Overall survival (OS) results from PARAMOUNT study of maintenance Pemetrexed plus best

supportive care (BSC) versus Placebo plus BSC, immediately after induction with Pemetrexed-

Cisplatin, in patients with advanced Nonsquamous Non-small Cell Lung Cancer (NS-NSCLC)

J. Corral1, 2 L. Paz-Ares1, 2, F. De Marinis3, M. Dediu4, M. Thomas5, J. L. Pujol6, P. Bidoli7, O. Molinier8, T. P. Sahoo9, C. Gridelli10 et al*

1Instituto de Biomedicina de Sevilla, 2University Hospital Virgen del Rocío, Seville, Spain; 3San Camillo–Forlanini Hospital,

Rome, Italy; 4Institute of Oncology Bucharest, Bucharest, Romania; 5Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 6Montpellier CHRU Academic Hospital, Montpellier, France; 7Medical Oncology Unit, S. Gerardo Hospital, Monza,

Italy; 8Le Mans Regional Hospital, Le Mans, France; 9Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal, India; 10San Giuseppe Moscati Hospital, Avellino, Italy

*M. Reck (Hospital Grosshansdorf, Grosshansdorf, Germany), E. Laack (University Medical Center Hamburg-Eppendorf, Hamburg, Germany) , S. A. Melemed, W. J. John, A. Zimmermann (Eli Lilly and Company, Indianapolis, IN, USA), N. Chouaki (Eli Lilly and Company, Suresnes, Hauts de Seine, France), and C. M. Visseren-Grul (Eli Lilly and Company,

Houten, The Netherlands) have participated as co-authors.

Background

Most patients have stage IIIB/IV NSCLC when diagnosed1

Platinum-based combinations are recommended for first-line

treatment2

Pemetrexed has demonstrated efficacy in advanced non-

squamous NSCLC (NS-NSCLC):

─ in combination with cisplatin as first-line doublet3

─ as maintenance agent following non-pemetrexed platinum doublet4

PARAMOUNT evaluated pemetrexed maintenance after

pemetrexed + cisplatin induction:

─ Primary endpoint was met: pemetrexed reduced risk of disease

progression over placebo (HR: 0.62 [0.49-0.79], Wald P<0.0001) 5

─ Final survival analysis occurred after ≥390 deaths;

log-rank test compared OS between arms, with α level of 0.0498

1 http://seer.cancer.gov/statfacts/html/lungb.html; 2Azzoli CG et al. J Clin Oncol. 2009; 3Scagliotti GV et al. J Clin Oncol. 2008; 4Ciuleanu T et al. Lancet 2009; 5Paz-Ares L et al. Lancet Oncol. 2012.

PARAMOUNT: Study Design

Induction Therapy 4 cycles, q21d

Continuation Maintenance Therapy q21d until PD

Pemetrexed + BSC

Placebo + BSC

Pemetrexed

+ Cisplatin

CR/PR/SD per

RECIST

R 2:1

Stratified for:

• PS (0 vs 1)

• Disease stage (IIIB vs IV) prior to induction

• Response to induction (CR/PR vs SD)

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

• Previously

untreated

• PS 0/1

• Stage IIIB-IV

NS-NSCLC

400 Patients Not Randomized 217 Progressive Disease

62 Adverse Event 56 Death 29 Study Disease 15 AE 11 Drug-Related AE 1 Procedure-Related AE 65 Other Reasons

1022 Patients Screened

939 Patients Enrolled

539 Patients Randomized (2:1 Randomization)

Pemetrexed Arm N=359

Placebo Arm N=180

83 Patients Failed Screening

Induction Phase

Maintenance Phase

256 (71%) Pts with events at data cut off 350 (97%) Pts discontinued treatment

141 (78%) Pts with events at data cut off 178 (99%) Pts discontinued treatment

PARAMOUNT: Patient Disposition

548 Patients Eligible for Maint 8 Discontinued Pt Decision 1 Discontinued Phys Decision

OS Endpoint

PARAMOUNT: Patient Characteristics

*Protocol violations.

Pemetrexed

(N=359)

Placebo

(N=180)

Age

Median Age, yrs 61 62

< 65 yrs, % 66 62

Male, % 56 62

Caucasian, % 94 95

Smoker, %

Ever Smoker 76 80

Never Smoker 23 19

ECOG PS, %

0 32 33

1 68 66

2/3* 0.3 1

PARAMOUNT: Disease Characteristics

Pemetrexed

(N=359)

%

Placebo

(N=180)

%

Disease stage IV* 91 90

Histology

Adenocarcinoma 86 89

Large cell 7 7

Other Nonsquamous 7 4

Induction Response

CR/PR 44 42

SD 53 53

PD/Unknown† 3 6

* TNM Staging System for Lung Cancer, 5th edition. † Protocol violations.

PARAMOUNT: Drug Administration

Maintenance Phase Pemetrexed

(N=359)

Placebo

(N=180)

Patients Treated* 357 178

Number of Cycles/Patient

Median 4 4

Range 1–44 1–38

Mean 7.9 5.0

Patients Completing > 6 Cycles 37% 18%

Dose Intensity of Planned

Mean Dose 93.7% NA

Median Follow-up, months (95% CI)

For all Patients 12.5 (11.1–13.7)

For all Alive Patients 24.3 (23.2–25.1)

*Two patients on each arm were randomized but did not receive treatment.

PARAMOUNT: Patient Discontinuation

Reasons for Discontinuation

Pemetrexed

(N=359)

%

Placebo

(N=180)

%

Progressive Disease 69 84

Adverse Event 18 7

Subject Decision 6 4

Investigator Decision 1 1

Death 2 2

Study Disease 0.8 0.6

Adverse Event/Toxicity 1 2

PARAMOUNT: Final OS from Randomization

Patients at Risk

Pem + BSC 359 333 272 235 200 166 138 105 79 43 15 2 0

Placebo + BSC 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)

13.9

(12.8-16.0)

11.0

(10.0-12.5)

Censoring (%) 28.7 21.7

Survival Rate (%) (95% CI)

1-year 58 (53-63) 45 (38-53)

2-year 32 (27-37) 21 (15-28)

Pemetrexed

Placebo

Log-rank P = 0.0195

Unadjusted HR: 0.78

(95% CI: 0.64–0.96)

PARAMOUNT: Final OS 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 =16.9 mos (95% CI: 15.8–19.0)

Placebo

Median OS =14.0 mos (95% CI: 12.9–15.5)

Log-rank P=0.0191

HR=0.78 (95% CI: 0.64–0.96)

Patients at Risk

Pem + BSC 359 335 276 234 200 164 138 106 77 42 15 2 0

Placebo + BSC 180 168 132 103 78 63 49 35 23 12 8 3 0

Favors Pemetrexed Favors Placebo

Hazard Ratio

0.78

0.79

0.82

0.81

0.76

0.82

0.70

0.75

0.83

0.82

0.73

0.75

0.89

0.82

0.71

0.81

0.44

0.80

Treatment Hazard Ratio (95% CI)

0.0 0.5 1.0 1.5 2.0 2.5

Adenocarcinoma (n=471)

Large Cell Carcinoma (n=36)

Other Histologic Diagnosis (n=32)

Age 65 (n=189)

Age < 65 (n=350)

Age 70 (n=92)

Age < 70 (n=447)

Female (n=226)

Male (n=313)

Smoker (n=418)

Non-smoker (n=117)

Pre-randomization ECOG PS 0 (n=173)

Pre-randomization ECOG PS 1 (n=363)

Induction Response SD (n=285)

Induction Response CR/PR (n=234)

Stage IIIB (n=49)

Stage IV (n=490)

All Randomized Patients (N=539)

PARAMOUNT: Subgroup OS Hazard Ratios

♦ The survival results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: Induction Response Subgroups OS Hazard Ratios

♦ The survival results were consistent across both induction response subgroups

CR/PR HR = 0.81

SD HR = 0.76

Time from Randomization (Months)

Su

rviv

al p

rob

ab

ility

S

urv

iva

l p

rob

ab

ility

0 9 18 27 36

0 9 18 27 36 0.70

0.75

0.83

0.82

0.73

0.75

0.89

0.82

0.71

0.81

0.44

0.80

0.0 0.5 1.0 1.5 2.0

All Randomized Patients (N=539)

Stage IV (n=490)

Stage IIIB (n=49)

