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To test or not to test – that’s the questionStatus and lessons learned from checkpoint

inhibition in NSCLC

Egbert F. Smit MD PhD

Dept. Thoracic Oncology

Netherlands Cancer Institute

e.smit@nki.nl

Checkpoint inhibition in NSCLC

<2015 >2015

Phase I experience

Brahmer et al. NEJM 2012, Topalian et al. NEJM 2012

Subset of patients derives benefitNo responses in PD-L1 negative patients

Brahmer et al. NEJM 2012, Topalian et al. NEJM 2012

Pembrolizumab Phase I by tumor proportion score

Garon et al. NEJM 2015

Phase III experience

• In 2nd line treatment of NSCLC

PD-(L)1, second line study design

QoL, quality of life.

PD-(L)1 checkpoint inhibitor

PD or toxicity

DocetaxelPD or

toxicity

Key patient-inclusion criteria

• Previously treated with a first-line platinum-based regimen

Differences between studies

• PD-L1 status

• PD-L1 cut-off

• Histology

R

Primary endpoint: OS

Secondary endpoint: PFS, response rate, QoL

NivolumabNon-squamous, no PD-L1 selection

Borghaei H, et al. New Engl J Med. 2015;373:1627-39.

At risk, n

Nivolumab 292 232 194 169 146 123 62 32 9 0

Docetaxel 290 244 194 150 111 88 34 10 5 0

Deaths, n/Patients, N

Median OS(95% Cl), mo

1-year OS rate (95% Cl), %

Nivolumab 190/292 12.2 (9.7–15.0) 51 (45–56)Docetaxel 223/290 9.4 (8.1–10.7) 39 (33–45)

HR for death, 0.73 (95% Cl 0.59–0.89)p = 0.002

51

39

0 3 6 9 12 15 18 21 24 27

010203040

60708090

100

50

Time (months)

OS

(%)

Nivolumab

Docetaxel

Borghaei et al., NEJM 2015

OS by PD-L1 Expression

Borghaei et al., NEJM 2015

Borghaei et al. NEJM 2015

Dose it Look Familiar ?

Nivolumab – Checkmate 057 Gefitinib – IPASS

Mok T, et al. N Engl J Med 2009; 361:947-957 Borghaei et al, NEJM 2015

Patient Selection Works !

Nivolumab – Checkmate 057 Gefitinib – IPASS

Paz-Ares, ASCO, 2015Zhou et al. Lancet 2011

PembrolizumabAll histologies, PD-L1 cut-off > 1%

Herbst RS, et al. Lancet. 2016; 387:1540-50.

At risk, nPembrolizumab 2 mg/kg 139 110 51 20 3 0

Pembrolizumab 10 mg/kg 151 115 60 25 1 0Docetaxel 152 90 38 19 1 0

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

OS

(%)

Pembrolizumab 2 mg/kgPembrolizumab 10 mg/kgDocetaxel

Time (months)

Atezolizumab with docetaxel in 2L/3L NSCLC,No selection

aStratified HR. ITT, intention to treat. Barlesi F, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA44_PR.

OS, ITT (n = 850)

HR 0.73a

(95% CI 0.62–0.87)

p = 0.0003

Minimum follow-up = 19 months

Time (months)

At risk, nAtezolizumab

Docetaxel

425 407 382 363

425

342 326 305 279 260 248 234 223 218 205 198 188 175 163 157 141 116 74 54 41 28 15 4 1

390 365 336 311 286 263 219 195 179 168 151 140 132 123 116 104 98 90 70 51 37 28 16 6 3236

OS

(%

)

Median 9.6 mo

(95%CI 8.6–11.2)

Median 13.8 mo

(95%CI 11.8–15.7)

2721 241815129630

100

80

60

40

20

0

Atezolizumab

Docetaxel

Atezolizumab based on PD-L1 positivity

Response Rate for Patientswith PD-L1 Negative NSCLC

Drug (Trial) Histology Testing Cut-off for PDL1<0

ORR

Nivolumab (Checkmate 017) Squamous Dako 28.8 <1% 17%

Nivolumab (Checkmate 057) Non-squamous Dako 28.8 <1% 9%

Atezolizumab (OAK) All histologiesVentanaSP142

TC0 + IC0 8%

Atezolizumab (Poplar) All histologies Ventana SP142 TC0 + IC0 7.8%

Durvalumab (phase I) All histologies Ventana SP263 <25% 5%

Pembrolizumab (phase I) All histologies Dako 22C3 <1% 8.1%

Avelumab (phase Ib) All histologies Not specified <1% 10%

Brahmer, NEJM 2015; Borghaei H et al. N Engl J Med 2015;373:1627-39; Fehrenbacher; Lancet 2016;

Garon, NEJM 2015; Rebelatto, ASCO 2015; Herbst, Lancet 2015; Barlesi ESMO 2016.

Limitations in defining PD-L1 as the biomarker

•PD-L1 “biomarker” is to be defined (mAB, platform & technique, criteria

& thresholds, tumour material & sampling)

•PD-L1 expression is dynamic

•PD-L1 is heterogeneous within tissue

•Cytoplasmic vs membranous?

