PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC.

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Maintenance strategies in non-squamous NSCLC

Maintenance strategies in non-squamous NSCLC

1PARAMOUNT: patient & disease characteristics, drug administration

PARAMOUNT: patient & disease characteristics, drug administration

3

PARAMOUNT: PFS resultsPARAMOUNT: PFS results

4PARAMOUNT: post-discontinuation therapy

PARAMOUNT: post-discontinuation therapy

5PARAMOUNT: safety & tolerabilityPARAMOUNT: safety & tolerability

6PARAMOUNT: conclusionsPARAMOUNT: conclusions

7

PARAMOUNT: study design and objectives

PARAMOUNT: study design and objectives

2

Increase the duration

of disease control

Improve overall survival

Maintainingtolerability

Objectives of maintenance

therapy1

Tolerance to maintenance drug is known from induction

treatment Potential advantages

of continuation maintenance approach2–4

Maximisethe potential

of the drug used in 1st-line

Saves a drug for

subsequent treatment

lines

PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC1

2:1

ran

do

mis

atio

n2:

1 ra

nd

om

isat

ion pemetrexed†

500 mg/m2 IV + BSCday 1, q 21 days; n=359

pemetrexed† 500 mg/m2 IV + BSCday 1, q 21 days; n=359

pemetrexed 500 mg/m2 IV +cisplatin 75 mg/m2

day 1, q 21 days; n=939Non-squamous* NSCLC patients only

pemetrexed 500 mg/m2 IV +cisplatin 75 mg/m2

day 1, q 21 days; n=939Non-squamous* NSCLC patients only

CR, PR, or SD after 4 cycles of pemetrexed/cisplatinn=539

CR, PR, or SD after 4 cycles of pemetrexed/cisplatinn=539

progressive diseaseprogressive disease

placebo† + BSC day 1, q 21 days; n=180placebo† + BSC day 1, q 21 days; n=180

*Adenocarcinoma, large cell carcinoma and other histologies† Vitamin B12, folic acid and dexamethasone given during induction therapy and in both maintenance arms. BSC=Best Supportive Care

Patients enrolled if:• non-squamous* NSCLC• no prior systemic treatment for lung cancer• ECOG PS 0/1

Stratified for:• PS (0 vs 1)• disease stage (IIIB vs IV) prior to induction• response to induction (CR/PR vs SD)

PARAMOUNT: study objectives1

• Progression-free survival (PFS)Primary

objective

Secondary objectives

• Overall survival (OS)• Objective tumour response rate (RR) (RECIST 1.0)• Patient-reported outcomes (EQ-5D) • Resource utilisation• Adverse events (AEs)

PARAMOUNT: patient characteristics (randomised patients)1

placebon=180

placebon=180

Median age, yrsAge <65 yrsMaleCaucasianSmoker Ever smoker Never smokerECOG PS 0 1 2/3*

*Protocol violations

pemetrexed n=359

pemetrexed n=359

61 62

Caucasian 339 (94%) 171 (95%)

PARAMOUNT: disease characteristics (randomised patients)1

placebon=180

placebon=180

Disease stage IV*Histology Adenocarcinoma/bronchoalveolar Large cell Other non-squamousBest tumour response to induction CR/PR SD PD/Unknown†

* Lung Cancer Staging System Version V† Protocol violations

pemetrexed n=359

pemetrexed n=359

328

3102425

166186

7

(91%)

(86%)(7%)(7%)

(46%)(52%)

(2%)

161

16012

8

769410

(89%)

(89%)(7%)(4%)

(42%)(52%)

(6%)

Disease stage IV* 328 (91%) 161 (89%)

Adenocarcinoma/bronchoalveolar 310 (86%) 160 (89%)

PARAMOUNT: drug administration (randomised patients)1

Data related to the primary endpoint (PFS) data analysis. Figures are likely to change at the time of the final OS analysis.

pemetrexed n=359

pemetrexed n=359

placebon=180

placebon=180

mean # of cycles patients > 6 cycles dose intensity

4.9

4.2

23%

14%

95%

n.a.

Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1

Time (months)

3 6 9 12 150

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

pemetrexed + BSC (n=359)

placebo + BSC (n=180)

HR=0.62 (95% CI 0.49–0.79); p<0.0001

BSC=Best Supportive Care

Median PFS (95% CI)Pemetrexed 4.1 (3.2-4.6)Placebo 2.8 (2.6-3.1)

4.12.8HR 0.62 reduction in the

risk of progression38%

Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1

Time (months)

3 6 9 12 150

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

pemetrexed + BSC (n=316)

placebo + BSC (n=156)

HR=0.64 (95% CI 0.51–0.81); p<0.0002

† 88% of patients were independently reviewed (472/539); BSC=Best Supportive Care

Median PFS (95% CI)Pemetrexed 3.9 (3.0–4.2)Placebo 2.6 (2.2–2.9)

HR 0.643.92.6

Progression-free survival

HRs in subgroups1

PFS results were internally consistent; benefit was seen

across all subgroups

All

Stage

IIIB

IV

Induction response

CR/PR

SD

Pre-randomisation ECOG PS

0

1

Smoking status

Non-smoker

Smoker

Sex

Male

Female

Age (years)

