Questions and answers about PARAMOUNT:
phase III study of pemetrexed continuation maintenance
therapy in advanced non-squamous NSCLC.
All questions at a glance: please click on question to review
2
1
PARAMOUNT study design:
why were 4 cycles
of induction used?
4
3
Does PARAMOUNT address
the question of pemetrexed
clinical resistance?
5
Based on the results of
PARAMOUNT, can response to
induction determine who should
receive maintenance therapy?
What is the impact of the
PARAMOUNT survival
results on the treatment
paradigm in advanced
NSCLC?
6
2nd-line
Did study patients get
treatments? Were there any
differences between the two
study arms?
7
8
How do the results of the
pemetrexed/cisplatin induction regimen of
PARAMOUNT compare with those of the
pemetrexed/cisplatin-treated
nonsquamous patients in study JMDB?
Are the PARAMOUNT
results meaningful from a
patient perspective?
9
How is
PARAMOUNT
different from study
JMEN?
Can we compare
pemetrexed continuation
versus pemetrexed switch
maintenance therapies?
PARAMOUNT study design:
why were 4 cycles of induction used?
Current recommendations for number of cycles
in 1st-line treatment
ASCO and ESMO: 4 to 6 cycles of a platinum-based regimen
JMDB: 91% of CR or PR
occurred in the first 4 cycles*,7,8
* of all responders
Does PARAMOUNT address the question
of pemetrexed clinical resistance?
Pemetrexed continuation maintenance demonstrated
significant PFS benefit for patients9
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
Progression-free survival (%)
NOT reflected in the data endpoints
Induction = 4 cycles
of pemetrexed/cisplatin
Investigator-assessed PFS
0.9
0.8
HR=0.62 (95% CI 0.49–0.79); p<0.0001
0.7
0.6
2.8
4.1
HR 0.62
0.5
Median PFS (95% CI)
reduction in the
Pemetrexed 4.1 (3.2–4.6)
risk of progression
Placebo 2.8 (2.6–3.1)
38%
0.4
0.3
0.2
0.1
0
0
3
6
9
Time (months)
BSC=Best Supportive Care
12
15
PARAMOUNT: median PFS according to response
to induction treatment9
Response to induction treatment
Complete/Partial
response
pemetrexed (n=166)
n=242, HR=0.48
(0.34–0.67)
placebo (n=76)
Stable disease
pemetrexed (n=186)
n=280, HR=0.74
(0.53–1.04)
4.1 (3.1–6.0)
2.6 (1.6–2.9)
4.1 (3.0–4.6)
3.0 (2.8–4.1)
placebo (n=94)
0
1
2
3
Survival time (months)
Numbers in brackets are the 95% CI values.
4
5
What is the impact of the PARAMOUNT
survival results on the treatment paradigm
in advanced NSCLC?
PARAMOUNT study was powered 9,10,11
for PFS – primary end-point
for OS – primary end-point
Pemetrexed continuation maintenance demonstrated
significant PFS benefit for patients 9
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
Progression-free survival (%)
NOT reflected in the data endpoints
Induction = 4 cycles
of pemetrexed/cisplatin
Investigator-assessed PFS
0.9
0.8
HR=0.62 (95% CI 0.49–0.79); p<0.0001
0.7
0.6
2.8
4.1
HR 0.62
0.5
Median PFS (95% CI)
reduction in the
Pemetrexed 4.1 (3.2–4.6)
risk of progression
Placebo 2.8 (2.6–3.1)
38%
0.4
0.3
0.2
0.1
0
0
3
6
9
Time (months)
BSC=Best Supportive Care
12
15
Pemetrexed/cisplatin followed by pemetrexed
demonstrated a statistically significant OS benefit
in advanced non-squamous NSCLC10
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
