Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC

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

PARAMOUNT study design: why were 4 cycles of induction used?


1

Does PARAMOUNT address the question of pemetrexed clinical resistance?


2

What is the impact of the PARAMOUNT survival results on the treatment paradigm in advanced NSCLC?


3

Based on the results of PARAMOUNT, can response to induction determine who should receive maintenance therapy?


4Did study patients get 2nd-line treatments? Were there any differences between the two study arms?

Did study patients get 2nd-line treatments? Were there any differences between the two study arms?

5Are the PARAMOUNTresults meaningful from a patient perspective?

Are the PARAMOUNTresults meaningful from a patient perspective?

6

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?


7How is PARAMOUNT different from study JMEN?

How is PARAMOUNT different from study JMEN?

8Can we compare pemetrexed continuation versus pemetrexed switch maintenance therapies?

Can we compare pemetrexed continuation versus pemetrexed switch maintenance therapies?

9


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


Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients9

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%

Survival time (months)

0 1 2 3 54

placebo (n=76)

placebo (n=94)

2.6 (1.6–2.9)

3.0 (2.8–4.1)

Numbers in brackets are the 95% CI values.

PARAMOUNT: median PFS according to response to induction treatment9

pemetrexed (n=166)

pemetrexed (n=186)

4.1 (3.1–6.0)

4.1 (3.0–4.6)


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

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



HR=0.62 (95% CI 0.49–0.79); p<0.0001


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/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC10


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



HR=0.78 (95% CI 0.64–0.96); p=0.0195

13.911.0HR 0.78

36



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



HR=0.78 (95% CI 0.64–0.96); p=0.0195


32%

21%

36

24-months survival rate32%

PARAMOUNT: Final OS from induction 9,10


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



HR=0.78 (95% CI 0.64–0.96); p=0.0191


16.914.0

36

PFSHR 0.62

p<0.000195% CI 0.49 – 0.79

PFSHR 0.62

p<0.000195% CI 0.49 – 0.79

OS*HR 0.78

p=0.019595% CI 0.64 – 0.96

OS*HR 0.78

p=0.019595% CI 0.64 – 0.96

* Overall survival from randomisation

PARAMOUNT: PFS and OS results 9,10


Progression-free survival HRs in subgroups9,11

539

49049

234 285

363

173

117 418

313 226

447 92

350 189

47136 32

Favours placebo

All

Stage

Induction response

Pre-randomisation ECOG PS

Smoking status

Sex

Age (years)

Histology

IVIIIB

CR/PRSD

10

Never-smokerSmoker

MaleFemale

<70 ≥70<65 ≥65

Adenocarcinoma Large cell carcinoma Other

0.78

0.790.82

0.810.76

0.820.70

0.750.83

0.820.73

0.750.890.820.71

0.800.440.81

0.2 0.4 0.8 1.2 1.60 2.00.6 1 1.4 1.8Favours

pemetrexed

HR (95% CI)N

Pemetrexed continuation maintenance helps improve survival for patients achieving either SD or a tumour response following pemetrexed-based induction10

Time from randomisation (months)6 12 18 240

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

pemetrexed + BSC placebo + BSC

36

CR/PRHR 0.81

30Time 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 placebo + BSC

SDHR 0.76

36

HR (95% CI)N

All 539 0.78

Induction response

CR/PR 234 0.81

SD 285 0.76

Favours pemetrexed Favours placebo0.2 0.4 0.8 1.2 1.60 2.00.6 1 1.4 1.8

Did study patients get 2nd-line treatments? Were there any difference between the two study arms?

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

PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)10

72

Are the PARAMOUNT results meaningful from a patient perspective?

What matters to patients

longer survival

time

potential additional

toxicity




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



HR=0.78 (95% CI 0.64–0.96); p=0.0195

13.911.0HR 0.78

36

2-year survival rate10

pemetrexed + BSC 32%placebo+ BSC 21%

* 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.

placebo (n=180)

Fatigue†

Mucositis/stomatitis‡

Vomiting

Neuropathy

pemetrexed (n=359)

0 10 20 30 0 10 20 30

Anaemia†

Neutropenia†

Leucopenia

Nausea

ALT (SGPT)

Values expressed as % of randomised patients

PARAMOUNT: possible drug related CTCAEs*,10

4.7%

0.6%

0.3%

0.3%

6.4%0.6%

5.8%0%%

2.2% 0%

0.6%0%

1.1%

0%

0%

0.6%0.3%

0%

PARAMOUNT: EQ-5D results9

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

What matters to patients

longer survival

time

potential additional

toxicity

PARAMOUNT demonstrated that pemetrexed continuation maintenance

• has a positive risk/benefit ratio

• can meet all the requirements for an acceptable continuation maintenance therapy

PARAMOUNT demonstrated that pemetrexed continuation maintenance

• has a positive risk/benefit ratio

• can meet all the requirements for an acceptable continuation maintenance therapy


PARAMOUNT induction vs JMDB8

InductionCompleting ≥ 4 cycles

JMDBJMDB

71%

PARAMOUNTPARAMOUNT

68%

28.6%63.8%

30.1%74.5%

Response and controlTumour response ratesDisease control rates

21.4%21.9%

13.7%14.8%

ToxicityLaboratory toxicitiesNon-laboratory toxicities

How is PARAMOUNT different from study JMEN?

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

JMENJMENPARAMOUNTPARAMOUNT

PFS

Yes(18–24 mos btwn PFS & OS)

Pemetrexed vs placebo

Yes

Pemetrexed and erlotinibapproved in maintenance

PFS

Yes(1 yr btwn PFS & OS)

Pemetrexed vs placebo

Yes

No therapies approved for maintenance

*Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.

How is PARAMOUNT different from Study JMEN?9,12

Pemetrexed + cisplatinDocetaxel + platinumPaclitaxel + platinum

Gemcitabine + platinum

Induction plus maintenance

Non-squamous* onlyprimarily EU

Maintenance only

All histologiesglobal

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

Gain positive risk/benefit

Maximise outcomes and patient survival

Keep other effective treatments available

for further lines

Approach to maximise outcomes for patients throughout their multiple lines of therapy

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.

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Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC