Treating second-line and beyond in non-mutated, non ... · 3ESMO 2018 Congress, Munich, Germany, 19...

Treating second-line and beyond in non-mutated, non-squamous NSCLC:

now and tomorrow

Sanjay Popat, BSc, MBBS, FRCP, PhD

Royal Marsden Hospital

London, United Kingdom

ESMO 2018 Congress, Munich, Germany, 19-23 October 2018

2

• Personal financial interests:

– Honoraria: BMS, Roche, Takeda, AstraZeneca, Chugai, Novartis, Pfizer, MSD, EMD Serono,

Guardant Health, AbbVie, Boehringer Ingelheim, Medscape, Tesaro, OncLive

– Leadership: none

– Stock: none

– Licensing: none

– Direct funding: Elsevier

• Institutional financial interests:

– Institutional research funding: BMS, Clovis Oncology, Roche, Eli Lilly, Takeda, Pfizer, Epizyne,

Ariad, Bayer, Boehringer Ingelheim, Celgene, EMD Serono, MSD, Synta

• Non-financial interests: none

Disclosures


3

Nonsquamous NSCLC

• NSCLC accounts for 85%-90% of lung cancers1

– ADC accounts for 40% of all lung cancers, and is the most common NSCLC subtype

• Driver mutations have been identified in NSCLC and are used to guide therapy2

– EGFR mutations: 10%-12% of whites1

– ALK rearrangement: 5% of patients1

• First-line immunotherapy trial outcomes have led to a rapid shift in treatment paradigms

for patients with NSCLC with no EGFR or ALK mutations3–5

– In the EU, pembrolizumab is approved as a first-line monotherapy for patients with metastatic

NSCLC and PD-L1 ≥50% and in combination with chemotherapy for patients with metastatic

nonsquamous NSCLC regardless of PD-L1 tumour expression status4,5

• Despite recent advancements, treatment of refractory or progressive disease after first-

line chemotherapy remains a challenge6

1. ESMO Web site. www.esmo.org/content/download/7252/143219/file/EN-Non-Small-Cell-Lung-Cancer-Guide-for-Patients.pdf. Accessed 2 October 2018; 2. Planchard et al. Ann Oncol. 2018; 29 (suppl 4):

iv192–iv237.; 3. Pabani and Butts. Curr Oncol. 2018;25:S944: 4. Keytruda SmPC. Merck Sharp & Dohme B.V. 2018; 5. Merck press release. https://investors.merck.com/news/press-release-

details/2018/European-Commission-Approves-Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-the-First-Line-Treatment-of-Patients-with-Metastatic-

Nonsquamous-NSCLC-with-No-EGFR-or-ALK-Genomic-Tumor-Aberrations/default.aspx. Accessed 2 October 2018; 6. Corrales et al. Front Med (Lausanne). 2017;4:13. doi: 10.3389/fmed.2017.00013.


4

Current Treatment Landscape for Stage IV

Nonsquamous NSCLC: ESMO Guidelines

a In the absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based ChT, this strategy will be preferred to platinum-based ChT in patients with PS 0-1 and PD-L1 < 50%. Alternatively, if TMB can accurately be evaluated, and conditioned by the registration and accessibility, nivolumab plus ipilimumab should be preferred to platinum-based standard ChT in patients with NSCLC with a high TMB. bNot EMA-approved. ESMO = European Society for Medical Oncology; PD-L1 = programmed death-ligand 1; PS = performance status; Mb = megabases; MCBS = Magnitude of Clinical Benefit Scale; ChT = chemotherapy; nab-PC, albumin-bound paclitaxel and carboplatin; BSC = best supportive care; IO = immuno-oncology; EMA = European Medicines Agency.

Maintenance treatment:

Pemetrexed (continuation) [I,A]

Gemcitabine (continuation) [I,B]

Pemetrexed (switch) [I,B]

± bevacizumab (if given before)

Nivolumab [I,A; MCBS 5]

Atezolizumab [I,A; MCBS 5]

Pembrolizumab if PD-L1 >1% [I,A; MCBS 5]

Docetaxel [I,B]

Pemetrexed [I,B]

Ramucirumab/docetaxel [I,B; MCBS 1]

Nintedanib/docetaxel [II,B]

Erlotinib [II,C]

PD-L1 ≥50%

4-6 cycles:

Carboplatin-based doublets:

<70 years and PS 2 [II, A]

≥70 years and PS 0-2 [I,A]

Single-agent ChT:

Gemcitabine, vinorelbine,

docetaxel [I,B]

or pemetrexed [III,B]

BSC [II,B]

Any expression of PD-L1a

PS 0-1

Pembrolizumab

[I,A; MCBS 5]

PS 0-1

High TMB

≥10 mutations/Mb

Nivolumab/

ipilimumab

[I,A]b

Pembrolizumab/pe

metrexed and

platinum-based

ChT (4 cycles),

followed by

pembrolizumab

[I,A; MCBS 4]

Atezolizumab/

pemetrexed/

platinum-based

ChT (4-6 cycles),

followed by

atezolizumab

[I,B]b

Atezolizumab/

bevacizumab with

carboplatin and

paclitaxel

(4-6 cycles),

followed by

atezolizumab/

bevacizumab [I,A]b

4-6 cycles

Cisplatin/gemcitabine [I,A]

Cisplatin/docetaxel [I,A]

Cisplatin/paclitaxel [I,A]

Cisplatin/vinorelbine [I,A]

Carboplatin/gemcitabine [I,A]

Carboplatin/docetaxel [I,A]

Carboplatin/paclitaxel [I,A]

Carboplatin/vinorelbine [I,A]

Cisplatin/pemetrexed [II,A]

Carboplatin/pemetrexed [II,B]

nab-PC [I,B]

+/- bevacizumab [I,A with

carboplatin/paclitaxel, otherwise III,B]

PS 0-1

Platinum-based ChT

(see first-line treatment without IO)

Disease progression Partial response

or stable disease

Disease progression

BSC

Stage IV NSCC: Molecular tests negative (ALK/BRAF/EGFR/ROS1)

<70 years and PS 2 or

Selected ≥70 years and PS 0-2 PS 3-4

PS 3-4 PS 0-2


Planchard et al. Ann Oncol. 2018; 29 (suppl 4): iv192–iv237.

5

First-Line Immunotherapy for Patients With NSCLCa

Trial Treatment Median PFS (mo) HR for PFS Median OS (mo) HR for OS ORR (%)

KEYNOTE-0241,2,e ≥50% PD-L1: Pembrolizumab (n=154) vs chemo (n=151)

Mixed: nonsquamous (pembrolizumab, n=125; chemo, n=124)

10.3 vs 6.0

–

0.50b

0.55

30.0 vs 14.2

–

0.63c

–

45.5 vs 29.8

–

KEYNOTE-0423

≥1% PD-L1: Pembrolizumab (n=637) vs chemo (n=637)

Mixed: nonsquamous (pembrolizumab, n=394; chemo, n=388)

TPS ≥50%: 7.1 vs 6.4 0.81d 20.0 vs 12.2 0.69b 39.5 vs 32.0

TPS ≥20%: 6.2 vs 6.6 0.94 17.7 vs 13.0 0.77c 33.4 vs 28.9

TPS ≥1%: 5.4 vs 6.5

–

1.07

–

16.7 vs 12.1

–

0.81c

0.86

27.3 vs 26.5

–

KEYNOTE-1894,e Pembrolizumab + chemo (n=410) vs placebo + chemo (n=206)

All nonsquamous

8.8 vs 4.9 0.52b

NR vs 11.3

0.49b 47.6 vs 18.9

IMpower1505,6

Arm A: atezolizumab + chemo (n=402)

Arm B: atezolizumab + bevacizumab + chemo (n=400)

Arm C: bevacizumab + chemo (n=400)

All nonsquamous

B vs C 8.3 vs 6.8 0.59b 19.2 vs 14.7 0.78d 56 vs 41

A vs C – – 19.4 vs 14.7 0.88 40 vs 41

IMpower1327 Atezolizumab + chemo (n=292) vs chemo (n=286)

All nonsquamous 7.6 vs 5.2 0.60b 18.1 vs 13.6 0.81 47 vs 32

Checkmate 227

Part I8,9

≥1% PD-L1: nivo + ipi (n=396); chemo (n=397); or

nivo (n=396)

<1% PD-L1: nivo + ipi (n=187); chemo (n=186); or

nivo + chemo (n=177)

Mixed: nonsquamous (n=1252)

Nivo + ipi vs

chemo

TMB ≥10

mut/Mb):

7.2 vs 5.5

9.5 vs 5.6

0.58b

0.55

23.0 vs 16.4

–

0.79

–

45.3 vs 26.9

–

IMpower130 (N=724), an ongoing phase 3 clinical trial comparing atezolizumab + chemo with chemo alone, met its coprimary end points of OS and PFS10,11

a These are not head-to-head trials and study designs are different; direct cross-trial comparisons cannot be made; P<0.001; cP=0.002; dP<0.05; eUsed as basis for regulatory approval in the United States and EU. PFS = progression-free survival; HR = hazard ratio; OS = overall survival; ORR = objective response rate; chemo = chemotherapy; nivo = nivolumab; ipi = ipilimumab. 1. Reck et al. N Engl J Med. 2016;375:1823; 2. Brahmer et al. WCLC 2017. Abstract OA 17.06. 3. Lopes et al. ASCO 2018. Abstract LBA4; 4. Gandhi et al. N Engl J Med. 2018;378:2078; 5. Socinski et al. N Engl J Med. 2018;378:2288; 6. Socinski et al. ASCO 2018. Abstract 9002; 7. Papadimitrakopoulou et al. WCLC 2018. Abstract OA05.07. 8. Hellmann et al. N Engl J Med. 2018;378:2093; 9. Hellmann et al. AACR 2018. Abstract CT077; 10. Roche. Media release. May 2018. www.roche.com/media/releases/med-cor-2018-05-29.htm. Accessed 2 October 2018; 11. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02367781. Accessed 3 August 2018.


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a These are not head-to-head trials and study designs are different; direct cross-trial comparisons cannot be made; b P<0.01; c P<0.05; d P<0.001; e Pooled pembrolizumab doses; f Used as basis for regulatory approval; g By independent central review.

1. Borghaei et al. N Engl J Med. 2015;373:1627; 2. Herbst et al. Lancet. 2016;387:1540; 3. Herbst et al. ASCO 2017. Abstract 9090; 4. Rittmeyer et al. Lancet. 2017;389:255;

5. Fehrenbacher et al. J Thorac Oncol. 2018;13:1156; 6. Garon et al. Lancet. 2014;384:665; 7. Reck et al. Lancet Oncol. 2014;15:143; 8. Nintedanib SmPC 2018.

Second-Line Trials in Patients With NSCLCa

Trial Treatment Median PFS (mo) HR for PFS Median OS

(mo) HR for OS ORR (%)

Checkmate 0571f Nivolumab (n=292) vs docetaxel (n=290)

All nonsquamous

2.3 vs 4.2

0.92

12.2 vs 9.4

0.73b

19 vs 12c

KEYNOTE-0102,3,f

≥1% PD-L1: Pembrolizumab (2 mg/kg n=344; 10 mg/kg, n=346) vs

docetaxel (n=343)

Mixed: nonsquamous (pembrolizumab 2 mg/kg, n=240; 10 mg/kg,

n=244; docetaxel, n=240)

2 mg: 3.9 vs 4.0

10 mg: 4.0 vs 4.0

–

2 mg: 0.88

10 mg:

0.79b

0.86e

10.5 vs 8.6

13.4 vs 8.6

–

0.73d

0.59d

0.63e

18.0 vs 9.0d

18.0 vs 9.0d

–

OAK4,5,f Atezolizumab (n=425) vs docetaxel (n=425)

Mixed: nonsquamous (atezolizumab, n=313; docetaxel, n=315)

2.8 vs 4.0

–

0.93

–

13.8 vs 9.6

15.6 vs 11.2

0.75d

0.74b

14.6 vs 13.4

–

REVEL6,f

Ramucirumab + docetaxel (n=628) vs placebo + docetaxel (n=625)

Mixed: nonsquamous (ramucirumab + docetaxel, n=465; docetaxel,

n=447)

4.5 vs 3

4.6 vs 3.7

0.76d

0.77d

10.5 vs 9.1

11.1 vs 9.7

0.86c

0.83c

22.9 vs 13.6d

21.9 vs 14.5b

LUME-Lung 17,8,f

Nintedanib + docetaxel (n=655) vs placebo + docetaxel (n=659)

Mixed:nonsquamous ADC (nintedanib + docetaxel, n=322 vs placebo +

docetaxel, n=336)

3.4 vs 2.7

4.0 vs 2.8

0.79b

0.77c

10.1 vs 9.1

12.6 vs 10.3

0.94

0.83c

4.4 vs 3.3g

4.7 vs 3.6g

Use of first-line immunotherapy will affect which treatments,

including immunotherapy, will be available for use in second-line therapy and beyond


7

• Currently available antiangiogenic therapies

target different signalling pathways

• Many patients are intrinsically refractory or develop

resistance to existing antiangiogenic agents that

principally target VEGF-A or -B and VEGFR-2

• A multitargeted approach to treatment may limit

the development of resistance and maximise

antitumour efficacy

• Nintedanib is an oral triple angiokinase inhibitor

targeting VEGFR 1-3, FGFR 1-3, PDGFR α/β

Multiple Targets of Angiogenesis Inhibitors

VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor;

FLT-3 = fms-like tyrosine kinase 3.

Zhao and Adjei. Oncologist. 2015;20:660. ESMO 2018 Congress, Munich, Germany, 19-23 October 2018

8

Nintedanib for NSCLC: Phase 3 LUME-Lung 1 Study

Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs no) Histology (squamous vs nonsquamous) Brain metastases (yes vs no)

Regions: Europe/Asia/South Africa

Accrual: 23 Dec 2008 to 09 Feb 2011

Primary Endpoint: PFS by independent central review

Key Secondary Endpoint: OS, prespecified hierarchical analyses of patients with ADC who progressed in <9 months after start of first-line therapy, all patients with ADC, and ITT population

Nintedanib 200 mg BID PO, days 2-21

+ docetaxel 75 mg/m2 IV, day 1,

21-day cycles (n=655)

Placebo BID PO, days 2-21,

+ docetaxel 75 mg/m2 IV, day 1,

21-day cycles (n=659)

N=1,314

R

A

N

D

O

M

I

S

E

1:1

PD

PD

Monotherapy allowed after ≥4 cycles of combination therapy

Stage IIIB/IVa

or recurrent

NSCLC patients after

first-line chemotherapy

(all histologies)

PO = orally; IV = intravenously; PD = disease progression; ITT = intent-to-treat.

Reck et al. Lancet Oncol. 2014;15:143. ESMO 2018 Congress, Munich, Germany, 19-23 October 2018

9

LUME-Lung 1:

Consistent PFS Benefit Regardless of Histology

• For patients with adenocarcinoma histology, median PFS was 4 vs 2.8 months (HR [95% CI], 0.77 [0.62-0.96];

P=0.0193) for nintedanib + docetaxel vs placebo + docetaxel

• For patients with SqCC histology, median PFS was 2.9 vs 2.6 months (HR [95% CI], 0.77 [0.62-0.96]; P=0.02)

for nintedanib + docetaxel vs placebo + docetaxel

PFS (Total Population)

Docetaxel plus nintedanib

Docetaxel plus placebo

2 4 6 12 16

PF

S (

%)

100

80

60

40

0

20

0 10 8 14

HR 0.79, 95% CI 0.68-0.92, P=0.0019

CI = confidence interval; SqCC = squamous cell carcinoma.

