Maintenance Therapy for Lung Cancers: Get Off to the Right...
Transcript of Maintenance Therapy for Lung Cancers: Get Off to the Right...
Maintenance Therapy for Lung
Cancers: Get Off to the Right Start
and Stick With a Winner
Mark G Kris, MD
The William and Joy Ruane Chair in Thoracic Oncology
Member and Attending Physician
Memorial Sloan-Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, NY
Maintenance Therapy for Lung Cancers: Stick with a Winner
Disclosures
Consultant/Trial Support: Pfizer, Genentech/Roche, Novartis,
Clovis, Ariad
Stock/Royalties: None
Mark G. Kris, MD Maria C. Pietanza, MD Gregory J. Riely, MD, PhD Naiyer A. Rizvi, MD
Marjorie Zauderer, MD Alexander E. Drilon, MD
Helena A. Yu, MD
Stephen Veach, MD
Kenneth Ng, MD John Fiore, MD
Stephanie
Smith-Marrone, MD Afsheen Iqbal, MD
Lee M. Krug, MD
Paul K. Paik, MD Jamie Chaft, MD
Charles Rudin, MD, PhD Service Chief
Stefan Berger, MD Michael Fannuchi, MD
Memorial Sloan-Kettering Thoracic Oncology Service
Maintenance Therapy for Lung Cancers: Stick with a Winner
Introduction
• Make the right choice on day 1
• What drugs to continue
• What drugs to stop and when to do it
• Role of maintenance in personalizing care
NSCLCs Chemotherapy 1975-2013
No Chemotherapy 0% 10% 0%
Single Agent 15% 20% 10%
Two Drugs 25% 35% 20%
Three Drugs 35% 35%
20%
Two Drugs plus Cetuximab 36% 47% 20%
Two Drugs plus Bevacizumab 35% 51% 23%
Erlotinib with EGFR
Exon 19/21 Mutation 67% 90% 60%
Crizotinib with ALK
Rearrangement 57% 81% 61%
Response Rate 1 Year Survival 2 Year Survival
Lung Cancers
Memorial Sloan-Kettering 2000-2010
Squamous Cell Carcinomas
20%
Carcinoids 4%
Large Cell Neuroendocrine
Carcinomas 1% Small Cell Lung
Cancers 13%
Adenocarcinomas
60%
Large Cell
Carcinomas
2%
(N=14,418)
1% of Adenocarcinomas
Represents 1357 Cases
Annually in the USA
LCMC: Frequency of Oncogenic Drivers
733 Specimens with All 10 Drivers Assayed
NCCN Guidelines for NSCLCs:
Selection of Initial Chemotherapy
Agents by Histologic Type
Agent Adenocarcinoma Squamous
Cell
Small
Cell
Pemetrexed
Gemcitabine
Bevacizumab
Docetaxel
Cisplatin
Etoposide
Fossella J Clin Oncol 2003
Sandler NEJM 2006
Scagliotti J Clin Oncol 2008
Bevacizumab Works
A pearl in the SATURN and ATLAS oysters
Trial Initial Treatment Entered
(Randomized)
“Non-PD” After
4 Initial Cycles
SATURN
(Cappuzzo)
4 Cycles of First-Line
Platinum-Based
Doublet
1949
(889)
46%
P=0.0001
(Fishers Exact)
ATLAS
(Miller)
Bevacizumab plus
4 Cycles of First-Line
Platinum-Based
Doublet
1160
(768)
66%
11/6/2013 template 12 Cappuzzo et al and Miller et al Proc ASCO 2009
1. Roche, data on file; 2. Miller, et al. ASCO 2009
3. Reck, et al. Ann Oncol 2010; 4. Barlesi, et al. EMCC 2011
5. Patel, et al. IASLC 2012 (Chicago); 6. Belani, et al. ASCO 2010
7. Fidias, et al. J Clin Oncol 2009; 8. Paz-Ares, et al. Lancet Oncol 2012
How many patients with lung cancers get to
maintenance?
