management of brain metastases and oligometastases in non ... · management of brain metastases and...

01

Management of Brain Metastases and Oligometastases in Non–Small Cell Lung Cancer (NSCLC)Terufumi Kato, MDChief PhysicianKanagawa Cardiovascular and Respiratory CenterYokohama, Japan

02

Objectives

• Review the current approaches in the management of brain metastases and oligometastases in NSCLC

• Review the emerging data supporting the role of ErbBfamily blockers in the treatment of patients with oligometastases

03

Brain Metastases in NSCLC

• The brain is a common site of metastatic spread in NSCLC, affecting 21%-64% of patients1

• These patients have a poor prognosis with median survival2-8:

– 1 month from diagnosis if untreated – 2 months with glucocorticoid therapy– 2-5 months with WBRT

WBRT, whole brain radiotherapy; TKI, tyrosine kinase inhibitor.1. Nguyen T and Deangelis LM. J Support Oncol. 2004;2:405; 2. Langer CJ and Mehta MP.J Clin Oncol. 2005;23:6207; 3. Eichler AF and Loeffler JS. Oncologist. 2007;12:884;

4. Fan Y et al. Onco Targets Ther. 2013;6:1789; 5. Hoffknecht P et al. J Thorac Oncol.2015;10:156; 6. Khuntia D et al. J Clin Oncol. 2006;24:1295; 7. Ruderman N et al. Cancer. 1965;18:298; 8. Zimm S et al. Cancer. 1981;48:384.

04

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015.

NCCN Guidelines for the Treatment of Brain Metastasis in Patients With NSCLC

05

RTOG, Radiation Therapy Oncology Group; RPA, recursive partitioning analysis. *In patients with asymptomatic brain metastases who have not received prior systemic therapy (e.g. chemotherapy, TKIs), treatment with systemic chemotherapy and deferred WBRT should be considered.

Class I: < 65 years old, have a good PS (Karnofsky Index [KI] ≥ 70%), have no other extra-cranial metastases and have a controlled primary tumourClass II: non–class I or class III patient (all other patients)Class III: KI < 70%

Based on Reck M et al. Ann of Oncol. 2014(suppl 3):iii27-29.

ESMO Guidelines for the Treatment of Brain Metastasis in Patients With NSCLC

RTOG Classification

RPA Class I and II

RPA Class III

Whole Brain Radiotherapy (WBRT)

Best Supportive Care (BSC)

Treatment Options

1 to 3

> 3

Number of Brain Metastases

Symptomatic

Asymptomatic Systemic Chemotherapy*

Stereotactic Radiosurgery (SRS)

06

Japanese Lung Cancer Society Guideline (2014) for the Treatment of Brain Metastasis in Patients With NSCLC

Standard therapy for brain lesion:Local treatment

Treatment Options Gradea Radiation therapy for symptomatic lesion Ab SRS or surgery for solitary meta without other

active lesionB

c WBRT for multiple metaSRS if number is 4 or less, 3 cm or smaller in size

BB

07

What Is the Role of Adjuvant WBRT in the Treatment of Brain Metastases in Patients With Lung Cancer?

08

Phase III Randomised Trial of WBRT in Addition to SRS in Patients With 1-3 Brain Mets (NCCTG N0574)

Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.

09

NCCTG N0574 Trial: Baseline Characteristics


010

NCCTG N0574 Trial: Cognitive Progression at 3 Mo (Primary Endpoint)


013

NCCTG N0574 Trial: Intracranial Tumor Control

Time to intracranial progression


014

NCCTG N0574 Trial: OS


015

Conclusions


• Decline in cognitive function more frequent with the addition of WBRT to SRS

– Specifically immediate recall, memory and verbal fluency• Adjuvant WBRT improved brain control but no impact on overall

survival• Worse QoL with WBRT

– Specifically overall QoL and functional well-being• Long-term survivors

– Small numbers– Nonetheless trend is worse cognitive function long term with WBRT

• For patients with newly diagnosed brain metastases that are amenable to SRS, a treatment option is initial therapy with SRS alone and close monitoring to better preserve cognitive function and QoL

016

What Is the Role of WBRT in the Treatment of Brain Metastases That Are Not Suitable for Resection or Stereotactic Radiotherapy in Patients With Lung Cancer?

