Martin Reck AirwayResearch Center North (ARCN ... · RAM+DOC PL+DOC Progression-Free Survival (%)...

SECOND LINE TREATMENT NSCLC

Martin Reck

Airway Research Center North (ARCN)

LungenClinic

Grosshansdorf, Germany

DISCLOSURE SLIDE

Honoraria for lectures and consultancy from:

Abbvie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche

Institutional support for clinical research from:

BMS

I declare no conflict of interest with the discussed content

THE PRINCIPAL PROBLEM

• Rising incidence and high mortality of lung cancer

• Low frequency of specific early symptoms (> 60% of patientsdiagnosed with advanced stage of disease)

• Low frequency of targetable oncogenic alterations in caucasianpatients

• Ultimate progression following each systemic treatment (nearly eachpatient will be in need of an efficacious second-line treatment)

311.03.2019

CHALLENGES IN SECOND-LINE TREATMENT I

• Pretreated Patients

• Reduced performance status: Tolerability becomes moreimportant.

• Low response rates: Tumor control becomes important.

• More symptomatic patients: Symptom control and symptomimprovement become important .

• It is hard to show any improvement in efficacy...

0 10 20 30 40 50 60 70 80

SECOND-LINE TREATMENT – CHALLENGES II

1J Clin Oncol 2002;20:1335–43; 2J Clin Oncol 2003;21:2933–39; 3Lung Cancer 2006;52:155–63; 4Br J Cancer 2006;95:966–73; 5J Thoracic Oncol 2007;2(Suppl. 4):S666 Abs. P2-235; 6J Clin Oncol 2007;25:5233–39; 7J Clin Oncol 2008;26(Suppl. 15S):426s Abs. 8011; 8J Clin Oncol 2008;26(Suppl. 15S):6s Abs. 3; 9J Clin

Oncol 2008;26:3543–51; 10J Clin Oncol 2009;27:591–98

In recent studies, approximately 50% of patients did not receive second-line therapy

Fidias et al. 200910

Scagliotti et al. 20089

Pirker et al. 20088

Ciuleanu et al. 20087

Park et al. 20076

Barata et al. 20075

von Plessen et al. 20064

Brodowicz et al. 20063

Belani et al. 20032

Socinski et al. 20021

Patients receiving 2nd-line therapy (%)

1. Before Immunotherapy

THE THREE PERIODS OF SECOND-LINE TREATMENT

SECOND LINE TREATMENT NSCLC – FIRST RESULTS

Docetaxel Pemetrexed Erlotinib

RR, % 5.0–12.0 7.1–11.8 7.9–9.0

Median PFS, m 2.0–3.1 2.6–2.9 2.2–3.6

Median OS, m 5.7–8.0 6.7–8.9 6.7–7.9

1-year OS,% 28.7–37.0 29.7–38.5 31.0–35.7

Shepherd, et al. JCO 2000; Fossella, et al. JCO 2000; Ramlau, et al. JCO 2006; Paz-Ares, et al. BJC 2008 Kim, et al. Lancet 2008; Krzakowski, et al. JCO 2010; Hanna, et al. JCO 2004, Cullen, et al. Ann Oncol 2008

Shepherd, et al. NEJM 2005; Vamvakas, et al. ASCO 2010; Ciuleanu, et al. IASLC Chicago 2010; Reck M , et al, Lancet Oncology 2014; Garon E et al, Lancet 2014; Soria JC, Lancet Oncology 2015

THE NON INSPIRING TRUTH IN SECOND LINE TREATMENTStudy Treatment HR for PFS Median PFS (mo) HR for OS Median OS (mo)

Tax 320 (n=373) Docetaxel (D75/100) vs ifofosfamide or vinorelbine TTP: 2.0 (D75) vs 1.8 (p=0.093) NR (p=ns) 5.7 (D75) vs 5.6

Tax 317 (n=104) Docetaxel (D75/100) vs BSC TTP: 2.4 (D75) vs 1.5 (p=0.001) NR (p=0.01) 7.5 (D75) vs 4.6

