can we select patients most likely to benefit from pemetrexed continuation maintenance? seonc00109
TRANSCRIPT
Can we select patients most likely to benefit from pemetrexed continuation maintenance?
SEONC00109
Baseline
61
66
56
94
76
23
32
68
91
86
7
44
53
3
Pemetrexed Arm %Pts
Median age (yrs)
Sex/ethnic group
Age <65
Male
Caucasian
Smoker
Ever smoker
Never smoker
ECOG PS
0
1
Stage IV
Histology
Adenocarcinoma
Large cell
Induction response
CR/PR
SD
PD/Unknown
Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
6 mos
61
65
55
95
72
27
39
61
92
89
6
44
55
1
12 mos
62
62
54
96
69
30
42
59
92
89
7
45
54
2
18 mos
62
62
47
96
66
33
46
54
92
88
7
48
50
2
24mos
63
61
49
96
68
30
53
47
90
89
6
47
51
3
6 mos
61
65
55
95
72
27
39
61
92
89
6
44
55
1
12 mos
62
62
54
96
69
30
42
59
92
89
7
45
54
2
18 mos
62
62
47
96
66
33
46
54
92
88
7
48
50
2
24mos
63
61
49
96
68
30
53
47
90
89
6
47
51
3
Baseline
61
66
56
94
76
23
32
68
91
86
7
44
53
3
Pemetrexed Arm %Pts
Median age (yrs)
Sex/ethnic group
Age <65
Male
Caucasian
Smoker
Ever smoker
Never smoker
ECOG PS
0
1
Stage IV
Histology
Adenocarcinoma
Large cell
Induction response
CR/PR
SD
PD/Unknown
Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
6 mos
61
65
55
95
72
27
39
61
92
89
6
44
55
1
12 mos
62
62
54
96
69
30
42
59
92
89
7
45
54
2
18 mos
62
62
47
96
66
33
46
54
92
88
7
48
50
2
24mos
63
61
49
96
68
30
53
47
90
89
6
47
51
3
32
68
ECOG PS
0
1
39
61
42
59
46
54
53
47
44
53
3
Induction response
CR/PR
SD
PD/Unknown
44
55
1
45
54
2
48
50
2
47
51
3
Baseline
61
66
56
94
76
23
32
68
91
86
7
44
53
3
Pemetrexed Arm %Pts
Median age (yrs)
Sex/ethnic group
Age <65
Male
Caucasian
Smoker
Ever smoker
Never smoker
ECOG PS
0
1
Stage IV
Histology
Adenocarcinoma
Large cell
Induction response
CR/PR
SD
PD/Unknown
Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
6 mos
61
65
55
95
72
27
39
61
92
89
6
44
55
1
12 mos
62
62
54
96
69
30
42
59
92
89
7
45
54
2
18 mos
62
62
47
96
66
33
46
54
92
88
7
48
50
2
24mos
63
61
49
96
68
30
53
47
90
89
6
47
51
3
PARAMOUNT data shows
OS benefit seen across all subgroups
Basis for maintenance treatment decision
Overall treatment
goals
Performancestatus
Tolerance to induction therapy
Maintenance Treatment Decision
Did PARAMOUNT assess patients’ Quality of Life?
PARAMOUNT: study objectives2
• Progression-free survival (PFS)
Primary objective
• Overall survival (OS)• Objective tumor resposne rate (RR) (RESIST 1.0)• Patient-reported outcomes (EQ-5D)• Resource utilisation• Adverse events (AEs)
Secondary objective
EQ-5D: EuroQol 5-dimensional questionnaire3
Questionnaire
By placing a tick in one box in each group below, please indicate which statements best describe your own health state today.
Mobility I have no problems in walking about ☐I have some problems in walking about ☐I am confined to bed ☐
Self-CareI have no problems with self-care ☐I have some problems washing or dressing myself ☐I am unable to wash or dress myself ☐
Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities ☐I have some problems with performing my usual activities ☐I am unable to perform my usual activities ☐
Pain/DiscomfortI have no pain or discomfort ☐I have moderate pain or discomfort ☐I have extreme pain or discomfort ☐
Anxiety/DepressionI am not anxious or depressed ☐I am moderately anxious or depressed ☐I am extremely anxious or depressed ☐
By placing a tick in one box in each group below, please indicate which statements best describe your own health state today.