0.9
Survival probabality (%)
NOT reflected in the data endpoints
Induction = 4 cycles
of pemetrexed/cisplatin
Overall survival from randomisation
0.8
HR=0.78 (95% CI 0.64–0.96); p=0.0195
0.7
0.6
11.0
13.9
HR 0.78
0.5
0.4
0.3
0.2
0.1
0
0
6
12
18
24
Time from randomisation (months)
BSC=Best Supportive Care
30
36
Pemetrexed/cisplatin followed by pemetrexed
demonstrated a statistically significant OS benefit
in advanced non-squamous NSCLC10
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
0.9
Survival probabality (%)
NOT reflected in the data endpoints
Induction = 4 cycles
of pemetrexed/cisplatin
Overall survival from randomisation
0.8
HR=0.78 (95% CI 0.64–0.96); p=0.0195
0.7
0.6
32%
0.5
0.4
24-months
survival rate
32%
0.3
0.2
21%
0.1
0
0
6
12
18
24
Time from randomisation (months)
BSC=Best Supportive Care
30
36
PARAMOUNT: Final OS from induction 9,10
Overall survival from induction
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
Survival probability (%)
0.9
0.8
HR=0.78 (95% CI 0.64–0.96); p=0.0191
0.7
0.6
14.0
16.9
0.5
0.4
0.3
0.2
0.1
0
0
6
12
18
24
Time from randomisation (months)
BSC=Best Supportive Care
30
36
PARAMOUNT: PFS and OS results 9,10
PFS
HR 0.62
OS*
HR 0.78
p<0.0001
95% CI 0.49 – 0.79
p=0.0195
95% CI 0.64 – 0.96
* Overall survival from randomisation
Based on the results of PARAMOUNT,
can response to induction determine
who should receive maintenance therapy?
Progression-free survival HRs in subgroups9,11
N
539
0.78
IV
IIIB
490
49
0.79
0.82
CR/PR
SD
234
285
0.81
0.76
1
0
363
173
0.82
0.70
Never-smoker
Smoker
117
418
0.75
0.83
Male
Female
313
226
0.82
0.73
<70
≥70
<65
≥65
447
92
350
189
0.75
0.89
0.82
0.71
Adenocarcinoma
Large cell carcinoma
Other
471
36
32
0.80
0.44
0.81
All
Stage
Induction
response
Pre-randomisation
ECOG PS
Smoking status
Sex
Age (years)
Histology
HR (95% CI)
Favours
pemetrexed
Favours
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8 2.0 placebo
Pemetrexed continuation maintenance helps improve
survival for patients achieving either SD or a tumour
response following pemetrexed-based induction10
N
All
HR (95% CI)
539
0.78
CR/PR
234
0.81
SD
285
0.76
Induction response
Favours pemetrexed
0
0.2 0.4 0.6 0.8 1
placebo + BSC
HR 0.81
CR/PR
HR 0.81
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
18
24
12
Time from randomisation (months)
30
36
Favours placebo
pemetrexed + BSC
Survival probability (%)
Survival probability (%)
pemetrexed + BSC
1.0
0.9
0.8
0.7
1.2 1.4 1.6 1.8 2.0
1.0
0.9
0.8
0.7
placebo + BSC
HR 0.76
SD
HR 0.76
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
18
24
12
Time from randomisation (months)
30
36
Did study patients get 2nd-line treatments?
Were there any difference between the two
study arms?
PARAMOUNT: post-discontinuation therapy
(PDT-eligible patients)10
Patients with PDT
Drug name
Erlotinib
Docetaxel†
Gemcitabine
Vinorelbine
Investigational drug
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
pemetrexed
(n=359) %*
placebo
(n=180) %*
64
64
72
40
32
10
8
6
5
3
2
1
43
43
8
6
4
4
3
4
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).
Are the PARAMOUNT results meaningful
from a patient perspective?