<70

≥70

<65

≥65

Histology

Adenocarcinoma

Large Cell Carcinoma

Other

0.62 (0.59-0.79)

0.55 (0.24-1.26)

0.62 (0.49-0.80)

0.48 (0.34-0.67)

0.74 (0.53-1.04)

0.53 (0.35-0.79)

0.67 (0.50-0.90)

0.41 (0.24-0.71)

0.70 (0.53-0.90)

0.74 (0.55-1.00)

0.49 (0.34-0.72)

0.69 (0.54-0.90)

0.35 (0.20-0.63)

0.70 (0.53-0.94)

0.51 (0.34-0.75)

0.62 (0.49-0.80)

0.39 (0.14-1.07)

0.64 (0.22-1.89)

0.2 0.4 0.8 1.2 1.60 2.00.6 1 1.4 1.8

Favours pemetrexed Favours placebo

539

50

489

242

280

170

366

116

419

313

226

447

92

350

189

471

36

32

HR (95% CI)N

Survival time (months)

0 1 2 3 54

Numbers in brackets are the 95% CI values.

PARAMOUNT: median PFS according to responseto induction treatment1

pemetrexed (n=166)

pemetrexed (n=186)

4.1 (3.1-6.0)

4.1 (3.0-4.6)

placebo (n=76)

placebo (n=94)

2.6 (1.6-2.9)

3.0 (2.8-4.1)

PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)1

placebon=122

placebon=122

Patients with PDTDrug nameErlotinibDocetaxelGemcitabineInvestigational drugVinorelbineBevacizumabCisplatinOther†

p-valuep-value

0.35

0.330.270.150.580.331.001.00–

pemetrexed n=200

pemetrexed n=200

† Systemic therapies administered to 1% or fewer patients in both groups are summarised under “Other”. These therapies included carboplatin, pemetrexed, BIBF 1120, paclitaxel, placebo, aspirin, aflibercept, cyclophosphamide, gefitinib, ifosfamide, vinflunine, and other antineoplastic drugs.

Overall, toxicity was low in both armsOverall, toxicity was low in both arms

* Difference between treatment groups was significant (Fisher’s exact test p ≤0.05).

placebon=180

placebon=180

pemetrexed n=359

pemetrexed n=359

Patients with ≥ 1 grade 3/4/5laboratory toxicity

Patients with ≥ 1 grade 3/4/5non-laboratory toxicity

9%*n=33

9%n=32

<1%*n=1

4%n=8

Maintenance therapy with pemetrexed: generally well tolerated1

* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006)Alanine aminotransferase, Nausea, Vomiting, Mucositis or Stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4/5 adverse events were reported for less than 1% of patients.

placebo (n=180)

Anaemia

Neutropenia

Fatigue

PainLeucopenia

Thrombocytopenia

Infection

Neuropathy

pemetrexed (n=359)

0 10 20 30 0 10 20 30

PARAMOUNT: CTCAEs grade 3/4/5 drug-related toxicities (randomised patients)1†

4%* n=16

4%* n=13

2% n=6

1% n=4

4%* n=15

1% n=3

1% n=4

<1% n=1

<1%* n= 1

0%* n= 0

0% n=0

0% n=0

<1%* n= 1

1% n=2

0% n=0

<1% n=1

PARAMOUNT: health-related quality of life assessment (EQ-5D)1

• Compliance at all time points during maintenance phase was >80%

• No statistical differences in EQ-5D index score or visual analog scale were observed between treatment arms

• EQ-5D results suggest that patients can tolerate long-term maintenance treatment with pemetrexed while maintaining their QoL

• Pemetrexed continuation maintenance therapy offers significantlyimproved PFS

• Pemetrexed continuation maintenance therapy is well tolerated

PARAMOUNT demonstrates a positive risk/benefit ratio for the administration of pemetrexed continuation maintenance1,10

PARAMOUNT demonstrates a positive risk/benefit ratio for the administration of pemetrexed continuation maintenance1,10

PARAMOUNT: conclusions1,10

Pemetrexed continuation maintenance therapy:approach to maximise outcomes for patients1,2

Proven efficacy ✔

Acceptable toxicity ✔

Conveniently administered ✔

Keeps other treatments available ✔

Acknowledgements

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

References

1. Paz-Ares L et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012; 13:247-255

2. Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol 2009;4:243–50.

3. Novello S et al. Maintenance therapy in NSCLC: why? To whom? Which agent? J Exp Clin Cancer Res 2011;30:50.

4. Fidias P, Novello S. Strategies for prolonged therapy in patients with advanced non–small-cell lung cancer. J Clin Oncol. 2010;28:5116-23.

5. Azzoli CG, Temin S, Aliff T, et al. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol. 2011 Sep 6.[Epub ahead of print].

6. D’Addario G, Felip E. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:iv68–iv70.

7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V.3.2011. Fort Washington, PA: NCCN, 2011.

8. Scagliotti GV et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-51.

9. Ciuleanu T et al. Maintenance pemetrexed plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet 2009;347:1432-40.

10. ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. November 2011.