Induction Response CR/PR (n=234)

Induction Response SD (n=285)

Pre-randomization ECOG PS 1 (n=363)

Pre-randomization ECOG PS 0 (n=173)

Non-smoker (n=117)

Smoker )n=418)

Male (n=313)

Female (n=226)

Age < 70 (n=447)

Age > 70 (n=92)

Age < 65 (n=350)

Age > 65 (n=189(

Other Histologic Diagnosis (n=32)

Large Cell Carcinoma (n=36)

Adenocarcinoma (n=471)

0.78

0.79

0.82

0.81

0.76

0.82

Hazard Ratio

Treatment Hazard Ratio (95%% CI)

Favors Pemetrexed Favors Placebo

Time (Months)

0 3 6 9 12 15

Su

rviv

al P

rob

ab

ilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS: Primary Efficacy Endpoint

Pemetrexed

Placebo

Unadjusted HR: 0.62 (0.49-0.79)

Patients at Risk

Pem + BSC 359 132 57 21 4 0

Plac+ BSC 180 52 15 5 0 0

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS: Reassessed at Time of Final OS

Pemetrexed

Placebo

Unadjusted HR: 0.60 (0.50-0.73)

Su

rviv

al

Pro

ba

bil

ity

Time (Months)

Patients at Risk

Pem +BSC 359 215 139 97 67 47 32 22 16 10 5 0

Plac + BSC 180 75 33 16 9 7 6 4 2 0 0 0

PARAMOUNT: PFS from Randomization

PARAMOUNT: Post-discontinuation Therapy

Pemetrexed

(N=359)

%*

Placebo

(N=180)

%*

Patients Receiving Post

Discontinuation Therapy 64 72

Erlotinib 40 43

Docetaxel† 32 43

Gemcitabine 10 8

Vinorelbine 8 6

Investigational drug 6 4

Carboplatin 5 4

Paclitaxel 3 3

Pemetrexed 2 4

Cisplatin 1 2 *Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm

are shown. †Only docetaxel usage differed significantly between arms (P=0.013).

PARAMOUNT: Possible Drug-related CTCAEs*

Pemetrexed (N=359) Placebo (N=180)

Grade 1/2

%

Grade 3/4

%

Grade 1/2

%

Grade 3/4

%

Fatigue† 17.5 4.7 10.6 1.1

Nausea 13.4 0.6 2.2 0

Anemia† 11.7 6.4 4.4 0.6

Vomiting 7.5 0.3 1.1 0

Mucositis/stomatitis‡ 5.8 0.6 2.2 0

Neuropathy/sensory 5.3 0.3 6.1 0.6

Neutropenia† 5.0 5.8 0.6 0

Leukopenia 2.8 2.2 0 0

ALT (SGPT) 2.5 0.3 0.6 0

* Data derived from the March 2011 safety update. Toxicities of any grade, occurring in ≥5% of patients in either arm, are listed,

along with some select toxicities. †P<0.05 Fisher’s exact test of Gr 3/4 toxicities . ‡Combined term.

Maintenance safety similar to known profile of single-agent pemetrexed1,2

1Hanna N, et al. J Clin Oncol. 2004; 2Ciuleanu T, et al. Lancet 2009

PARAMOUNT: Conclusions

These final results show that survival is significantly

improved when patients are treated with pemetrexed

continuation maintenance therapy compared with

placebo (HR=0.78)

The survival results were internally consistent across

all subgroups, including response to induction

(complete/partial response versus stable disease)

PARAMOUNT is the first study to show continuation

maintenance has an impact on the disease course of

advanced NSCLC (including PFS and OS), supporting

a change in the treatment paradigm in this setting

Acknowledgements

We thank all of the patients and their caregivers for participating in this

trial. We also thank all the Investigators and their support staff who

generously participated in this work with a special mention to the Spanish

Investigators:

• D. Isla (Hospital Clínico Universitario Lozano Blesa, Zaragoza, España)

• Y. García (Hospital Universitari Parc Tauli, Sabadell, España)

• D. Almenar (Hospital Universitario Dr. Peset, Valencia, España)

• R. Bernabé (Hospital Universitario de Valme, Sevilla, España)

• M. Domenech (Hospital Althaia de Manresa, Barcelona, España)