Mobility I have no problems in walking about ☐I have some problems in walking about ☐I am confined to bed ☐
Self-CareI have no problems with self-care ☐I have some problems washing or dressing myself ☐I am unable to wash or dress myself ☐
Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities ☐I have some problems with performing my usual activities ☐I am unable to perform my usual activities ☐
Pain/DiscomfortI have no pain or discomfort ☐I have moderate pain or discomfort ☐I have extreme pain or discomfort ☐
Anxiety/DepressionI am not anxious or depressed ☐I am moderately anxious or depressed ☐I am extremely anxious or depressed ☐
✔
✔
✔
✔
✔
Best imaginable health state
Worst imaginable health state
Best imaginable health state
Worst imaginable health state
VAS (Visual Analog Scale)
High EQ-5D compliance3
InductionPemetrexed
arm Placeboarm
79.4%84.3% 80.9%
PARAMOUNT: EQ-5D results and safety data
Safety data4EQ-5D results3
>10 MTC Cycles
Grade 1 Grade 2 Grade 3/4
Event (%) PEM PBO PEM PBO PEM PBO
Fatigue 15 0 13 13 8 6
Renal* 4 6 8 0 1 0
Rash 4 0 1 0 0 0
Edema 13 13 8 0 0 0
Anemia 4 6 12 0 7 0
Neutropenia 4 0 7 0 11 0
What are the QoL and safety results in PARAMOUNT?
QoL and safety in PARAMOUNT
Good Overall QoL during maintenance
Induction therapy Maintenance therapy
QoL and safety in PARAMOUNT
Good Overall QoL during maintenance
Induction therapy Maintenance therapy
Anaemia
Neutropenia
Leucopenia
Thrombo-cytopenia
Fatigue
Infection
Pain
Neuropathy
Pemetrexed(n=359)
placebo(n=180)
0 10 20 30 0 10 20 30
QoL and safety in PARAMOUNT
Rate of AEs possibly related to maintenance pemetrexed vs placebo2,†
* 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 adverse events were reported for less than 1% of patients.
Adapted from: 1,2
4%* n=15
<1%* n=1
1% n=4
1% n=2
1% n=3
0% n=1
1% n=1
1% n=1
4%* n=16
<1%* n=1
4%* n=13
0%* n=1
2% n=6
0%* n=1
1% n=4
0% n=1
Low rate of discontinuations due to adverse events3
9.2% for maintenance pemetrexed 3.9% for placebo
100
90
80
70
60
50
40
30
20
10
0
Pemetrexed Placebo
Worse
No Change
Better
QoL and safety in PARAMOUNT
Change in ECOG PS from randomisation to last maintenance treatment3
14.7% 12.6%
77.8% 77.3%
7.5% 10.2%
* 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 adverse events were reported for less than 1% of patients.
Adapted from: 1,2
QoL and safety in PARAMOUNT
EQ-5D index scores: Quality of life was maintained throughout treatment3
0.8
0.7
0.6
Induction cycles
1 2 3 4 1 2 3 4 5 6
* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3
QoL and safety in PARAMOUNT
EQ-5D index scores: Quality of life was maintained throughout treatment3
0.8
0.7
0.6
Induction cycles Maintenance cycles
Pemetrexed
Placebo
1 2 3 4 1 2 3 4 5 6
* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3
QoL and safety in PARAMOUNTVAS: No overall treatment differences in quality of life were observed during induction3
0.8
0.7
0.6
Induction cycles Maintenance cycles
Pemetrexed
Placebo
1 2 3 4 1 2 3 4 5 6
† p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3
QoL and safety in PARAMOUNTVAS: No overall treatment differences in quality of life were observed during induction3
0.8
0.7
0.6
Induction cycles Maintenance cycles
Pemetrexed
Placebo
1 2 3 4 1 2 3 4 5 6
† p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3
QoL and safety in PARAMOUNT
• Survival significantly improved with pemetrexed continuation maintenance therapy vs placebo5
• HR=0.78 (95% CI: 0.64-0.96)5
• No statistical differences observed in patient-reported QoL between maintenance treatment arms3
Does long-term pemetrexed maintenance have an impact on QoL?
