Management of Brain Metastases and Oligometastases in Non–Small Cell Lung Cancer (NSCLC) Terufumi Kato, MD Chief Physician Kanagawa Cardiovascular and Respiratory Center Yokohama, Japan
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
Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.
010
NCCTG N0574 Trial: Cognitive Progression at 3 Mo (Primary Endpoint)
Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.
013
NCCTG N0574 Trial: Intracranial Tumor Control
Time to intracranial progression
Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.
014
NCCTG N0574 Trial: OS
Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.
015
Conclusions
Brown PD et al. J Clin Oncol. 2015;33(suppl). Abstract LBA4.
• 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
Mulvenna PM et al. J Clin Oncol. 2015;33(suppl). Abstract 8005.
020
QALYS = quality adjusted life years
Mulvenna PM et al. J Clin Oncol. 2015;33(suppl). Abstract 8005.
QUARTZ Trial: Components of the Primary Outcome Measures (QALYS)
021
QUARTZ Trial: QALYS (Primary Outcome Measure)
Mulvenna PM et al. J Clin Oncol. 2015;33(suppl). Abstract 8005.
022
QUARTZ Trial: Conclusion
Mulvenna PM et al. J Clin Oncol. 2015;33(suppl). Abstract 8005.
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 Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015.
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)
PFS in overall population
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
AfatinibPemetrexed + Cisplatin
PFS in overall population
Afatinib Cis/Pem
Median, months 13.8 8.1
HR (95% CI)Log-rank P value
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
AfatinibGemcitabine + Cisplatin
3 6 9 12 15 18 21 24 27 30 33 36Time (months) Time (months)
PFS in overall population
Afatinib Cis/Gem
Median, months 8.2 4.7
HR (95% CI)Log-rank P value
0.47 (0.18-1.21)P=0.1060
PFS in overall population
Afatinib Cis/Gem
Median, months 11.1 5.6
HR (95% CI)Log-rank P value
0.22 (0.15-0.33)P<0.0001
Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.
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)
Median, months 8.2 5.4
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
Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.
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
AfatinibPemetrexed + Cisplatin
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
AfatinibPemetrexed + Cisplatin
AfatinibGemcitabine + Cisplatin
AfatinibGemcitabine + Cisplatin
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)
PFS in overall population
Afatinib Cis/Pem
25th, months 16.36 14.23
Median, months 19.78 33.22
75th, months 41.66 NE
HR (95% CI)Log-rank P value
1.15 (0.49-2.67)P=0.7517
PFS in overall population
Afatinib Cis/Pem
25th, months 19.65 15.31
Median, months 33.64 28.16
75th, months NE 43.17
HR (95% CI)Log-rank P value
0.71 (0.50-1.00)P=0.0510
PFS in overall population
Afatinib Cis/Gem
25th, months 15.05 11.79
Median, months 23.56 20.04
75th, months NE 34.76
HR (95% CI)Log-rank P value
0.75 (0.55-1.02)P=0.0682
PFS in overall population
Afatinib Cis/Gem
25th, months 10.51 16.03
Median, months 22.44 24.74
75th, months 35.55 NE
HR (95% CI)Log-rank P value
1.13 (0.56-2.26)P=0.7315
Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.
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)
Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.
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 (%
)
Schuler et al. Manuscript in press. 2015; Schuler et al. World Conference on Lung Cancer 2013. Abstract MO07.13.
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
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015.
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
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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