017

QUARTZ Trial: A Phase 3 Non-Inferiority Trial of WBRT + OSC + Dex vs OSC + Dex in Patients With Brain Mets

Mulvenna PM et al. J Clin Oncol. 2015;33(suppl). Abstract 8005.

019

QUARTZ Trial: Baseline Characteristics


020

QALYS = quality adjusted life years


QUARTZ Trial: Components of the Primary Outcome Measures (QALYS)

021

QUARTZ Trial: QALYS (Primary Outcome Measure)


022

QUARTZ Trial: Conclusion


023

Prophylactic Cranial Irradiation in Japanese Patients

024

Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: Results of a Japanese randomized phase III trial Seto et al:

ASCO2015

UMIN ID; 000001 755

025

Time to Brain Metastasis

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39

months

Arm A: PCIn=84

Arm B: no PCIn=79

BM at 12 months 32.4% 58.0%

Gray’s test: P<0.001 (2-sided)

Arm B: No PCIArm A: PCI

026

Overall Survival

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39

months

Stratified log-rank test: P=0.091 (2-sided)

Arm B: No PCIArm A: PCI

Arm A: PCIn=84

Arm B: no PCIn=79

No. of OS Events 61 50

Hazard ratio (95% CI) 1.38 (0.95-2.02)

Median OS (95% CI), mo 10.1 (8.5-13.2) 15.1 (10.2-18.7)

028

EGFR-targeted TKI in the Treatment of Brain Metastases in Patients With Lung Cancer

029

Alterations of ErbB Pathways in NSCLC and Brain Metastases From NSCLC

1. Sun et al. Clin Cancer Res. 2009;15:4829; 2. Cappuzzo et al. J Natl Cancer Inst. 2005;97:643; 3. Hirsch et al. J Clin Oncol. 2003;21:3798;4. Dacic et al. Am J Clin Pathol. 2006;125:860; 5. Lopez-Malpartida et al. Lung Cancer. 2009;65:25; 6. Lee et al. Lung Cancer. 2010;68:375; 7. Gately et al. Clin Lung Cancer. 2014;15:58; 8. Hirsch. Oncogene. 2009;28:S32; 9. Nguyen et al. J Support Oncol. 2004;2:405; 10. Hirsch and Bunn. Lancet Oncol. 2009;10:432; 11. D’Arcangelo et al. Future Oncol. 2013;9:699; 12. Ji et al. Proc Natl Acad Sci U S A. 2006;103:7817; 13. Stephens et al. Nature. 2004;431:525; 14. Yi et al. Mod Pathol. 1997;10:142; 15. Kan et al. Nature. 2010;466:869.

ErbBreceptor Alteration NSCLC

[%]SCC-

NSCLC [%]BM–NSCLC

[%]

EGFR

High copy number

≈302 453-7

Over-expression

40-808 57-713-7 399

mutation 10-5010 ≈111

VIII 1-212 5-811

Her2Over-

expression18-338 89

mutation 2-413,14

ErbB3 Over-expression

16-2914 ≈3014 219

ErbB4 mutation - 2-315

P<0.0001

P=0.001

Levels of pErbB3, pEGFR, and their ligands are significantly higher in brain metastases than in corresponding primary tumours1

030


NCCN Guidelines: Systemic Therapies for Brain Metastases

033

Randomized Phase 3 Trial of Erlotinib Plus Concurrent WBRT for Patients With Brain Metastases From NSCLC

WBRT, whole brain radiotherapy; PFS, progression-free survival; OS, overall survival; AEs, adverse events; QoL, quality of life. Lee SM et al. J Natl Cancer Inst. 2014;106:dju151. (Clinical trial no. NCT00554775)

Patients with histologically or

cytologicallyconfirmed NSCLC

and newly diagnosed multiple BM documented by MRI or contrast CT

scan(n=80)

Endpoints

Primary: 2-month neurological PFS

(nPFS)

Others: OS, AEs, and QoL

• WBRT administered 20 Gy in 5 daily fractions

• Erlotinib (100 mg/day) or placebo was taken starting day 1 of WBRT

• After completion of WBRT, erlotinib dose was given at standard dosage (150 mg/day) until PD with symptomatic deterioration

Randomise

WBRT + Erlotinib

WBRT + Placebo

1:1

Median follow-up = 12.6 months

034

Combination of Erlotinib With WBRT Versus Placebo With WBRT: Neurological PFS or OS

Frequency of EGFR mutation was low, with 1 of 35 (2.9%) of patients with available samples

HR=0.95 (95% CI: 0.59 to 1.54); P=0.84 HR=0.95 (95% CI: 0.58 to 1.55); P=0.83

Lee SM et al. J Natl Cancer Inst. 2014;106:dju151. (Clinical trial no. NCT00554775)

035

Afatinib Is an Irreversible ErbB Family Blocker

• Afatinib covalently binds and irreversibly blocks EGFR, HER2, and ErbB4

O

N

N

N

F

Cl

O

N

ON

N

S

O

N

S

O

N

N

N

F

Cl

O

O

N

ON

Afatinib

Afatinibcovalently bound

• ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

• Afatinib prevents ligand-dependent ErbB3 phosphorylation in preclinical studies

0 0 300 1000 300 100

– + – + + +

Afatinib (nM)

Heregulin

pErbB3

Anti-phospho-immunoblotting has shown that afatinib prevents ligand (heregulin)-

stimulated ErbB3 phosphorylation

Li D et al. Oncogene. 2008;27:4702; Solca F et al. J Pharmacol Exp Ther. 2012;343:342.

Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications..

036

Complete Blockade of the ErbB Family Enhances the Effect on Important Signaling Pathways

Targeting the whole ErbB Family enhances the effect on important

signaling pathways

Li D et al. Oncogene. 2008;27:4702; Solca F et al. J Pharmacol Exp Ther. 2012;343:342.

ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

037

LUX-Lung 3 and LUX-Lung 6 Study Design

Afatinib 40 mg/db

Cisplatin + Pemetrexed75 mg/m2 + 500 mg/m2

IV q21d, up to 6 cycles

Stage IIIB (wet)/IV lung adenocarcinomaEGFR mutation in tumour

(central lab testing; TheraScreen® EGFR29a RGQ PCR)

Cisplatin + Gemcitabine75 mg/m2 + 1000 mg/m2 D1, D8

IV q21d, up to 6 cycles

Randomisation 2:1 Stratified by EGFR mutation

(Del19/L858R/other)

Primary endpoint: PFS (RECIST 1.1, independent review)c

Secondary endpoints: OS, PRO,d ORR, DCR, DOR, tumour shrinkage, safetyaEGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I.bDose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10-mg decrements in case of related G3 or prolonged G2 AE.cTumour assessments: q6 weeks until week 48 and q12 weeks thereafter until progression/start of new therapy. dPatient-reported outcomes: EQ-5D, EORTC QLQ-C30 and LC 13 at randomisation and q3 weeks until progression or new anticancer therapy. Note: 24 patients in LUX-Lung 3 and 28 patients in LUX-Lung 6 were still on treatment as of December 2013.RGQ, rotor-gene Q; PCR, polymerase chain reaction; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours; ORR, objective response rate; DCR, disease control rate; DOR, duration of response; OS, overall survival.1. Sequist LV et al. J Clin Oncol. 2013;31:3327; 2. Wu YL et al. Lancet Oncol. 2014;15:213.

LUX-Lung 31

(n=345)LUX-Lung 62

(n=364; Asian pts)

039

LUX-Lung 3 and LUX-Lung 6: Primary Endpoint—PFS in Patients With Common Mutations* by Independent Review

Months

PFS

(pro

babi

lity)

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

Afatinib LUX-Lung 3Cis/Pem LUX-Lung 3Afatinib LUX-Lung 6Cis/Gem LUX-Lung 6

No. at risk:LL3 Afatinib 204 169 143 115 75 49 30 10 3 0LL3 Cis/Pem 104 62 35 17 9 6 2 2 0 0LL6 Afatinib 216 186 152 116 82 55 33 11 4 0LL6 Cis/Gem 62 21 7 1 0 0 0 0 0 0

PFS in overall population

LUX-Lung 31 (n=308)Afatinib vs Cis/Pem

LUX-Lung 62,3 (n=324)Afatinib vs Cis/Gem

Median PFS 13.6 mo vs 6.9 mo 11.0 mo vs 5.6 mo

HR for PFS 0.47, P<0.0001 0.25, P<0.0001

*Exon 19 deletions or exon 21 [L858R] substitutions.PFS = progression-free survival.1. Sequist LV et al. J Clin Oncol. 2013;31:3327; 2. Wu YL et al. Lancet Oncol. 2014;15:213; 3. Data on file. Boehringer Ingelheim.

040

Preplanned Subgroup Analysis of LUX-Lung 3 & 6: Brain Metastases

041

LUX-Lung 3 and LUX-Lung 6: Patients With Common EGFR Mutations With or Without Asymptomatic Brain Metastases

ECOG PS = Eastern Cooperative Oncology Group performance status.Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.

Characteristic

LUX-Lung 3 LUX-Lung 6Afatinib Cis/Pem Afatinib Cis/Gem

w/o BM(n=166)

With BM(n=20)

w/o BM(n=82)

With BM(n=15)

w/o BM(n=185)

With BM(n=28)

w/o BM(n=86)

With BM(n=18)

Median age 63.0 60.5 61.0 63.0 58.0 53.5 58.0 55.0

Female (%) 66.3 70.0 67.1 80.0 64.3 67.9 68.6 66.7

White (%) 28.3 15.0 29.3 20.0 0.0 0.0 0.0 0.0

Asian (%) 70.5 85.0 68.3 80.0 100.0 100.0 100.0 100.0

Never smoker 68.1 70.0 65.9 86.7 75.1 82.1 83.7 72.2

ECOG PS 1 (%) 56.6 80.0 63.4 53.3 78.9 85.7 65.1 72.2

Del19 (%) 53.6 55.0 56.1 53.3 56.8 60.7 60.5 38.9

L858R (%) 46.4 45.0 43.9 46.7 41.6 35.7 39.5 61.1

Prior WBRT (%) 1.2 35.0 0 .0 33.3 0 .0 21.4 0 .0 33.3

042

PFS in NSCLC Patients From LUX-Lung 3 With Common EGFRMutations, With and Without Brain Metastases by Independent Review

Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.

With brain metastases Without brain metastases

AfatinibPemetrexed + Cisplatin

No. at riskAfatinib 20 17 9 8 7 5 4 2 2 2 1 1 0 0 0 0Cis/Pem 15 9 3 3 1 1 0 0 0 0 0 0 0 0 0 0

1.0

Estim

ated

PFS

pro

babi

lity 0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. at riskAfatinib 166 141 123 100 78 61 44 34 28 21 18 15 10 7 3 0Cis/Pem 82 49 29 14 8 5 2 2 2 2 2 2 2 2 1 0

Estim

ated

PFS

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months) Time (months)


Afatinib Cis/Pem

Median, months 11.1 5.4

HR (95% CI)Log-rank P value

0.54 (0.23-1.25)P=0.1378



Afatinib Cis/Pem



0.48 (0.34-0.69)P<0.0001

043

PFS in NSCLC Patients From LUX-Lung 6 With Common EGFR Mutations, With and Without Brain Metastases by Independent Review

With brain metastases Without brain metastases

AfatinibGemcitabine + Cisplatin

No. at riskAfatinib 18 22 16 11 10 8 7 4 3 3 2 0 0 0Cis/Gem 18 7 2 0 0 0 0 0 0 0 0 0 0 0

1.0

Estim

ated

PFS

pro

babi

lity 0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39

No. at riskAfatinib 185 162 134 102 76 54 43 33 27 21 15 9 1 0Cis/Gem 86 52 17 6 1 0 0 0 0 0 0 0 0 0

Estim

ated

PFS

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

00 39


3 6 9 12 15 18 21 24 27 30 33 36Time (months) Time (months)


Afatinib Cis/Gem



0.47 (0.18-1.21)P=0.1060


Afatinib Cis/Gem



0.22 (0.15-0.33)P<0.0001


044

PFS in Patients With Brain Metastases (Combined Analyses From LUX-Lung 3/6)

Time (months)No. at riskAfatinib 48 39 25 19 17 13 11 6 5 3 Chemo 33 16 5 3 1 1 0 0 0 0

Combined LUX-Lung 3 and LUX-Lung 6

Afatinib(n=48)

Chemo(n=33)


HR (95% CI)P value

0.50 (0.27-0.95) P=0.03

1.0E

stim

ated

PFS

pro

babi

lity 0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27


045

OS in NSCLC Patients From LUX-Lung 3/6 With CommonEGFR Mutations With and Without Brain Metastases

LL3: With brain metastases LL3: Without brain metastases


No. at riskAfatinib 20 20 19 17 16 15 11 9 9 8 8 6 4 4 2 0 0 0Pemetrexed + 15 14 13 12 11 9 8 7 7 7 7 7 5 4 1 1 0 0Cisplatin

LL6: With brain metastases LL6: Without brain metastases

Time (months)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Est

imat

ed O

S p

roba

bilit

y




No. at riskAfatinib 28 28 24 23 20 17 17 15 13 12 9 4 2 0 0 0Gemcitabine + 18 17 17 17 16 15 13 13 11 6 4 1 1 0 0 0Cisplatin

No. at riskAfatinib 185 183 175 164 149 139 122 101 89 79 69 46 17 9 1 0Gemcitabine + 86 80 72 66 61 52 45 39 35 28 25 15 6 2 0 0Cisplatin

No. at riskAfatinib 156 162 155 152 145 137 124 117 107 95 89 81 51 42 27 8 1 0Pemetrexed + 82 77 72 66 65 57 51 45 42 37 32 27 20 15 8 3 1 0Cisplatin

Time (months)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Est

imat

ed O

S p

roba

bilit

y

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Estim

ated

OS

prob

abili

ty

Time (months)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Est

imat

ed O

S p

roba

bilit

y

Time (months)


Afatinib Cis/Pem

25th, months 16.36 14.23


75th, months 41.66 NE


1.15 (0.49-2.67)P=0.7517


Afatinib Cis/Pem

25th, months 19.65 15.31


75th, months NE 43.17


0.71 (0.50-1.00)P=0.0510


Afatinib Cis/Gem

25th, months 15.05 11.79


75th, months NE 34.76


0.75 (0.55-1.02)P=0.0682


Afatinib Cis/Gem

25th, months 10.51 16.03


75th, months 35.55 NE


1.13 (0.56-2.26)P=0.7315


046

Time to CNS Progression; CNS Progression Rate

LL3 LL6Afatinib

(n=9) Cis/Pem

(n=5)Afatinib

(n=6) Cis/Gem

(n=5)

CNS progression rate (%) 45 33 22 28

Time to CNS progression, months (95% CI) 15.2 (7.7-29.0) 5.7 (6-8.2) 15.2 (3.8-23.7) 7.3 (3.7-10.9)


047

Tumour Response Rates in Patients With and Without Brain Metastases and Common EGFR Mutations in LUX-Lung 3 and 6

70%

95%

20%

80%

60%

95%

23%

79%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ORR DCR

75%

89%

28%

72%67%

92%

22%

77%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ORR DCR

LL3 LL6

Afatinib with BM

Cis/Pem with BM

Afatinib without BM

Cis/Pem without BM

Afatinib with BM

Cis/Gem with BM

Afatinib without BM

Cis/Gem without BM

Pat

ient

s (%

)

Pat

ient

s (%

)


048

Summary

• In combined analysis, PFS was significantly improved with afatinib versus chemotherapy in patients with brain metastases with a trend in both independent trials; no OS benefit was observed

• The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases

• Afatinib significantly improved ORR versus chemotherapy in patients with brain metastases

• Median time to CNS progression was longer with afatinib versus chemotherapy

Schuler M et al. Manuscript in press. 2015; Prior presentation Schuler M et al. Mini-oral presentation, World Conference on Lung Cancer 2013. Abstract MO07.13.

049

Management of Oligometastases in Patients With NSCLC

050

Oligometastases in NSCLC

• Oligometastases are as defined as at maximum five metastatic lesions in the body and can be either synchronous or metachronous1

• Common sites of extracranial oligometastases in NSCLC include adrenal gland, lung and bone2

– 33% of patients have adrenal and lung mets

• Represents an area of unmet need3

1. Reck M et al. Ann of Oncol. 2014;(suppl 3):iii27.2. NCCN guidelines V7.2015.3. Kavanagh BD. J Clin Oncol. 2014;32:2827.