Time from randomisation (months)
6 12 18 24 300
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=0.78 (95% CI 0.64–0.96); p=0.0195
36
Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC6
24-months survival rate32%
32%
21%
Summary of maintenance therapy4
Adapted from: 4
Pemetrexed
(n=359)
Placebo
(n=180)
Median number of cycles (range) 4 (1–44) 4 (1–38)
Mean number of cycles 8 5
% of pts receiving MTC
≤10 cycles 76 90
>10 cycles 24 9
% discontinuations due to
possibly drug-related AE12 4
Median number of cycles (range) 4 (1–44) 4 (1–38)
Mean number of cycles 8 5
>10 cycles 24 9
Possible drug-related CTCAEs occurring in all cycles of maintenance therapy4
>10 MTC Cycles
Grade 1 Grade 2 Grade 3/4
Event (%) PEM PBO PEM PBO PEM PBO
Fatigue 15 0 13 13 8 6
Renal* 4 6 8 0 1 0
Rash 4 0 1 0 0 0
Edema 13 13 8 0 0 0
Anemia 4 6 12 0 7 0
Neutropenia 4 0 7 0 11 0
* creatinine, GFR, ranal failure, and genitourinary-other.
No significant differences in drug-related grade 3/5 toxicities – except grade 3/4 neutropenia3
2.2% 8.3% p=0.015
2.9% 1.2% p=0.691
maintenance cycles≤6 >6
50 0 50
Infections Grade 3/5
Neutropenia Grade 3/4
Possible drug-related grade 1/2 adverse events3
8.7% 16.7% p=0.044
2.5% 11.9% p=0.001
1.5% 6.0% p=0.036
2.5% 13.1% p=0.001
0.4% 3.6% p=0.041
maintenance cycles≤6 >6
Nausea
50 0 50
Neutropenia
Sensory neuropathy
Ocular/visual events
Headache
Long-term pemetrexed maintenance impact on QoL
EQ-5D results
Pemetrexed well-tolerated safety profile
PS changes
Majority of patients maintain QoL
Majority of patients maintain QoL
Are PARAMOUNT QoL and safety results consistent with JMEN?
Maintenance pemetrexed in PARAMOUNT2 and JMEN7,8
PARAMOUNTPaz-Ares et al. 2012
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
JMENCiuleanu et al. 2009
Maintenance pemetrexed plus best supportive care versus
placebo plus best supportive care for non-small-cell lung
cancer: a randomised, double-blind, phase 3 study
• Well-tolerated
safety profile,
consistently reported
• QoL is well maintained
and similar to placebo
Grades 3 or 4
Pemetrexed Placebo
Hematologic toxicities
Neutropenia* 13 (3%) 0
Anemia 12 (3%) 1 (<1%)
Leukoperia 7 (2%) 1 (<1%)
Non-hematologic toxicities
ALT 1 (<1%) 0
AST 0 0
Fatigue† 22 (5%) 1 (<1%)
Anorexia 8 (2%) 0
Infection 7 (2%) 0
Diarrhoea 2 (<1%) 0
Nausea 4 (<1%) 1 (<1%)
Vomiting 1 (<1%) 0
Sensory neuropathy 3 (<1%) 0
Mukositis stomatitis 3 (<1%) 0
Rash 1 (<1%) 0
JMEN: Drug-related toxic effects8
Adapted from: 4
ALT=alanine aminotransferase. AST=aspartate aminotransferase. *p<0.05 for grade 3 or 4 rates of neutropenia and fatigue between study groups. †Updated safety analysis done 6 months after initial analysis of progression-free survival. For the purpose of this table, a cut-off of 5% was used for inclusion of all events for which the investigator considered a possible link with pemetrexed.
Fatigue† 22 (5%) 1 (<1%)
Neutropenia* 13 (3%) 0
Grades 3 or 4
Pemetrexed Placebo
Toxicity*
Laboratory
Anemia 16 1 (0.6%)
Neutropenia 13 0
Non-laboratory
Fatigue (asthenia, lethargy, malaise) 15 (4%) 1 (0.6%)
Anorexia 1 (0.3%) 0
Constipation 0 0
Diarrhea 0 0
Mucositis stomatitis 1 (0.3%) 0
Nausea 1 (0.3%) 0
Vomoting 0 0
Edema 0 0
Sensory neuropathy 1 (0.3%) 1 (0.6%)
Watery eye (epiphora, tearing) 0 0
Pain 3 (0.8%) 0
PARAMOUNT: CTCAEs possibly related to study drug during maintenance3
Adapted from: 4
Toxicities were reported using CTCAE version 3.0 (National Cancer Institute 2006). Toxicities occurring in ≥ 3% of patients on either or both arms are listed. Two grade 5 events (deaths) considered possibly related to study drug occurred during the maintenance period: pemetrexed – pneumonia; placebo-sudden death. Difference between treatment arms is statistically significant (Fisher‘s exact test p ≤0.05). CTCAE, Common Terminology Criteria for Adverse Events.
