240 mg Q2W); eNIVO (360 mg Q3W); fTMB primary endpoint analysis conducted at January 24, 2018 database lock in subset of patients randomized to NIVO + IPI or chemo; alpha allocated was 0.025; gAlpha allocated was 0.025 overall (0.023 for final analysis)

PD-L1expression

≥ 1%

Part 1b

Part 1a

Treatment until disease progression, unacceptable toxicity, or for 2 years

for immunotherapy

Secondary endpoints (PD-L1 hierarchy):• PFS: NIVO + chemo vs chemo in PD-L1 < 1%

• OS: NIVO + chemo vs chemo in PD-L1 < 1%

• OS: NIVO vs chemo in PD-L1 ≥ 50%

Independent co-primary endpoints: NIVO + IPI vs chemo

• PFS in high TMB (≥10 mut/Mb) populationf

• OS in PD-L1 ≥ 1% populationg

I-O + I-O in PD-L1≥50%

CM227 Peters et al. ESMO 2019

Efficacy With NIVO + IPI and NIVO vs Chemo in Patients With Tumor PD-L1 Expression ≥ 50%

22

NIVO + IPI

Chemo

NIVO

Part 1a

PFS by BICR ORR by BICR OS

Dosages were NIVO (3 mg/kg Q2W) plus IPI (1 mg/kg Q6W), and NIVO (360 mg Q3W) plus chemo.

0

10

20

30

40

50

NIVO + IPI NIVO Chemo

OR

R (

%)

n / N:

44.4

36.98.8

35.6

2.1

33.3

4.7

32.2

35.4

PR

CR

6 12 18 24 30 36 423 9 15 21 27 33 39

OS

(%

)

00 45

100

80

60

40

20

Months

54%

67%

61%P

FS

(%

)

00 39

100

80

60

40

20

Months

6 12 18 24 30 363 9 15 21 27 33

15%

41%34%

NIVO + IPI

NIVO + IPI

NIVO

NIVO

Chemo

Chemo

NIVO + IPI(n = 205)

NIVO(n = 214)

Chemo(n = 192)

Median OS, mo95% CI

21.2 15.5–38.2

18.114.4–22.1

14.0 10.0–18.6

HR (vs chemo)95% CI

0.700.55–0.90

0.790.63–1.01

NIVO + IPI(n = 205)

NIVO(n = 214)

Chemo(n = 192)

Median PFS, mo95% CI

6.74.5–11.0

5.64.2–8.3

5.6 4.6–6.6

HR (vs chemo)95% CI

0.620.49–0.79

0.750.59–0.95

36%

48%

42 %

5%

31%20%

NIVO + IPI NIVO Chemo

79 / 214 68 / 19291 / 205

• Median DOR with NIVO + IPI, NIVO and chemo was 31.8, 17.5 and 5.8 months, respectively


CheckMate 227 Part 1: NIVO + IPI in 1L NSCLC

Most Frequent TRAEs (≥ 15%) With NIVO + IPI and NIVO + Chemo in Patients With Tumor PD-L1 Expression < 1%a

Dosages were NIVO (3 mg/kg Q2W) plus IPI (1 mg/kg Q6W), and NIVO (360 mg Q3W) plus chemo.aIncludes events reported between first dose and 30 days after last dose of study drug.

Vomiting

Neutropenia

Decreased appetite

Rash

Decreased neutrophil count

50%50%Patients (%)

NIVO + IPI (n = 185) NIVO + chemo (n = 172)

40% 30% 20% 10% 0 10% 20% 30% 40%

Grade 1–2

Grade 3–4

Grade 1–2

Grade 3–4

Nausea

Anemia

Fatigue

Diarrhea

Constipation

23

CheckMate 227 Part 1: NIVO + IPI in 1L NSCLC

Rek M, arassino MC, AACR 2019

Outcomes by histology

KEYNOTE-024


CM 227

Do we need to Boost I-O in PD-L1–high expressors?

advantage

7. Paz-Ares L et al. N Engl J Med. 2018;379:2040-2051 [supplementary appendix].

*Treatment-related adverse events. †ITT population. ‡All CRs are from the PD-L1 TPS 1–49% population. §All-cause adverse events. ∥Any-cause adverse events.1. Brahmer JR et al. Oral presentation at WCLC 2017. OA17.06. 2. Mok TSK et al. Oral presentation at ELCC 2019. 102O. 3. Gadgeel S et al. Oral presentation at ASCO 2019.336. 4. Gandhi L et al. Oral presentation at AACR 2018. CT075. 5. Paz-Ares L et al. N Engl J Med. 2018;379:2040-2051. 6. Paz-Ares L et al. Oral presentation at ASCO 2018.105.