1. Reck et al. Lancet Oncol 2014;15:143; Reck M et al. J Clin Oncol 2013;31(Suppl.):Abstract LBA8011.

Time (mo)


10

LUME-Lung 1: Significant Improvement

in Median OS in Patients With Adenocarcinoma

Reck et al. Lancet Oncol. 2014;15:143.

Key Secondary Endpoint, Prespecified Hierarchical Analysis

No. at Risk

Nintedanib 322 263 203 163 131 96 72 46 25 10

Placebo 336 269 184 139 101 73 55 33 15 7

4 8 12 24 36

Pro

ba

bilit

y o

f S

urv

iva

l (%

)

100

80

60

40

20

0 20 16 28 32

Time (mo)

52.7%

44.7% 25.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

19.1%

Nintedanib

+

Docetaxel

Placebo

+

Docetaxel

Median OS (mo) 12.6 10.3

HR = 0.83 (95% CI: 0.70-0.99); P=0.0359

0


11

LUME-Lung 1: OS in Patients With ADC Who

Progressed <9 Months After Start of First-Line Therapy

Reck et al. Lancet Oncol. 2014;15:143; Reck and Mellemgaard. Biologics. 2015;9:47.

Key Secondary Endpoint, Prespecified Hierarchical Analysis

No. at Risk

Nintedanib 206 167 119 92 73 51 35 16 9 3

Placebo 199 154 91 62 42 25 17 12 5 1

4 8 12 24 36

Pro

ba

bilit

y o

f S

urv

iva

l (%

)

100

80

60

40

20

0 20 16 28 32

Time (mo)

Nintedanib

+

Docetaxel

Placebo

+

Docetaxel

Median OS (mo) 10.9 7.9

HR = 0.75 (95% CI: 0.60-0.92); P=0.0073

46.8%

34.3% 20.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

10.4%

0


12

LUME-Lung 1:

OS in the European ADC Populationa,b

a Exploratory analysis. b Patients without documented death were censored at the date of last contact when the patient was known to be alive.

Gottfried et al. Target Oncol. 2017;12:475; Heigener et al. 1276P, ESMO 2016.

No. at Risk

Nintedanib 229 215 188 168 151 132 116 107 92 80 68 60 50 42 34 26 19 17 8

Placebo 234 218 183 146 122 101 91 79 67 58 50 43 39 31 22 20 11 10 6

4 8 12 24 36

Es

tim

ate

d P

erc

en

tag

e A

live

100

80

60

40

0

20

0 20 16 28 32

Time From Randomization (mo)

2 6 10 14 18 22 26 30 34

Nintedanib

+

Docetaxel

Placebo

+

Docetaxel

Median (mo) 13.4 8.7

HR (95% CI) 0.79 (0.65-0.97);

P=0.0254 53.3%

41.8%

18.8%

25.3%

1-YEAR SURVIVAL

2-YEAR SURVIVAL


13

No. at Risk

Nintedanib 237 225 193 162 141 123 109 96 86 72 60 55 44 34 24 17 11 8 3 2 2 1 0

Placebo 230 210 178 138 111 89 77 64 53 44 34 28 24 21 15 13 5 2 0

4 8 12

Es

tim

ate

d P

erc

en

tag

e A

live

100

80

60

40

0

20

0 20 16


2 6 10 14 18 22 44 42 40 38 36 34 32 30 28 26 24

No. at Risk

Nintedanib 53 50 44 35 27 25 22 20 18 14 13 12 10 9 7 5 4 4 2

Placebo 64 57 51 31 24 16 14 12 11 10 7 4 3 3 2 2 2 2 1

4 8 12

Es

tim

ate

d P

erc

en

tag

e A

live

100

80

60

40

0

20

0 20 16


2 6 10 14 18 22 36 34 32 30 28 26 24

LUME-Lung 1:

OS in European Patients With Faster-Progressing ADCa

a Exploratory analysis.