JMEI (n=571) Pemetrexed vs docetaxel

Adenocarcinoma (n=302)

Squamous (n=172)

0.97

0.83

1.4 (p=0.046)

2.9 vs 2.9

3.5 vs 3.5

2.3 vs 2.7

0.99

0.92

1.56 (p=0.018)

8.3 vs 7.9

9.0 vs 9.2

6.2 vs 7.4

BR.21 (n=727) Erlotinib vs placebo


Squamous (n=222)

0.61 (p<0.001) 2.2 vs 1.8 0.70 (p<0.001)

0.70 (p=0.008)

0.67

6.7 vs 4.7

ISEL (n=1692) Gefitinib vs placebo


TTP: 0.82 TTP: 3.0 vs 2.6 0.89

0.84

5.6 vs 5.1

ZODIAC (n=1391) Vandetanib + docetaxel vs docetaxel


Squamous (n=344)

0.79 (p<0.0001)

0.80 (p<0.05)

0.79

4.0 vs 3.2 0.91

0.89

0.98

10.6 vs 10.0

ZEAL (n=534) Vandetanib + pemetrexed vs pemetrexed


Squamous (n=114)

0.86

0.80

1.04

4.1 vs 2.8 0.86

0.82

1.08

10.5 vs 9.2

ZEST (n=1240) Vandetanib vs erlotinib


Squamous (n=272)

0.98

1.00

1.09

2.6 vs 2.0 1.01

0.99

1.25

6.9 vs 7.8

VITAL (n=913) Aflibercept + docetaxel vs docetaxel 0.82 (p<0.05) 5.2 vs 4.1 1.01 10.1 vs 10.4

BETA (n=636) Bevacizumab + erlotinib vs erlotinib


Squamous (n=28)

0.62 (p<0.0001) 3.4 vs 1.7 0.97

1.07

0.91

9.3 vs 9.2

TAILOR (n=222) Docetaxel vs erlotinib, non-EGFR mutations 0.69 (p=0.014) 3.4 vs 2.4

TITAN (n=304) Docetaxel/pemetrexed vs erlotinib, fast progressors


Squamous (n=154)

1.19 2.2 vs 1.6 0.96

0.95

0.86

5.5 vs 5.3

Vinflunine (n=551) Vinflunine vs docetaxel 1.004 2.3 vs 2.3 0.973 6.7 vs 7.2

Topotecan (n=829) Oral topotecan vs docetaxel 1.20 (p=0.02) TTP: 11 vs 13 wk 1.23 (p=0.0568) 6.4 vs 7.1

SUN1087 (n=960) Sunitinib + erlotinib vs erlotinib

Non-squamous (n=568)

Squamous (n=270)

0.807 (p=0.023)

0.859

0.797

3.6 vs 2.0 0.922

0.943

0.935

9.0 vs 8.5

NEW PRINCIPLES OF ANTIANGIOGENIC

TREATMENT

Ramucirumab:• Humanised, monoclonal IgG1 AB• Specific Binding of VEGFR2 Nintedanib (Vargatef)

• orale Angiokinaseinhibitor• Binding to VEGF 1-3, PDGF α,β; FGF 1-3

REVEL-Trial: Docetaxel + Ramucirumab vs Docetaxel + Placebo in 2nd line

treatment of NSCLC

• Study objective

– To compare the efficacy and safety of ramucirumab+docetaxel with placebo+docetaxel in

pretreated patients with stage IV non-squamous and squamous NSCLC

Lancet 2014; 384: 665-73

Primary endpoint

• OS

Secondary endpoints

• PFS, objective response rate, safety and PROs

R

1:1

PD

PDKey patient inclusion criteria

• Stage IV NSCLC

• Non-squamous or squamous

• Previous platinum-based CT

• ECOG PS 0/1

(n=1253)

Placebo + docetaxel 75 mg/m2 q3w

(n=625)

Ramucirumab 10 mg/kg + docetaxel 75 mg/m2 q3w

(n=628)

Stratification

• Gender, region (East Asia vs ROW),

ECOG PS (0 vs 1), prior maintenance

therapy

• Key results

– Ramucirumab+docetaxel significantly improved survival over placebo + docetaxel

Median (95% CI) Censoring rateRAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5, 11.2) 31.8%PL+DOC 9.1 (8.4, 10.0) 27.0%

Stratified HR (95% CI) 0.857 (0.751, 0.979)Stratified log-rank p=0.0235

0

20

40

60

80

100

Overa

ll s

urv

ival

(%)

RAM+DOCPL+DOC

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

36

Survival time (months)

628625

00

RAM+DOCPL+DOCCensored

OS PFS

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC:

4.5 (4.2, 5.4) 11.1%3.0 (2.8, 3.9) 6.7%

Stratified HR (95% CI) 0.762 (0.677, 0.859)Stratified log-rank p<0.0001

RAM+DOCPL+DOC

Pro

gre

ssio

n-F

ree

Su

rviv

al

(%)

RAM+DOCPL+DOC

Number at risk

RAM+DOCPL+DOCCensored

0 3 6 9 12 15 18 21 24 27 30 33

383301

204172

12095

5937

3817

119

74

33

32

00

00

36Survival Time (months)

628625

00

0

20

40

60

80

100

RAM, ramucirumab; DOC, docetaxel

REVEL-Trial: Docetaxel + Ramucirumab vs Docetaxel + Placebo in 2nd line

treatment of NSCLC

RAM+DOC PL+DOC P-value

Response 22.9% 13.6% <0.01

DCR 64.0% 52.6% <0.001 Lancet 2014; 384: 665-73

NINTEDANIB IN NSCLC

DESIGN: LUME 1

12

Nintedanib 200mg BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=655)

Nintedanib 200mg BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,


Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,


Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,


N=1314

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

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

Stage IIIB/IVor recurrent

NSCLC patients after 1st line

chemotherapy

(all histologies)

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Regions: Europe / Asia / South AfricaAccrual: Dec 23, 2008 to Feb 9, 2011

Reck et al., Lancet Oncology 2014, published online Jan 09

LUME 1 TRIAL: DOCETAXEL + NINTEDANIB VS DOCETAXEL +

PLACEBO IN 2ND LINE TREATMENT OF NSCLC

PFS in ITT (Primary Endpoint) OS in ADCA (Secondary Endpoint)

Reck M, et al. Lancet Oncol. 2014;15(2):143-55

LUME 1: EFFICACY IN UNFAVORABLE POPULATIONS

OS in patients with PD as best response to FL(exploratory analysis)

OS in patients with early progressing tumor(key secondary endpoint)

Mellemgaard et al. Eur J Cancer 2013;49(suppl 2):Abstract 3409; Reck et al. Lancet Oncol 2014;15:143–155

Docetaxel Pemetrexed ErlotinibAfatinib(SCC)

Docetaxel+ Ramucirumab

(NSCLC)

Docetaxel+ Nintedanib

(NSCLC)

RR, % 5.0–12.0 7.1–11.8 7.9–9.0 6 234.4

Central Review

Median PFS, m 2.0–3.1 2.6–2.9 2.2–3.6 2.4 4.5 3.4

Median OS, m 5.7–8.0 6.7–8.9 6.7–7.9 7.9 10.5 10.1

1-year OS,% 28.7–37.0 29.7–38.5 31.0–35.7 nr nr nr

Shepherd, et al. JCO 2000; Fossella, et al. JCO 2000; Ramlau, et al. JCO 2006; Paz-Ares, et al. BJC 2008

Kim, et al. Lancet 2008; Krzakowski, et al. JCO 2010; Hanna, et al. JCO 2004, Cullen, et al. Ann Oncol 2008

Shepherd, et al. NEJM 2005; Vamvakas, et al. ASCO 2010; Ciuleanu, et al. IASLC Chicago 2010; Reck M , et al, Lancet Oncology

