Chandra P Belani, MD Deputy Director Penn State Cancer Institute
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Transcript of Chandra P Belani, MD Deputy Director Penn State Cancer Institute
Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw,
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Chandra P Belani, MD
Deputy Director
Penn State Cancer Institute
Miriam Beckner Distinguished Professor of Medicine
Penn State College of Medicine
Maintenance Therapy for Advanced NSCLC(SWITCH vs CONTINUATION)
Use of systemic therapy following first-line treatment before progression
To be considered for patients with CR/PR or stable disease
Also referred to as ‘consolidation’ (but not ‘early second-line’ therapy)
What Is Maintenance Therapy?
Continuing one of the same agents from the original combination (“CONTINUATION”)• Cisplatin and pemetrexed followed by
pemetrexed as maintenance Continuation of a targeted agent
• Carboplatin, paclitaxel and bevacizumab followed by bevacizumab
Initiating a new agent (“SWITCH”)• Carboplatin and paclitaxel followed by
pemetrexed
Maintenance Therapy: Strategies
Advanced non-squamous cell cancer patients whose disease is stable or responding to first-line chemotherapy should generally be offered maintenance pemetrexed
Absolutely agree, provided they do not have • Evidence of EGFR mutation• Declining PS
Maintenance Therapy
Is there an improvement in
survival?
Is the treatment tolerated well?
Are patient selection methods
available?
Key Questions
Stage IIIB/IV NSCLCPS 0-14 prior cycles of gem,
doc, or tax + cis or carb, with CR, PR, or SD
Randomization factors: genderPSstagebest tumor response to
inductionnon-platinum induction
drugbrain mets
Pemetrexed 500 mg/m2 (d1, q21d) + BSC (N = 441)*
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC (N = 222)*
*B12, folate, and dexamethasone given in both arms
2:1Randomization
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
Phase III Trial of Maintenance Pemetrexed in Advanced NSCLC
Ciuleanu…Belani, Lancet 374(9699):1432-40, 2009Belani et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 7506)
Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Advanced
NSCLC
Ciuleanu…Belani, Lancet 374(9699):1432-40, 2009Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)
Pemetrexed Placebo HR (95% CI)
p-value
OS, non-squamous(n = 481)
15.5 mo 10.3 mo 0.70 (0.56-0.88) 0.002
OS, squamous(n = 182)
9.9 mo 10.8 mo 1.07 (0.49-1.73) 0.678
Effect of Response to Induction on OS in JMEN
Ciuleanu…Belani, Lancet 374(9699):1432-40, 2009Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)
Pemetrexed Placebo HR (95% CI) p-value
OS, nonsquamous pts with CR/PR
14.4 mo 11.7 mo 0.81 (0.58, 1.12) 0.19854
OS, nonsquamous pts with SD
16.6 mo 8.6 mo 0.61 (0.45, 0.83) 0.00171
Primary endpoint dependent review with 80% power to detect 50% improvement in median PFS: PFS by or each comparison (Gem vs Obs and Erl vs Obs)
Secondary endpoints: OS, safety, symptom control, prognostic and predictive effect of tumor EGFR status (IHC, EGFR mut)
Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507)
IFCT-GFPC 0502: Study Design
Patients who received 2nd-line pemetrexed: 73% (Obs), 55% (Gem), and 60% (Erl)
Grade 3-4 treatment-related AEs were more common in Gem (27%) andErl (14%) than in Obs (2%)
Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507)
IFCT-GFPC 0502: Results
Observation N = 152
Gemcitabine N = 149
Median PFS, mo
1.9 3.8
PFS at 3 mo, %
30.3 55.0
PFS at 6 mo, %
8.6 22.1
PFS by independent review, gemcitabine versus observation
HR = 0.55 (0.43-0.70)Log-rank test, p < 0.0001
Observation
N = 152 Erlotinib N = 153
Median PFS, mo
1.9 2.9
PFS at 3 mo, %
30.3 35.3
PFS at 6 mo, %
8.6 16.3
PFS by independent review, erlotinib versus observation
HR = 0.82 (0.73-0.93)Log-rank test, p = 0.002
1:1Chemonaïve
advanced NSCLC
n = 1,949
4 cycles of first-line platinum doublet
chemotherapy* Placebo PD
Erlotinib150 mg/day
PD
Mandatory tumor sampling
Stratification Factors:• EGFR IHC (positive vs negative vs
indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs
others)• Smoking history (current vs former vs
never)• Region
Co-Primary Endpoints:
• PFS in all patients
• PFS in patients with EGFR IHC+ tumors
Secondary Endpoints:
• OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC– tumors; biomarker analyses; safety; time to symptom progression; QoL
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel
SATURN Study Design
Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010
Non-PDn = 889(46%)
*OS is measured from time of randomization into the maintenance phase;ITT = intent-to-treat population
SATURN Survival* All Patients (ITT)
Cappuzzo et al, Lancet Oncol, 11(6):521-9, 2010
OS probability
• Erlotinib (n = 438), 12.0 months
• Placebo (n = 451), 11.0 months
• HR = 0.81 (0.70-0.95)
• Log-rank p = 0.0088
Brugger et al. J Clin Oncol 2009; 27(suppl):411s (abstract 8020).