051

NCCN Guideline for the Treatment of Oligometastases in Patients With NSCLC

• Definitive local therapy to isolated or limited metastatic sites (oligometastases) (including but not limited to brain, lung, and adrenal gland) may prolong OS in good performance patients receiving radical therapy to the intrathoracic disease

• Definitive radiotherapy to oligometastases, particularly stereotactic body radiation therapy (SBRT) is an appropriate option in such cases if it can be delivered safely to the involved sites

• Aggressive local therapy may be appropriate for selected patients with limited-site oligometastatic disease


052

ESMO Guideline for the Treatment of Oligometastases in Patients With NSCLC

• Stage IV NSCLC patients with 1 to 3 synchronousmetastases may experience long-term disease-free survival (DFS) after systemic therapy and a radical local treatment (high-dose radiotherapy or surgery)

• Stage IV patients with a few metachronous metastases may be treated with a radical local treatment and experience long-term DFS

• In general, consider including patients with oligometastases outside of the brain in trials

Reck M et al. Ann of Oncol. 2014;(suppl 3):iii27.

053

Ongoing and Planned Trials on the Treatment of Oligometastases in Patients With NSCLC

Trial Study Title Treatment 1° Endpoint Status

Phase 3NCT02417662

Stereotactic Ablative Radiotherapy for Oligometastatic Non-small Cell Lung Cancer (SARON)

Combination Radical Radiotherapy with standard chemotherapy vs chemotherapy

alone OS Not yet

recruiting

Phase 3NCT02076477

The Optimal Intervention Time of Radiotherapy for OligometastaticStage IV NSCLC (OITROLC)

Concurrent CRT→chemo vsChemo→concurrent CRT ORR Recruiting

Phase 2NCT02316002

Phase II Study of PembrolizumabAfter Curative Intent Treatment for Oligometastatic Non-Small Cell Lung Cancer

Pembrolizumab PFS Recruiting

Phase 2NCT01796288

The Value of Radiotherapy in the Oligometastatic Non-squamous Non-small Cell Lung Cancer With Clinical Benefits From Erlotinib as Second-line Treatment (ROLE)

Radiotherapy + erlotinib vs erlotinib PFS Recruiting

Phase 2NCT01725165

Local consolidation therapy (LCT) after induction chemotherapy LCT (RT, surgery, or both) vs no LCT PFS Recruiting

Phase 2NCT02054819

Induction chemotherapy with concurrent radiation

Induction chemo + concurrent RT→ consolidation RT OS Recruiting

Phase 2NCT01941654 Preemptive local ablative therapy Preemptive local ablative therapy PFS (1-yr) RecruitingPhase 2NCT01185639

SBRT with response or stable disease after 4 cycles 1st-line chemo

Stereotactic body radiation therapy (SBRT) PFS Recruiting

Pilot studyNCT02450591

Local Therapies for OligometastaticNon-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

Local therapies + erlotinib Safety Recruiting

Pilot studyNCT01781741

Stereotactic Body Radiation Therapy After Surgery in With or Without Minimal Invasive Surgery for Stage III-IV Non-small Cell Lung Cancer

TEMLA→SBRT Safety Recruiting

1. Available at: www.clinicaltrial.gov. Accessed September 02, 2015.

CRT = chemoradiation therapy; LCT = local consolidative therapy; TEMLA = Transcervical extended mediastinal lymphadenectomy

054

Summary and Conclusion

• Local therapies are standard-of-care in the treatment of patients with limited metastases

• Emerging data suggest that adding WBRT to SRS is associated with a decline in cognitive function compared with SRS alone in patients with <3 brain metastases (NCCTG N0574) and WBRT does not provide additional benefit when added to optimal supportive care and dexamethasome in patients ineligible for SRS (QUARTZ)

• The ErbB signaling pathway has been implicated in the development of brain metastases in patients with NSCLC as evidenced by overexpression and higher activity than in corresponding primary tumor

• EGFR-targeted TKIs appear to be active in patients with brain metastasis from NSCLC and are a valid option the treatment of patients with asymptomatic brain disease

• In a planned subgroup analysis, afatinib, an irreversible ErbB family blocker, demonstrated robust and comparable clinical activity in patients with or without brain metastases

• Local therapies are an option for patients with extra-cranial oligometastases.Treatmentof this disease is an area of unmet need and an active area of clinical research and development

management of brain metastases and oligometastases in non ... · management of brain metastases and...

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