2014; Garon E et al, Lancet 2014; Soria JC, Lancet Oncology 2015

*Second- and third-line therapy

SECOND LINE TREATMENT NSCLC – UPDATED RESULTS

1. Before Immunotherapy

2. During Immunotherapy


INHIBITION OF PD-1 /PD-L1:

A NEW CONCEPT TO OVERCOME AVOIDANCE OF IMMUNE

DESTRUCTION

Hanahan D, Weinberg RA. Cell. 2011;144:646–674; Wolchok J: ASCO 2013 17

Inhibition of PD-1 /PD-L1

ANTI – PD-1 MONOTHERAPY IN PRETREATED PATIENTSPRIMARY ENDPOINT: OS!

Nivolumab – CheckMate 017 (PIII)1

2nd Line, squamous, PD-L1 All-ComerNivolumab – CheckMate 057 (PIII)2

2nd Line, non-squamous, PD-L1 All-Comer

Pembrolizumab - Keynote 010 (PII/III)3

2nd+ Line, PD-L1 TPS ≥1%Atezolizumab – OAK (PIII)4

2nd+ Line, PD-L1 All-Comer

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

CONSISTENT BENEFIT IN OS

Borghaei et al., 2016, ASCO.1Time (Months)

100

80

60

40

20

00 6 30

OS

(%

)

1812 24 36

NivolumabDocetaxel

Checkmate 017 (SQ)1

Time (Months)

2-yr OS = 23%2-yr OS = 8%

NivolumabDocetaxel

100

80

60

40

20

00 6 30

OS

(%

)

1812 24 36

Checkmate 057 (NSQ)1

2-yr OS = 29%2-yr OS = 16%

Herbst et al., 2017, ASCO.3

OS

(%

)

Rittmeyer et al., 2017, Lancet.4Time (Months)

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27

Atezolizumab

Docetaxel

+++++++++++++++++++++++++++++++

+++++++++++++++++++++++++++

++

++++++++++

++

+++++++++

++

OAK4

18-mo OS = 40%18-mo OS = 27%

Time (Months)

100

80

60

40

20

00 5 10 15 20 25 30 35

OS

(%

)

Pembro 2 mg/kgPembro 10 mg/kgDocetaxel

KEYNOTE-010 (≥1% PD-L1)3

30-mo OS = 29.5%30-mo OS = 22.1%30-mo OS = 12.3%

Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

LONG TERM OS IN KN 010

OVERALL SURVIVAL (PRIMÄRER ENDPUNKT)

KN010_Herbst et al. #LBA63_ESMO_2018

PD-L1 =/> 50%Med OS: 16.9 vs 8.2 m3 y OS: 35% vs 13%HR 0.53, p<0.00001

PD-L1 =/> 1%Med OS: 11.8 vs 8.4 m3 y OS: 23% vs 11%HR 0.69, p<0.00001

CONSISTENT BENEFIT IN TOLERABILITYCheckmate 017 (SQ)1

N=272Checkmate 057 (NSQ)1

(N=582)

Nivo Doc Nivo Doc

TRAEs (%) 61 87 71 88

Grade 3–5 8 56 11 54

DC Rate (%) 6 10 6 15

Minimum follow-up: 24.2 mos

Cross-study comparisons are not intended.

2L=second line; atezo=atezolizumab; DC=discontinuation; doc=docetaxel; I-O=immuno-oncology; IQR=interquartile range; nivo=nivolumab; NSCLC=non-small cell lung cancer;PD-L1=programmed death ligand 1; pembro=pembrolizumab; TRAE=treatment-related adverse event.