Number of PatientsHazard Ratio p-value
Erlotinib Placebo
EGFR Mutation+a 22 27 0.10 <.0001
EGFR Wild Type
199 189 0.78 .0185
EGFR IHC+ 307 311 0.69 <.0001
EGFR IHC– 62 59 0.77 .01768
EGFR FISH+ 121 110 0.68 .0068
EGFR FISH– 128 127 0.81 .13
KRAS Mutation+ 49 41 0.77 .2246
KRAS Wild Type
205 198 0.70 .0009a Median PFS was 44.6 weeks in the erlotinib arm and 13.0 weeks in the placebo arm.
Biomarker Analyses of the Phase III SATURN Trial: Progression-Free Survival Benefit
Fidias JCO 27:591Ciuleanu, Belani Lancet 374:1432Cappuzzo Lancet Oncol 11:521Belani ASCO 2010 #7506Perol ASCO 2010 #7507
Fidias Belani Cappuzzo Belani Perol
Immed vs Delayed
Doc(n = 309)
Pem vs Placebo
(n = 663)
Erlot vsPlacebo*
Gem vs Placebo
(n = 255)
Gem vs Placebo
(n = 301)
Erlot vs Placebo
(n = 305)
Type Switch Switch Switch Cont Cont Switch
Median OS, months
12.3 vs 9.7
p = .0853
13.4 vs 10.6p = .012
12.0 vs 11.0
p = .0088
8.0 vs 9.3p = .838
HR 0.86 HR 0.91
Median PFS, months
5.7 vs 2.7p = .0001
4.3 vs 2.6p < .0001
2.8 vs 2.6†
p < .00017.4 vs 7.7p = .575
3.8 vs 1.9p < .0001
2.9 vs 1.9p = .002
*n = 884 for PFS; n = 889 for OS†12.3 weeks vs 11.1 weeks
Recent Trials of Maintenance Therapy: Efficacy
Bevacizumab– Was administered beyond
chemotherapy in ECOG 4599 and AVAiL studies?
Cetuximab– Was given as monotherapy following
combination therapy in FLEX and BMS-099 study?
CONTINUATION Maintenance Therapy
Is this definitive evidence of maintenance?
NO
Randomized, placebo-controlled, double-blind, phase III study
Folic acid and vitamin B12 administered to both arms
Primary objective: Progression Free Survival (PFS)
Study Treatment Period
ProgressionInduction Therapy (4 cycles) Maintenance Therapy (Until PD)21 to 42 Days
500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d
CR, PR, SD
PD
Placebo + BSC, d1, q21d
500 mg/m2 Pemetrexed + BSC, d1, q21d
2:1 Randomization
Patients enrolled if:Nonsquamous NSCLCNo prior systemic treatment for lung cancerECOG PS 0/1
Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to inductionResponse to induction (CR/PR vs SD)
Paz Ares, ASCO 2011, #7510
PARAMOUNT: Study Design
Paz-Ares et al, J Clin Oncol 29:15s, 2011 (suppl; abstr CRA7510)
PARAMOUNT: Independently Reviewed PFS
Pem + BSC (n = 316)
Placebo + BSC (n = 156)
Median PFS* (months)
3.9 2.6
Hazard ratio: 0.64, p = 0.0002
* 88% of patients were independently reviewed (472/539).
PFS results were internally consistent; benefit was seen across all subgroups
PARAMOUNT: Subgroup PFS Hazard Ratios
Paz-Ares et al, J Clin Oncol 29:15s, 2011 (suppl; abstr CRA7510)
Stage IIIB/IV Bev eligible NSCLC
PS 0-1 4 prior cycles of
CarbTax + Bev (1236), with CR, PR, SD (864)
Randomization factors: gender PS stage best tumor response
to induction
Pemetrexed 500 mg/m2 (q21d)
Primary Endpoint = OS
B12, folate, and dexamethasone given in Pem arms
ECOG 5508 Phase III Study DesignMaintenance Bev vs Pem vs Bev + Pem
RANDOMIZE
Bevacizumab 15mg/kg (q21d)
Pemetrexed 500 mg/m2 (q21d)Bevacizumab 15mg/kg (q21d)
Total 1236 patients with 864 randomized (288/arm)
Approximately 45% of eligible patients are receiving maintenance therapy in the US---# is increasing
Patients with PS ≥2 are not candidates for maintenance
Even on close follow-up on a clinical trial approximately 30-40% of patients are unable to receive second-line therapy, eg, PS 2 patients
Increasing the cycle duration to 4 weeks in certain patients will lead to increased acceptance
The next step is to personalize maintenance therapy
Maintenance Therapy US View
Saturday, February 11, 2012Hollywood, Florida
Faculty
Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD
Co-Chair and ModeratorNeil Love, MD
Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD
Thomas J Lynch Jr, MDHeather Wakelee, MD