Bevacizumab + carboplatin/paclitaxel 66% E45991
Bevacizumab + platinum doublet (no pemetrexed) 66% ATLAS2
Bevacizumab + pemetrexed/cisplatin 67% AVAPERL4
Carboplatin/paclitaxel 52% E4599 control arm1
Gem/Carbo 53% Doc maintenance7
Pemetrexed/cisplatin 57% PARAMOUNT (S124)8
Bevacizumab + cisplatin/gemcitabine 64% AVAiL‡3
Cisplatin/gemcitabine 59% AVAiL control arm3
Gem/Carbo 49% Gem maintenance6
Bevacizumab + carboplatin/pemetrexed 66% POINTBREAK5
Bevacizumab + carboplatin/paclitaxel 67% POINTBREAK5
Sandler J Thorac Oncol 2010;4:1416
Adding Bevacizumab to Chemotherapy Patients with Lung Adenocarcinoma
Duration of Therapy Trials in NSCLCs: More Initial Cycles,
Continue Initial Agents, Add Agent Without Progression
Author, Year Median
Survival
“Shorter”
Median
Survival
“Longer”
Change
With
“Longer”
Duration of Initial Rx Smith, 2001 6 7 +1 month
Socinski, 2002 7 9 +2 months
Von Plessen,2006 7 8 +1 month
Park, 2007 16 15 -1 month
Barata, 2007 7 12 +5 months
Maintenance Westeel, 2005 12 12 0 month
Belani, 2003 15 19 +4 months
Brodowicz, 2006 8 10 +2 months
Add New Agent Fidias, 2007 9 12 +3 months
Without Progression Ciuleanu, 2008 10 13 +3 months
Stinchcombe and Socinski JTO 2009
Duration of chemotherapy treatment: Meta-analysis of 13 trials
No. of patients Hazard Ratio
(95% CI) P-value
Progression
Free
Survival
2570 0.75 (0.69–0.81) <0.00001
Overall
Survival 3079 0.92 (0.86–0.99) 0.03
Soon J Clin Oncol 2009
Two Sides of Maintenance
Continuation vs Switch to a New Agent
Continuation to Progression or
Toxicity
Switch to a New Agent
Bevacizumab Pemetrexed
Pemetrexed Docetaxel
Afatinib/Erlotinib/Gefitinib Erlotinib
Crizotinib
Gemcitabine
*Data supports continuation even after progression of disease by RECIST
Riely Clin Cancer Res 2008, Chmielecki Science Trans Medicine 2011
Continuation Maintenance
The Ultimate Targeted Therapy
Therapy only to the right patient
Demonstrated objective benefit
Proven subjective benefit
Tolerance assured
11/6/2013 18
PARAMOUNT: Study Design
Induction Therapy 4 cycles, q21d
Continuation Maintenance Therapy q21d until PD
Pemetrexed
Placebo
Pemetrexed
+ Cisplatin
CR/PR/SD per RECIST
R 2:1
Randomized, placebo-controlled, double-blind phase III study
Pemetrexed 500 mg/m2; Cisplatin 75 mg/m2
Folic acid and vitamin B12 administered to both arms
• Untreated
• PS 0/1
• Stage IIIB-IV
NS-NSCLCs
PARAMOUNT: Overall Survival from Randomization
Patients at Risk
Pemetrexed 359 333 272 235 200 166 138 105 79 43 15 2 0
Placebo 180 169 131 103 78 65 49 35 23 12 8 3 0
Time from Randomization (Months)
0 3 6 9 12 15 18 21 24 27 30 33 36
Su
rviv
al
Pro
bab
ilit
y
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pem Placebo
OS Median (mo)
(95% CI)
14
(12.8-16.0)
11
(10.0-12.5)
Alive (%) 29 22
Survival Rate (%) (95% CI)
1-year 58 (53-63) 45 (38-53)
2-year 32 (27-37) 21 (15-28)
Log-rank P = 0.0195
Unadjusted HR: 0.78
(95% CI: 0.64–0.96)
PARAMOUNT: Overall Survival from Induction S
urv
ival
Pro
bab
ilit
y
Time from Induction (Months)
0 3 6 9 12 15 18 21 24 27 30 33 36
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pemetrexed
Median OS =17 months (95% CI: 15.8–19.0)
Placebo
Median OS =14 months (95% CI: 12.9–15.5)
