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Can we select patients most likely to benefit from pemetrexed continuation maintenance? SEONC00109.

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Presentation on theme: "Can we select patients most likely to benefit from pemetrexed continuation maintenance? SEONC00109."— Presentation transcript:

1 Can we select patients most likely to benefit from pemetrexed continuation maintenance? SEONC00109

2 Baseline 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 months 1 6 mos mos mos mos mos mos mos mos

3 Baseline 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 months 1 6 mos mos mos mos ECOG PS Induction response CR/PR SD PD/Unknown

4 Baseline 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 months 1 6 mos mos mos mos PARAMOUNT data shows OS benefit seen across all subgroups

5 Basis for maintenance treatment decision Overall treatment goals Performance status Tolerance to induction therapy Maintenance Treatment Decision

6 Did PARAMOUNT assess patients’ Quality of Life?

7 PARAMOUNT: study objectives 2 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

8 EQ-5D: EuroQol 5-dimensional questionnaire 3 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-Care I 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/Discomfort I have no pain or discomfort ☐ I have moderate pain or discomfort ☐ I have extreme pain or discomfort ☐ Anxiety/Depression I 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-Care I 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/Discomfort I have no pain or discomfort ☐ I have moderate pain or discomfort ☐ I have extreme pain or discomfort ☐ Anxiety/Depression I 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)

9 High EQ-5D compliance 3 Induction Pemetrexed armPlaceboarm 79.4% 84.3% 80.9%

10 PARAMOUNT: EQ-5D results and safety data Safety data 4 EQ-5D results 3 >10 MTC Cycles Grade 1Grade 2Grade 3/4 Event (%)PEMPBOPEMPBOPEMPBO Fatigue Renal* Rash Edema Anemia Neutropenia

11 What are the QoL and safety results in PARAMOUNT?

12 QoL and safety in PARAMOUNT Good Overall QoL during maintenance Induction therapyMaintenance therapy

13 QoL and safety in PARAMOUNT Good Overall QoL during maintenance Induction therapyMaintenance therapy

14 Anaemia Neutropenia Leucopenia Thrombo- cytopenia Fatigue Infection Pain Neuropathy Pemetrexed (n=359) placebo (n=180) QoL and safety in PARAMOUNT Rate of AEs possibly related to maintenance pemetrexed vs placebo 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 4%* n=15 <1%* n=1 1% n=4 1% n=2 1% n=3 0% 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 events 3 9.2% for maintenance pemetrexed 3.9% for placebo

15 % Change from Baseline in ECOG Performance Status PemetrexedPlacebo Worse No Change Better QoL and safety in PARAMOUNT Change in ECOG PS from randomisation to last maintenance treatment % 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

16 QoL and safety in PARAMOUNT EQ-5D index scores: Quality of life was maintained throughout treatment Improvement Mean score Induction cycles * 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

17 QoL and safety in PARAMOUNT EQ-5D index scores: Quality of life was maintained throughout treatment Improvement Mean score Induction cyclesMaintenance cycles Pemetrexed Placebo * 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

18 QoL and safety in PARAMOUNT VAS: No overall treatment differences in quality of life were observed during induction Improvement Mean score Induction cyclesMaintenance cycles Pemetrexed Placebo † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

19 QoL and safety in PARAMOUNT VAS: No overall treatment differences in quality of life were observed during induction Improvement Mean score Induction cyclesMaintenance cycles Pemetrexed Placebo † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

20 QoL and safety in PARAMOUNT Survival significantly improved with pemetrexed continuation maintenance therapy vs placebo 5 HR=0.78 (95% CI: ) 5 No statistical differences observed in patient-reported QoL between maintenance treatment arms 3

21 Does long-term pemetrexed maintenance have an impact on QoL?

22 Time from randomisation (months) Overall survival from randomisation Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p= Survival probabality (%) Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC 6 24-months survival rate 32% 21%

23 Summary of maintenance therapy 4 Adapted from: 4 Pemetrexed (n=359) Placebo (n=180) Median number of cycles (range)4 (1–44)4 (1–38) Mean number of cycles85 % of pts receiving MTC ≤10 cycles7690 >10 cycles249 % discontinuations due to possibly drug-related AE 124 Median number of cycles (range)4 (1–44)4 (1–38) Mean number of cycles85 >10 cycles249

24 Possible drug-related CTCAEs occurring in all cycles of maintenance therapy 4 >10 MTC Cycles Grade 1Grade 2Grade 3/4 Event (%)PEMPBOPEMPBOPEMPBO Fatigue Renal* Rash Edema Anemia Neutropenia * creatinine, GFR, ranal failure, and genitourinary-other.