•Quality of the biopsy

•Importance of co-localization with TILs

Phase III experience

• In 2nd line treatment of NSCLC

• In 1st line treatment of NSCLC

PD-1st line treatment design

Primary endpoint: PFS

Secondary endpoint: OS, response rate, QOL

PD-(L)1 checkpoint inhibitor

Cross over

Platinum chemotherapyCross over

Key patient inclusion criteria*

• Untreated stage IV NSCLC

Differences between studies

PD-L1 cut-off

Histology

R

KEYNOTE-024 study design (NCT02142738)

DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; OS, overall survival; PD, progressive disease; TPS, tumour proportion score. Reck M, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA8_PR.

Key endpointsPrimary: PFS (RECIST v1.1 per blinded, independent central review)Secondary: OS, ORR, safetyExploratory: DoR

Key eligibility criteria

• Untreated stage IV NSCLC

• PD-L1 TPS ≥ 50%

• ECOG PS 0–1

• No activating EGFR mutation or ALKtranslocation

• No untreated brain metastases

• No active autoimmune disease requiring systemic therapy

Pembrolizumab 200 mg i.v. q3w

(2 years)

R (1:1)N = 305

PDaPembrolizumab

200 mg q3w for 2 years

Platinum-doublet chemotherapy

(4–6 cycles)

aTo be eligible for crossover, PD had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.

KEYNOTE-024 Progression-free survival

Chemo, chemotherapy; Pembro, pembrolizumab. Reck M, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA8_PR.

Events(n)

Median (mo)

HR (95% CI)

p value

Pembro 73 10.30.50

(0.37–0.68)< 0.001

Chemo 116 6.0

PF

S (

%)

62%

50%

0 3 6 9 12 15 180

10

20

30

40

50

60

70

80

90

100

Time (months)

48%

15%

At risk, n154 104 89 44 22 3 1

151 99 70 18 9 1 0

PembroChemo

Overall Survival

Data cut-off: May 9, 2016.

80%72%

0 3 6 9 12 15 18 210

102030405060708090

100

Time, months

OS,%

No. at risk

154 136 121 82 39 11 0151 123 106 64 34 7 0

21

70%54%

Events, n Median,

mo

HR

(95% CI)

P

Pembro 44 NR 0.60

(0.41-0.89)0.005

Chemo 64 NR

Reck M, et al. ESMO 2016; LBA08

aDako 28-8 validated; archival tumor samples obtained ≤6 months before enrollment were permitted; PD-L1 testing was centralizedbSquamous: gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2; gemcitabine 1000 mg/m2 + carboplatin AUC 5; paclitaxel 200 mg/m2 + carboplatin AUC 6; Non-squamous:

pemetrexed 500 mg/m2 + cisplatin 75 mg/m2; pemetrexed 500 mg/m2 + carboplatin AUC 6; option for pemetrexed maintenance therapycNo washout required before crossover

Phase 3 CheckMate 026 Study Design:

Nivolumab vs Chemotherapy in First-line NSCLC

Nivolumab3 mg/kg IV Q2W

n = 271Randomize 1:1

Key eligibility criteria:

• Stage IV or recurrent NSCLC

• No prior systemic therapy for advanced disease

• No EGFR/ALK mutations sensitive to available targeted inhibitor therapy

• ≥1% PD-L1 expressiona

• CNS metastases permitted if adequately treated at least 2 weeks prior to randomization

Chemotherapy (histology dependent)b

Maximum of 6 cycles

n = 270

Disease progression or unacceptable toxicity

Disease progression

Crossover nivolumabc

(optional)

Tumor scans Q6W until wk48 then Q12W

Socinski et al. ESMO 2016; LBA07

No. of patients at risk:

Nivolumab 211 104 71 49 35 24 6 3 1 0

Chemotherapy 212 144 74 47 28 21 8 1 0 0

Nivolumab

Chemotherapy

Months

PFS

(%

)

2421181512963 27

100

80

60

40

0

20

0

Primary Endpoint (PFS per IRRC in ≥5% PD-L1+)CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC

Nivolumab

n = 211

Chemotherapy

n = 212

Median PFS, months

(95% CI)

4.2

(3.0, 5.6)

5.9

(5.4, 6.9)

1-year PFS rate, % 23.6 23.2

All randomized patients (≥1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)

HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511

Socinski et al. ESMO 2016; LBA07

No. of patients at risk:

Nivolumab 211 186 156 133 118 98 49 14 4 0 0

Chemotherapy 212 186 153 137 112 91 50 15 3 1 0

OS (≥5% PD-L1+)CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC

Nivolumab

n = 211

Chemotherapy

n = 212

Median OS, months

(95% CI)

14.4

(11.7, 17.5)

13.2

(10.7, 17.1)

1-year OS rate, % 56.3 53.6

Months

OS

(%)

2421181512963 30

100

80

60

40

0

20

0 27

Nivolumab

Chemotherapy

All randomized patients (≥1% PD-L1+): HR = 1.07 (95% CI: 0.86, 1.33)

HR = 1.02 (95% CI: 0.80, 1.30)

Socinski et al. ESMO 2016; LBA07

A novel clinical useful test at the horizon?

Carbone et al. NEJM 2017

Lessons learned

• Immune checkpoint inhibition is effective in a subset of NSCLC patients

• These patients are (in part) defined by high PD-L1 expression

• Cooperation between pathologists and clinicians is crucial