What matters to patients
longer
survival
time
potential
additional
toxicity
Pemetrexed/cisplatin followed by pemetrexed
demonstrated a statistically significant OS benefit
in advanced non-squamous NSCLC10
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
1.0
0.9
Survival probabality (%)
NOT reflected in the data endpoints
Induction = 4 cycles
of pemetrexed/cisplatin
Overall survival from randomisation
0.8
HR=0.78 (95% CI 0.64–0.96); p=0.0195
0.7
0.6
11.0
13.9
HR 0.78
0.5
0.4
0.3
0.2
0.1
0
0
6
12
18
24
Time from randomisation (months)
BSC=Best Supportive Care
30
36
2-year survival rate10
placebo
+ BSC+21%
pemetrexed
BSC 32%
PARAMOUNT: possible drug related CTCAEs*,10
Anaemia†
6.4%
0.6%
Fatigue†
4.7%
1.1%
Neutropenia†
5.8%
0%%
Vomiting
0.3%
0%
Leucopenia
2.2%
0%
0.6%
0%
Nausea
0.6%
0%
Mucositis/
stomatitis‡
Neuropathy
0.3%
0.6%
0.3%
0%
ALT (SGPT)
0
10
20
30
0
10
20
30
pemetrexed
placebo
(n=359)
(n=180)
Values expressed as % of randomised patients
* 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.
PARAMOUNT: EQ-5D results9
• EQ-5D results suggest that patients can
tolerate long-term maintenance treatment
with pemetrexed while maintaining their QoL
What matters to patients
PARAMOUNT demonstrated that pemetrexed continuation maintenance
• has a positive risk/benefit ratio
• can meet all the requirements for an acceptable continuation
maintenance therapy
longer
survival
time
potential
additional
toxicity
How do the results of the pemetrexed/cisplatin
induction regimen of PARAMOUNT compare with
those of the pemetrexed/cisplatin-treated
non-squamous patients in study JMDB?
PARAMOUNT induction vs JMDB8
PARAMOUNT
JMDB
Induction
Completing ≥ 4 cycles
68%
71%
Response and control
Tumour response rates
Disease control rates
30.1%
74.5%
28.6%
63.8%
Toxicity
Laboratory toxicities
Non-laboratory toxicities
13.7%
14.8%
21.4%
21.9%
How is PARAMOUNT different from study JMEN?
How is PARAMOUNT different from Study JMEN?9,12
Primary endpoints
Powered for OS
Maintenance therapy
Double-blind,
placebo-controlled
Induction therapy
(4 cycles for both studies)
Study included
Study population
External environment
at study completion
PARAMOUNT
JMEN
PFS
PFS
Yes
(18–24 mos btwn PFS & OS)
Yes
(1 yr btwn PFS & OS)
Pemetrexed vs placebo
Pemetrexed vs placebo
Yes
Yes
Pemetrexed + cisplatin
Docetaxel + platinum
Paclitaxel + platinum
Gemcitabine + platinum
Induction plus maintenance
Maintenance only
Non-squamous* only
primarily EU
All histologies
global
Pemetrexed and erlotinib
approved in maintenance
No therapies approved
for maintenance
*Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
Can we compare pemetrexed continuation versus
pemetrexed switch maintenance therapies?
PARAMOUNT9 vs JMEN12
Select the most suitable treatment upfront
based on histology, along with other
tumour and patient characteristics
Maximise outcomes
and patient survival
Gain positive
risk/benefit
Keep other effective
treatments available
for further lines
Approach to maximise outcomes for patients
throughout their multiple lines of therapy
References
1.
D’Addario G, et al. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol.
2009;20(suppl 4):68-70.
2.
Pfister DG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J
Clin Oncol. 2004;22:330-353.
3.
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.
4.
Lustberg MB, et al. Optimal duration of chemotherapy in advanced non-small cell lung cancer. Curr Treat Options Oncol. 2007;8:38-46.
5.
Socinski MA, et al. Duration of first-line chemotherapy in advanced non small-cell lung cancer: less is more in the era of effective
subsequent therapies. J Clin Oncol. 2007;25:5155-5157.
6.
Soon YY, et al. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of
randomized trials. J Clin Oncol. 2009;27:3277-3283.
7.
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;26:3543-3551.
8.
Scagliotti GV, et al. Poster presented at: 14th World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, The Netherlands.
9.
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
10.
Paz-Ares L. Presentation at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, USA
11.
ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. December 2011.
12.
Ciuleanu T et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung
cancer: a randomized, double-blind, phase 3 study. Lancet 2009;347:1432-40.