Post on 15-Dec-2015
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
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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.