Gottfried et al. Target Oncol. 2017;12:475; Heigener et al. 1276P, ESMO 2016.

ADC and Time From End of

First-Line Therapy ≤6 Months

ADC and Progressive Disease as Best

Response to First-Line Therapy

Nintedanib Placebo

Median (mo) 11.3 8.2

HR (95% CI) 0.75 (0.61-0.92);

P=0.0047

48.2%

36.5%

12.5%

22.4%

43.0%

24.6%

5.3%

21.5%

Nintedanib Placebo

Median (mo) 9.8 6.3

HR (95% CI) 0.62 (0.41-0.94);

P=0.0246

1-YEAR SURVIVAL

2-YEAR SURVIVAL

1-YEAR SURVIVAL

2-YEAR SURVIVAL


14

Summary of AEs in Patients With ADC

Patients With AEs, n (%)

Nintedanib +

Docetaxel

(n=320)

Placebo +

Docetaxel

(n=333)

Any AE, all grades 308 (96.3) 314 (94.3)

Drug-related AEs, all grades 260 (81.3) 241 (72.4)

Any AE, grades ≥3 243 (75.9) 228 (68.5)

Drug-related AEs, grades ≥3 176 (55.0) 152 (45.6)

Any AE leading to

discontinuation 67 (20.9) 59 (17.7)

Any serious AE 111 (34.7) 107 (32.1)

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common

Terminology Criteria for Adverse Events (aversion 3.0 was used)

1. Reck et al. Lancet Oncol. 2014;15(suppl):143; 2. Boehringer Ingelheim. Data on file.

Gastrointestinal events

• Diarrhea, nausea, and vomiting

• Manageable with supportive treatment

and dose modification

Liver enzyme elevations

(ALT/AST) • Reversible upon dose modification in

the majority of patients

Main AEs (Any Grade) That Were

More Common With Nintedanib1 AEs in Patients With ADC1,2,a

Median duration of treatment in ADC population:

• Overall treatment: nintedanib (4.3 mo) vs placebo (3.0 mo)

• Nintedanib/placebo treatment: nintedanib (4.2 mo) vs placebo (3.0 mo)


15

• Pembrolizumab, as a monotherapy or in combination with chemotherapy, has become

the first-line standard of care in patients with NSCLC without driver mutations1–3

• First-line use of immunotherapies is increasing, which will affect treatment options

for second-line use2–3

• LUME-Lung 1 trial of nintedanib + docetaxel in advanced NSCLC demonstrated4

– Significant prolongation of PFS regardless of histology

– Significant improvement in OS in patients with adenocarcinoma histology

– Manageable safety profile

• An exploratory analysis demonstrated a nearly 5-month median OS improvement

for European patients treated with nintedanib + docetaxel vs placebo + docetaxel5

• Nintedanib in combination with docetaxel is a viable second-line option

for the treatment of refractory or progressive adenocarcinoma NSCLC4,5

Conclusions

1. Pabani and Butts. Curr Oncol. 2018;25:S944: 2. Keytruda SmPC. Merck Sharp & Dohme B.V. 2018; 3. Merck press release. https://investors.merck.com/news/press-release-details/2018/European-

Commission-Approves-Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-the-First-Line-Treatment-of-Patients-with-Metastatic-Nonsquamous-

NSCLC-with-No-EGFR-or-ALK-Genomic-Tumor-Aberrations/default.aspx. Accessed 2 October 2018; 4. Reck et al. Lancet Oncol. 2014;15:143; 5. Gottfried et al. Target Oncol. 2017;12:475.


Treating second-line and beyond in non-mutated, non ... · 3ESMO 2018 Congress, Munich, Germany, 19...

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