Log-rank P=0.0191
HR=0.78 (95% CI: 0.64–0.96)
Patients at Risk
Pemetrexed 359 335 276 234 200 164 138 106 77 42 15 2 0
Placebo 180 168 132 103 78 63 49 35 23 12 8 3 0
ASCO 2010 Abstract 7507 – Perol
Continuation and Switch Maintenance
ASCO 2010 Abstract 7507 – Perol
Switch Maintenance: Erlotinib
ASCO 2010 Abstract 7507 – Perol
Continuation Maintenance: Gemcitabine
Phase III Trial of Bevacizumab
in Lung Adenocarcinoma: ECOG 4599
Paclitaxel 200 mg/m2
Carboplatin AUC = 6
(q 3 weeks) x 6 cycles
Paclitaxel 200 mg/m2
Carboplatin AUC = 6
(q 3 weeks) x 6 cycles
+
Bevacizumab
(15mg/kg q 3 wks)
Continue to Progression
Eligibility:
• No squamous
• No hemoptysis
• No CNS metastases
Stratification Variables:
• RT vs no RT
• Stage IIIB or IV vs recurrent
• Wt loss <5% vs >5%
• Measurable vs non-measurable
Sandler A, et al. New Engl J Med 2006;355(24):2542-2550
ECOG 4599 Phase III Trial of Chemotherapy +/-
Bevacizumab in NSCLC
Carboplatin
-plus-Paclitaxel
Only
Bevacizumab
15 mg/kg
+ Carboplatin
–plus- Paclitaxel
p
Entered 444 434
CR/PR Rate 15% 35% <0.0001
1 Yr Survival 44% 52%
Median Survival 10.2 months 12.5 months 0.007
• Randomized phase III trial in 878 patients – JUL 01- APR 04
• No prior therapy for stage IIIB/IV lung adenocarcinoma
Sandler NEJM 2006
PEM+CBP+BEV---PEM+BEV vs
PTX+CBP+BEV---BEV
PEM+CBP+BEV
---BEV+ PEM
PTX+CBP+BEV---
BEV
Entered 472 467
Median Overall Survival-1° Endpoint 13 mo 13 mo
Median Progression Free Survival 6 mo 6 mo
CR+PR Rate 34% 33%
Maintenance Overall Survival 18 mo 16 mo
Maintenance Progression Free Survival 9 mo 7 mo
Discontinuations due to AEs 3% 3%
Drug-Related Deaths 2% 2%
Patel J Clin Oncol 2012; 7(Suppl 4):S336
28
AVAPERL: Trial design
Barlesi Proc ESMO 2011
Previously
untreated
stage IIIB–IV
nsNSCLC
Arm A:
bevacizumab
Arm B:
bevacizumab +
pemetrexed
Bevacizumabb
+ pemetrexedb
+ cisplatinb
CR/PR/SD
per RECISTc
First-line induction
4 cycles, q3w
R
PD
Continuation maintenance
q3w until PD
Follow-up
29
AVAPERL
PFS from induction (1°Endpoint) Bev+pem 10.2 months (81 events)
Bev 6.6 months (104 events)
HR, 0.50 (0.37–0.69); P <.001
Pro
gre
ss
ion
-fr
ee
su
rviv
al (%
)
Time (months)
128 126 103 66 25 4 0
125 122 73 38 12 2 0
100
75
50
25
0
0 3 6 9 12 15 18
Pts at risk Bev+pem
Bev
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)
30
AVAPERL
Overall Survival from induction O
ve
rall
su
rviv
al (%
of p
atie
nts
)
100
75
50
25
0
0 3 6 9 12 15 18 21
128 127 120 103 56 20 3 0
125 123 110 96 45 17 2 0
Time (months)
Bev+pem NR (34 events)
Bev 15.7 months (42 events)
HR, 0.75 (0.47–1.20); P=0.23
Pts at risk Bev+pem
Bev
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)
“Switch Maintenance” Trials
Overall Survival Trial N Agent Median
Survival
“Control”
Median
Survival
“Agent
Added”
Survival
Benefit With
“Agent
Added”
Ciuleanu - All 633 pemetrexed 10.6 mo 13.4 mo +2.8 mo
(p=0.01)
Ciuleanu - AdenoCa 328 pemetrexed 11.5 mo 16.8 mo +5.3 mo
(p=0.03)
Fidias 566 docetaxel 9.7 mo 12.3 mo +2.6 mo
(p=0.08)
Cappuzzo 889 erlotinib 11 mo 12 mo +1 mo
(p=0.01)
Miller 743 erlotinib NR NR NR
NS
Results in EGFR mutation positive and negative
patients ( All Asian, 94% Never Smokers)
