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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