22

First-Line Therapy in PD-L1 <1%

Is there an optimum I-O

combination?

2



No Targetable

Alterations


KEYNOTE-4077

KEYNOTE-0423


IMpower 150*/1304/1325



KEYNOTE-0241

KEYNOTE-1896

KEYNOTE-0241

KEYNOTE-0423


IMpower13110

I-O

Mono

I-O I-O

I-O

Chemo

I-O + Chemo in PD-L1–negative

1. Kurata T et al. JSMO Annual Meeting 2019. Kyoto, Japan; 2. Socinski MA et al. Oral presentation at ASCO 2018. 9002; 3. Paz-Ares L et al. Oral presentation at ASCO 2018. 105. 4 Jotte R, WCLC 2019.

IMpower 131:

OS in PD-L1 TC0/IC0,SQ4

12.5 mo 14.0 mo

Non-Sq NSCLC Sq NSCLC

Boosting I-O in Patients With Tumor PD-L1–negative

Borghaei H, WCLC 2019

Pooled KN021G, KN189, KN047: I-O plus CHEMO KEYNOTE 227: CHEMO-SPARING

Median 19 months Median 17 months


31

ORR and DOR for NIVO + IPI and NIVO + Chemo vs Chemo in Patients With Tumor PD-L1 Expression < 1%

0

10

20

30

40

Nivo + Ipi Nivo Chemo

ORR by BICR

OR

R (

%)

51 / 187n / N: 67 / 177

27.3

37.9 PR

CR

2.1

25.1

1.1

22.036.2

23.1

NIVO + chemo

43 / 186

ChemoNIVO + IPI

DOR by BICRa

Dosages were NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), and NIVO (360 mg Q3W) plus chemo.aMedian time to response was 2.8 mo with NIVO + IPI, 1.7 mo with NIVO + chemo, and 1.5 mo with chemo.

NIVO + IPI(n = 51)

NIVO + chemo(n = 67)

Chemo(n = 43)

Median DOR, mo95% CI

18.0 12.4–28.6

8.35.9–9.4

4.8 3.7–5.81.7

NIVO + chemo

100

80

Months

60

40

20

00 3 6 9 12 21 2415 18 27 30 33 36

No. at riskNIVO + IPI 51 45 37 32 28 16 1524 19 12 6 4 0

Chemo 43 29 11 9 9 2 15 3 0 0 0 067 59 40 26 19 10 713 11 7 4 1 0

Pati

en

ts i

n r

esp

on

se (

%)

NIVO + chemo

Chemo

NIVO + IPI

NIVO + IPI

Chemo

NIVO + chemo

Part 1b

25%

71%

32%

5%

40%

16%


median 18 months

First-Line Therapy in PD-L1

low 1-49%

Is there an optimum I-O

combination?

3



No Targetable

Alterations


KEYNOTE-4077

KEYNOTE-0423


IMpower 150*/1304/1325



KEYNOTE-0241

KEYNOTE-1896

KEYNOTE-0241

KEYNOTE-0423


IMpower13110

I-O

Mono

I-O I-O

I-O

Chemo

Median (95% CI)

16.4 mo (14.0-19.7)

12.1 mo (11.3-13.3)

Median (95% CI)

13.4 mo (10.7-16.9)

12.1 mo (11.0-14.0)

34%

27%

0 6 18 24

Months

36 48423012

100

90

80

70

60

50

40

30

20

10

0

OS

, %

0 6 18 24

Months

36 48423012

39%

28%

100

90

80

70

60

50

40

30

20

10

0

OS

, %

HR (95% CI)

Pembrolizumab 0.82

(0.71-0.93)Chemotherapy

HR (95% CI)

Pembrolizumab 0.91

(0.77-1.09)Chemotherapy

No. at risk No. at risk

Pembro 637 463 368 304 178 91 30 1 0 Pembro 338 239 178 147 84 41 9 0 0

Chemo 637 485 319 236 126 65 20 2 0 Chemo 337 254 168 123 67 34 12 0 0

Mok TSK et al. Oral presentation at ELCC 2019. 102O.