Fatigue (asthenia, lethargy, malaise) 15 (4%) 1 (0.6%)
Anemia 16 1 (0.6%)
Neutropenia 13 0
QoL in PARAMOUNT and JMEN
PARAMOUNT3 EQ-5D
JMEN7 LCSS
QoL Measurement
Overall quality of
life
p=0.959
Fatigue
p=0.897
Overall quality of
life
p=0.897
Fatigue
p=0.959
QoL in PARAMOUNT and JMEN
Mean maximum improvement in LCSS items7
Adapted from: 1,2
12
10
8
6
4
2
0
Pemetrexed
Placebo
Inter-ference
with activity
Symptom distress
Pain Haemo-lysis
DyspnoeaCooghLoss of appetite
p=0.592
p=0.533
p=0.039
p=0.831
p=0.204p=0.192
p=0.136
Quality of lifeBest imaginable health state
Worst imaginable health state
QoL in PARAMOUNT and JMEN
Patients are able to maintain their overall good quality of life3
How robust are the findings of PARAMOUNT to support a change in the treatment paradigm?
The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10
The robust PARAMOUNT results are based on a number of valid points
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10
PFS: 4.1 vs 2.8 months
HR 0.62 (95% CI 0.49-0.79; p<0.0001)
OS: 16.9 vs 14.0 months from induction
HR 0.78 (95% CI 0.64-0.96; p=0.0195)
Investigator-determined PFS results confirmed by independent review
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10
PFS: Primary endpoint
1.00.90.80.70.60.50.40.30.20.1
0
0 3 6 9 12 15
pemetrexed + BSC (n=358)
placebo + BSC (n=180)
HR 0.62 (0.49–0.79)
Time (months)
Investigator-determined PFS results confirmed by independent review
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
Relative treatment effect of pemetrexed consistent across subgroups
The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10
Favours pemetrexed 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favours placebo
Subgroup OS Hazard Ratio N HR (95% CI)
All 539 0.78
Stage IV 490 0.79
IIIB 49 0.82
Induction responseCR/PR 234 0.81
SD 285 0.76
Pre-randomisation ECOG PS
1 363 0.82
0 173 0.70
Smoking status Never-smoker 117 0.75
Smoker 418 0.83
Sex Male 313 0.82
Female 226 0.73
Age (years) <70 447 0.75
≥70 92 0.89
<65 350 0.82
≥65 189 0.71
Histology Adenocarcinoma 471 0.80
Large cell carcinoma 36 0.44
Other 32 0.81
CR/PR patients: OS HR=0.81
SD patients: OS HR=0.76
Investigator-determined PFS results confirmed by independent review
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
Post-discontinuation treatment options were well balanced between the two arms
Relative treatment effect of pemetrexed consistent across subgroups
The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10
placebo(n=180) %*
placebo(n=180) %*
72
43438644342
pemetrexed(n=359) %*
pemetrexed(n=359) %*
64
403210865321
Patients with PDTDrug nameErlotinibDocetaxel†
GemcitabineVinorelbineInvestigational drugCarboplatinPaclitaxelPemetrexedCisplatin
* 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).
64 72
What are the key takeaways for clinical practice?
Key PARAMOUNT takeaways
Significant OS benefit in favor of Pemetrexed Continuation Maintenance10
OS Benefit consistent across all sub-groups, with acceptable toxicity2,10
PARAMOUNT: first study to show that Continuation Maintenance has an impact on disease course10
Results confirm the importance of choosing the best treatment up-front, based on histology and other patient characteristics2,10
2
13
References
1. Reck M et al. PARAMOUNT: Descriptive subgroup analyses of final overall survival (OS) for the phase III study of maintenance pemetrexed (PEM) versus placebo (PLB) following induction treatment with PEM plus cisplatin (CIS) for advanced nonsquamous (NS) non-small cell lung cancer. ESMO Congress, Vienna, Austria, 2012. Abstract 1235PD.
2. 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.
3. Gridelli C et al. Safety, resource use, and quality of life in PARAMOUNT: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012;7(11):1713-1721.
4. Pujol JL et al. Updated safety and quality of life results of PARAMOUNT study: maintenance pemetrexed + best supportive care (BSC) vs placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. ESMO Congress, Vienna, Austria, 2012. Abstract 3376.
5. Paz-Ares L et al. PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (PLB) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
6. ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. November 2012.
7. Belani CP et al. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 2012;13:292-299.
8. Ciuleanu T et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:1432-1440.
9. Hanna N et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.