1. Borghaei H et al. Presented at ASCO 2016. 9025. 2. Herbst RS et al. Lancet. 2016;387(10027):1540-1550. 3. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Table extracted from: Rittmeyer et al., 2017, Lancet.3

Pembro(2 mg/kg)

Pembro(10 mg/kg)

Doc

TRAEs (%) 63 66 81

Grade 3–5 13 16 35

DC Rate (%) 4 5 10

Median follow-up: 13.1 mos (IQR 8.6–17.7)

Atezo Doc

TRAEs (%) 64 86

Grade 3–5 15 43

DC Rate (%) 8 19

Median follow-up: 21 mos

KEYNOTE-010 (≥1% PD-L1)2

N=1034OAK3

N=850Table extracted from: Borghaei et al., 2016, ASCO.1

Table extracted from: Herbst et al., 2016, Lancet.2

IMPACT ON SYMPTOM CONTROL / QUALITY OF LIFE

EXAMPLE: CHECKMATE 17

Improvement of Health Status Time to Deterioration of Health Status

Reck M et al, J Thorac Oncol 2018

SECOND LINE IMMUNOTHERAPY: OPEN QUESTIONS

• Importance of PD-L1 Expression

CORRELATION OF PD-L1 EXPRESSION AND EFFICACY

Borghaei H, ASCO 2016; Rittmeyer A, Lancet 2016; Herbst R, Lancet 2015

EFFICACY OF IMMUNOTHERAPIES IN PDL-1 NEGATIVE PATIENTS

Brahmer J et al, ESMO Asia 2015; Rittmeyer A et al, Lancet 2016, Barlesi ESMO 2016

RR: 9%DOR: 18.3 months RR: 8% (Atezo) vs 11% (Doce)

OS: 12.6 vs 8.9 months (HR 0.75)

Nivolumab – CM 57 Atezolizumab - Oak



• Duration of treatment

Exploratory Analysis• Improvement in PFS (HR 0.42), 1 year PFS:

65% vs 40%• Improvement in PFS independent from RR• Trend in OS (HR 0.63)• Some stabilizations by reexposure

A Signal – CheckMate 153

Spigel D et al, ESMO 2017; abstract 1297O

SOMETIMES TREATMENT DURATION DOES MATTER

28

64 year old female patients, ADCA stage IV, EGFR -, ALK -, PDL-1 >50%PD after Cisplatin/Pemetrexed and Docetaxel / Nintedanib

Third Line Treatment with Pembrolizumab

04.01.17 18.05.17 02.11.17 07.01.19

A quality of clinical and radiological response that we could not achieve by chemotherapy




• Treatment beyond progression?

Atezo Post-PD Other Post PDNo Treatment

Post PD

Number 168 (51%) 94 (28%) 70 (21%)

Median OS12.7 m

(9.3 ; 14.9)8.8 m

(6.0 ; 12.1)2.2 m

(1.9 ; 3.4)

18 m OS 37% 20% 9%

Treatment beyond ProgressionExample Atezolizumab

Gandara D et al, ASCO 2017; abstract 9001




• Treatment beyond progression?

• The Question of Hyperprogression

Courtesy of S. Champiat, ESMO IO Course 2018

PATTERNS OF PROGRESSION

(DETERMINATION OF HYPERPROGRESSION IS COMPLEX)

Champiat et al.

Clin. Cancer Research

2016

Kato et al.

Clin. Cancer Research

2017

Saada-Bouzid et al.

Annals of Oncology 2017

Ferrara et al.

WLC presentation

Oct. 2017

Population

N = 131

Metastatic cancersphase 1 trials

PD1 or PD-L1 inhibitors monotherapy

N = 155

Metastatic cancerswith molecular profiling

CTLA-4, PD-1/PD-L1 inhibitors or other investigational agents

N= 34

recurrent and/or Metastatic

head and neck squamous

cell carcinoma

PD-1/PD-L1 inhibitors

N= 406

Advanced NSCLC

PD-1/PD-L1 inhibitors + IO combo

HPD rate ?9%

(12/131)

6%

(6/102)

29%

(10/34)

14%

(56/406)

Associated factors

Age(66 vs 55, p = 0.007)

All analysis were performedfor TTF < 2months only,

no correlation was evaluated for hyperprogression

Regional recurrence (TGKR≥2: 90% vs TGKR<2 : 37%, p=0.008)

Metastatic sites > 2(9% vs 19%, p = 0.005)