Pembro mono in PD-L1> 1% & 1-49%: Enough?

KEYNOTE-042

OS in PD-L1≥1%

KEYNOTE-042

OS in PD-L1 1-49%

1. Kurata T et al. JSMO Annual Meeting 2019. Kyoto, Japan.

2. Socinski MA et al. Oral presentation at ASCO 2018. 9002

Pembro plus Chemo in PD-L1 1-49% non-SQ NSCLC

KEYNOTE-189:

OS in TPS 1-49%platinum (cis/carbo)-pemetrexed (x4) +/- pembro

IMpower 150:

OS in PD-L1 Low (TC1/2 or IC1/2) carbo-taxol+/-bevacizumab (x 4-6 cycles) +/- atezo

PD-L1–LowTC1/2 or IC1/2

HRa, 0.80 (95% CI: 0.55, 1.15)

16.4 mo 20.3 mo

HR 0.62 (95% CI 0.42–0.92)HRa, 0.62

(95% CI: 0.42, 0.92)

1. Paz-Ares LG, ASCO 2018; 2. Jotte R, WCLC 2019

Pembro plus Chemo in PD-L1 1-49% SQ-NSCLC

KEYNOTE-4071:

OS in TPS 1-49%carbo-taxol or nabpac (x 4) +/- pembro

IMpower 131 (arm B, C)2:

OS in PD-L1 Low (TC1/2 or IC1/2)

carbo-nabpac (x 4-6) +/- atezo

12.8 mo 15.5 mo14.0 mo11.6 mo

Paz-Ares LG, ASCO 2018

First-Line Therapy in special

subgroups (liver metastases,

driver oncogenes)

4

Atezolizumab + BCP vs BCP Alone

HR: 0.54 (95% CI: 0.29-1.03)

ABCP BCP

Median OS, mos NE 17.5

Mos

OS

(%)

100908070605040302010

0300 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Patients at Risk, nAtezo + Bev + CP

Bev + CP4163

3961

3757

3749

3546

3239

3037

2028

1524

1117

912

511

47

22

Socinski. ASCO 2018. Abstr 9002.

Atezolizumab + CP vs BCP Alone

HR: 0.82(95% CI: 0.49-1.37)

Mos

OS

(%)

100908070605040302010

0300 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Patients at Risk, nAtezo + CP

Bev + CP5363

5161

5057

4849

4646

4139

3737

2428

2224

2017

1612

1311

87

62

17.5 mos 21.2 mos

4

Atezo + CPBev + CP

Special subgroups: EGFR/ALK+ After Prior Targeted Therapy, IMpower150

Socinski MA, ASCO Meeting 2018, abstr 9002.; NEJM 2018

Reck M, The Lancet 2019

Special subgroups: Liver metastasis, IMpower150

Garassino MC, AACR 2019

Special subgroups: Liver metastasis

KEYNOTE-189


CM 227

My decision-making algorithm for I-O

• I-O is a new SoC in first-line advanced NSCLC without drivers

• TPS PD-L1 remains the CORE I-O Biomarker

• WHEN can we spare I-O? ONLY if contraindications (severe autoimmunediseases, steroids, IS) or patients with poor PS ≥ 2

• Do we need to BOOST in PD-L1 ≥50%? Probably NOT

• WHEN do we need to BOOST I-O? if PD-L1< 50%, specially in PD-L1 <1%

• How do we BOOST I-O? Chemo (PD-L1< 50%) or anti-CTLA4 (PD-L1 <1%)

Thank you!! [email protected]

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Presentación de PowerPoint · Treatment-naïve NSCLC Non-squamous Squamous No Targetable Alterations PD-L1