25 No significant differences in drug-related grade 3/5 toxicities – except grade 3/4 neutropenia 3 2.2%8.3% p= %1.2% p=0.691 maintenance cycles ≤6> Infections Grade 3/5 Neutropenia Grade 3/4

26 Possible drug-related grade 1/2 adverse events 3 8.7%16.7% p= %11.9% p= %6.0% p= %13.1% p= %3.6% p=0.041 maintenance cycles ≤6>6 Nausea Neutropenia Sensory neuropathy Ocular/visual events Headache

27 Long-term pemetrexed maintenance impact on QoL EQ-5D results Pemetrexed well-tolerated safety profile PS changes Majority of patients maintain QoL

28 Are PARAMOUNT QoL and safety results consistent with JMEN?

29 Maintenance pemetrexed in PARAMOUNT 2 and JMEN 7,8 PARAMOUNT Paz-Ares 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 JMEN Ciuleanu 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 Well-tolerated safety profile, consistently reported QoL is well maintained and similar to placebo

30 Grades 3 or 4 PemetrexedPlacebo Hematologic toxicities Neutropenia*13(3%)0 Anemia12(3%)1(<1%) Leukoperia7(2%)1(<1%) Non-hematologic toxicities ALT1(<1%)0 AST00 Fatigue † 22(5%)1(<1%) Anorexia8(2%)0 Infection7(2%)0 Diarrhoea2(<1%)0 Nausea4(<1%)1 Vomiting1(<1%)0 Sensory neuropathy3(<1%)0 Mukositis stomatitis3(<1%)0 Rash1(<1%)0 JMEN: Drug-related toxic effects 8 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

31 Grades 3 or 4 PemetrexedPlacebo Toxicity* Laboratory Anemia161(0.6%) Neutropenia130 Non-laboratory Fatigue (asthenia, lethargy, malaise)15(4%)1(0.6%) Anorexia1(0.3%)0 Constipation00 Diarrhea00 Mucositis stomatitis1(0.3%)0 Nausea1(0.3%)0 Vomoting00 Edema00 Sensory neuropathy1(0.3%)1(0.6%) Watery eye (epiphora, tearing)00 Pain3(0.8%)0 PARAMOUNT: CTCAEs possibly related to study drug during maintenance 3 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%) Anemia161(0.6%) Neutropenia130

32 QoL in PARAMOUNT and JMEN PARAMOUNT 3 EQ-5D JMEN 7 LCSS QoL Measurement

33 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 items 7 Adapted from: 1, Mean maximum improvement (mm) 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=0.204 p=0.192 p=0.136

34 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 life 3

35 How robust are the findings of PARAMOUNT to support a change in the treatment paradigm?

36 The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm 2,5,10 The robust PARAMOUNT results are based on a number of valid points

37 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 paradigm 2,5,10 PFS:4.1 vs 2.8 months HR 0.62 (95% CI ; p<0.0001) OS:16.9 vs 14.0 months from induction HR 0.78 (95% CI ; p=0.0195)

38 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 paradigm 2,5,10 PFS: Primary endpoint Survival probability (%) pemetrexed + BSC (n=358) placebo + BSC (n=180) HR 0.62 (0.49–0.79) Time (months)

39 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 paradigm 2,5,10 Favours pemetrexed Favours placebo Subgroup OS Hazard RatioNHR (95% CI) All StageIV IIIB Induction response CR/PR SD Pre-randomisation ECOG PS Smoking statusNever-smoker Smoker SexMale Female Age (years)< ≥ < ≥ HistologyAdenocarcinoma Large cell carcinoma Other CR/PR patients:OS HR=0.81 SD patients:OS HR=0.76

40 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 paradigm 2,5,10 placebo (n=180) %* placebo (n=180) %* pemetrexed (n=359) %* pemetrexed (n=359) %* Patients with PDT Drug name Erlotinib Docetaxel † Gemcitabine Vinorelbine Investigational drug Carboplatin Paclitaxel Pemetrexed Cisplatin *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). 6472

41 What are the key takeaways for clinical practice?

42 Key PARAMOUNT takeaways Significant OS benefit in favor of Pemetrexed Continuation Maintenance 10 OS Benefit consistent across all sub-groups, with acceptable toxicity 2,10 PARAMOUNT: first study to show that Continuation Maintenance has an impact on disease course 10 Results confirm the importance of choosing the best treatment up-front, based on histology and other patient characteristics 2,

43 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, 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: 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): 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, Abstract 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 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: 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: 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.


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