Reported studies integrating tumor kinetics

No association with tumor PD-L1 status, baseline tumor burden, number or type of previous

therapeutic lines, baseline corticosteroid use, presence of inflammatory markers at baseline

Courtesy of S. Champiat, ESMO IO Course 2018

• Before Immunotherapy

• During Immunotherapy

• After Immunotherapy


OPPORTUNITIES OF POST PROGRESSION TREATMENT WILL CHANGE

TODAY

1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015

2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39

3. Sanofi Aventis. Taxotere® (docetaxel) prescribing information. Nov 2014

4. Eli Lilly and Company. Alimta® (pemetrexed) prescribing information. Sep 20135. Astellas Pharma and Genentech. Tarceva® (erlotinib) prescribing information. June 2015

Progression during or after platinum therapyProgression during or after platinum therapy

ChemotherapyChemotherapy AntiangiogenicsAntiangiogenics Immune checkpoint

inhibitors

Immune checkpoint

inhibitors

Nintedanib6,a

(+ docetaxel)

Nintedanib6,a

(+ docetaxel)Docetaxel3Docetaxel3 Pemetrexed4Pemetrexed4 Ramucirumab7

(+ docetaxel)

Ramucirumab7

(+ docetaxel)

Nivolumab8

Atezolizumab10

Nivolumab8

Atezolizumab10

Not suitable for

squamous NSCLC

Not suitable for

squamous NSCLC

US and EU approved

for squamous and

nonsquamous NSCLC

US and EU approved

for squamous and

nonsquamous NSCLC

Not suitable

for SqCLC

Not suitable

for SqCLC

If not given previouslyIf not given previously

If docetaxel

not given

previously

If docetaxel

not given

previously

EGFR TKIEGFR TKI

Erlotinib5Erlotinib5

May be

inferior to

chemotherapy in WT

patients

May be

inferior to

chemotherapy in WT

patients

6. Boehringer Ingleheim. Vargatef® (nintedanib) summary of product characteristics. March 2015

7. Eli Lilly and Company. Cyramza® (ramucirumab) prescribing information. April 2015

8. Bristol-Myers Squibb. Opdivo® (nivolumab) prescribing information. April 2016

9. Merck & Co., Inc. Keytruda® (pembrolizumab) prescribing information. October 2015

10. Chugai Pharmaceutical. Tecentriq® (atezolizumab) prescribing information in Japan. April 2018

Pembrolizumab9,bPembrolizumab9,b

Only approved for

patients whose tumors

express PD-L1

Only approved for


express PD-L1

aApproved in EU only; bApproved in US only

1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015

2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39

3. Sanofi Aventis. Taxotere® (docetaxel) prescribing information. Nov 2014

4. Eli Lilly and Company. Alimta® (pemetrexed) prescribing information. Sep 20135. Astellas Pharma and Genentech. Tarceva® (erlotinib) prescribing information. June 2015

6. Boehringer Ingleheim. Vargatef® (nintedanib) summary of product characteristics. March 2015

7. Eli Lilly and Company. Cyramza® (ramucirumab) prescribing information. April 2015

8. Bristol-Myers Squibb. Opdivo® (nivolumab) prescribing information. April 2016

9. Merck & Co., Inc. Keytruda® (pembrolizumab) prescribing information. October 2015

10. Chugai Pharmaceutical. Tecentriq® (atezolizumab) prescribing information in Japan. April 2018

EGFR TKIEGFR TKI

May be

inferior to

chemotherapy in WT

patients

May be

inferior to

chemotherapy in WT

patients

OPPORTUNITIES OF POST PROGRESSION TREATMENT WILL CHANGE

TOMORROW?