EGFR mutation positive EGFR mutation negative
HR (95% CI) = 0.48 (0.36, 0.64)
p<0.0001
No. events gefitinib: 97
No. events Chemo: 111
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)
HR (95% CI) = 2.85 (2.05, 3.98)
p<0.0001
No. events gefitinib: 88
No. events Chemo: 70
132 71 31 11 3 0 129 37 7 2 1 0
108 103
0 4 8 12 16 20 24
Gefitinib C / P
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f p
rog
ressio
n-f
ree s
urv
ival
At risk : 91 4 2 1 0 0 85 14 1 0 0 0
21 58
0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f p
rog
ressio
n-f
ree s
urv
ival
Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)
Months Months
Gefitinib CR/PR Rate 71%
CBP/PTX CR/PR Rate 47%
Gefitinib CR/PR Rate 1%
CBP/PTX CR/PR Rate 24%
Changes in FDG-PET SUVmax after discontinuation at
RECIST PD and re-introduction of EGFR TKI
-50%
0%
50%
100%
EGFR TKI stop re-start
3 weeks 3 weeks
20%
Ch
an
ge
fro
m b
ase
lin
e
Median Change in SUVmax +23% -11%
RECIST
PD
Disease “flare” post-TKI in EGFR-
mutant lung cancers with AR
• Pts with EGFR- mutant cancers on trials for treatment of AR
• “Flare” defined as hospitalization or death during TKI washout (7-21
days)
• 14 of 61 pts (23%, 95% CI 14-35%) experienced a flare
• Median time to flare was 8 days (range 3-21)
• Characteristics associated with flare:
– Shorter TTP on TKI (Median 9 vs 15 mo, p=0.002)
– Pleural disease (p=0.02) or CNS disease (p=0.01)
• Flare was not associated with T790M, type EGFR mutation, or prior
cytotoxic chemotherapy
Chaft Clin Cancer Res 2011
RECIST Criteria for Progression
A Signal to Stop the EGFR TKI?
EGFR TKI
1cm 5cm 1.3cm
EGFR TKI
EGFR TKI
Resistance
by RECIST
Stop
EGFR TKI?
Mok IASLC Santa Monica 2011
Local Therapy Outcomes
• The median time to progression after local therapy was 10 months (95% CI: 2-27).
• The median time from local therapy until a change in systemic therapy was 22 months (95%CI: 6 - 30).
• The median overall survival from local therapy was 41 months (95% CI: 26-not reached).
0 12 24 36 480
20
40
60
80
100
0 12 24 36 48 600
20
40
60
80
100
Time to Progression
Overall Survival
% P
rogr
essi
on
-fre
e %
Su
rviv
al
Time (months)
Time (months)
Yu, J Thorac Oncol 2012
Maemondo, NEJM 2010
Maintenance Therapy for Lung Cancers: Stick with a Winner
Conclusions
• Maintenance chemotherapy (a. k. a. continuing
successful drugs)
– Improves survival. Period
– The ultimate targeted therapy
– Results better than erlotinib for EGFR WT
• Continue bevacizumab until progression
• Continue erlotinib/gefitinib/afatinib and crizotinib (likely
all targeted therapies) until progression……and beyond
Efficacy Outcomes by Treatment Group in ECOG 4599
Patients Progression Free After 6 Cycles
CP nonprogressors
(n=134)
Bev maintenance
(n=217)
Median postinduction PFS, mo
3 4
p<.001
Median PFS, mo 7 9
Median postinduction OS, mo
11 13
p=0.03
Median Overall Survival, mo 16 17
1-year PFS rate, % (95% CI) 17 (11–25) 32 (26–39)
1-year OS rate, % (95% CI) 69 (61–77) 75 (69–81)
2-year OS rate, % (95% CI) 25 (18–34) 34 (28–42)
Sandler Proc IASLC 2011
ECOG 4599
Postinduction progression-free survival
Sandler Proc IASLC 2011
ECOG 4599
Postinduction overall survival
Sandler Proc IASLC 2011