Progression during or after platinum therapyProgression during or after platinum therapy

ChemotherapyChemotherapy AntiangiogenicsAntiangiogenics Immune checkpoint

inhibitors

Immune checkpoint

inhibitors

Nintedanib6,a

(+ docetaxel)

Nintedanib6,a

(+ docetaxel)Docetaxel3Docetaxel3 Pemetrexed4Pemetrexed4 Ramucirumab7

(+ docetaxel)

Ramucirumab7

(+ docetaxel)

Nivolumab8

AtezolizumabNivolumab8

Atezolizumab

Not suitable for

squamous NSCLC

Not suitable for

squamous NSCLC

US and EU approved

for squamous and

nonsquamous NSCLC

US and EU approved

for squamous and

nonsquamous NSCLC

Not suitable

for SqCLC

Not suitable

for SqCLC

If not given previouslyIf not given previously

If docetaxel

not given

previously

If docetaxel

not given

previously

Erlotinib5Erlotinib5 Pembrolizumab9,bPembrolizumab9,b

Only approved for


express PD-L1

Only approved for


express PD-L1

aApproved in EU only; bApproved in US only

Pemetrexed FLin most patients

VEGF: A KEY MEDIATOR OF THE IMMUNESUPPRESSIVE

MICROENVIRONMENT OF THE TUMOR

Adapted from Monjazeb AM et al. 1. Monjazeb AM et al. Front Oncol. 2013 Jul 26;3:197. 2. Fukumura D et al. Nat Rev Clin Oncol. 2018;15(5):325-340.

VEGF creates an immunosuppressive microenvironment2

• Upregulation of immunosuppressive cells:• Regulatory T-cells (T-regs)• Myeloid-Derived Suppressor Cells (MDSCs)

• Impaired antigen presentation: • Suppression of dendritic cell (DC) maturation, macrophages

(TAMs)• Impaired T-cell function (CTLs)

N

T

CD4

Treg

CD8

NK

TAM

MDSC

iDC

VEGF

EFFICACY OF DOCETAXEL + NINTEDANIB 3L TREATMENT AFTER

CHEMOTHERAPY AND IMMUNOTHERAPY

VARGADO (Cohort B) Interim Analysis 2018

Spanish NPU

Corral et al WCLC 2017

Population N

Median PFS

(Months)

Invest*

NMedian PFS (Months)

Invest*

3L Nintedanib + docetaxel

Prior IO 21 5.5 11 3.2

VARGADO (Cohort B) Interim Analysis 2018

Spanish NPU

Corral et al WCLC 2017

Population NORR

(%)

DCR

(%)N

ORR

(%)

DCR

(%)

3L Nintedanib + docetaxel

Prior IO 12 58 83 11 36.5 82.0

PFS

ORR & DCR

Interim Data Cut-Off 01 August 2018

1. Grohé et al. Ann Oncol. 2018;29 (suppl 10):55P. 2. Corral J et al. J Thorac Oncol. 2017;12(11 suppl 2):abstr P2.01-022.

OS data were not yet mature at the time of the analysis

VARGADO COHORT B (PRIOR IO):

TREATMENT DURATION BY TREATMENT

*Single-agent nintedanib treatment ongoing.§Previous therapies not documented.1. Grohé et al. Ann Oncol. 2018;29 (suppl 10):55P

Interim Data Cut-Off 01 August 2018

ENHANCING IMMUNOGENICITYBY COMBINATION

• Enhancement of T-Cell priming

• Removal of coinhibitory signals

• Supply of costimulatory signals

• Conditioning the tumor microenvironment

Whiteside TL, Clin Cancer Res (2016); 22(8): 1845–55

THE LANDSCAPE OF COMBINATION TRIALS(IT WILL BECOME DIFFICULT TO KEEP THE OVERVIEW...)

Combination trials with a

anti-PD-1/anti-PDL1

backbone

Tang J et al., Ann Oncol 2018, e-published

CONCLUSIONS

• Second Line Treatment represents an effective and important

part of lung cancer treatment

• Second Line Treatment should be offered to all eligible patients

(we should be able to beat the 50%)

• Second Line Treatment has undergone signficant changes with

the implementation of immunotherapies

• Second Line Treatment will have to undergo significant changes

with the introduction of immunotherapies in first-line treatment

Martin Reck AirwayResearch Center North (ARCN ... · RAM+DOC PL+DOC Progression-Free Survival (%)...

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