Pemetrexed (Page 6 of 9)

Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m² intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B₁₂ , and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN.

A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies.

Efficacy results are presented in Table 13 and Figure 5.

Table 13: Efficacy Results in Study JMEN

Efficacy Parameter	Pemetrexed	Placebo
Overall survival	N=441	N=222
Median (months) (95% CI)	13.4(11.9-15.9)	10.6(8.7-12)
Hazard ratioa (95% CI)	0.79(0.65-0.95)
p-value	p=0.012
Progression-free survival per independent review	N=387	N=194
Median (months) (95% CI)	4(3.1-4.4)	2(1.5-2.8)
Hazard ratioa (95% CI)	0.60(0.49-0.73)
p-value	p<0.00001

^a Hazard ratios are adjusted for multiplicity but not for stratification variables.

Figure 5: Kaplan-Meier Curves for Overall Survival in Study JMEN

The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 14 and Figures 6 and 7.

Table 14: Efficacy Results in Study JMEN by Histologic Subgroup

Efficacy Parameter	Overall Survival		Progression-Free Survival Per Independent Review
	Pemetrexed (N=441)	Placebo (N=222)	Pemetrexed (N=387)	Placebo (N=194)
Non-squamous NSCLC (n=481)
Median (months)	15.5	10.3	4.4	1.8
HRa (95% CI)	0.7(0.56-0.88)		0.47(0.37-0.6)
Adenocarcinoma (n=328)
Median (months)	16.8	11.5	4.6	2.7
HRa (95% CI)	0.73(0.56-0.96)		0.51(0.38-0.68)
Large cell carcinoma (n=20)
Median (months)	8.4	7.9	4.5	1.5
HRa (95% CI)	0.98(0.36-2.65)		0.4(0.12-1.29)
Otherb (n=133)
Median (months)	11.3	7.7	4.1	1.6
HRa (95% CI)	0.61 (0.40-0.94)		0.44(0.28-0.68)
Squamous cell NSCLC (n=182)
Median (months)	9.9	10.8	2.4	2.5
HRa (95% CI)	1.07(0.77-1.5)		1.03(0.71-1.49)

^a Hazard ratios are not adjusted for multiplicity

^b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.

Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN

Figure 7: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m² intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B₁₂ , and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization.

A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies.

Efficacy results for PARAMOUNT are presented in Table 15 and Figure 8.

Table 15: Efficacy Results in PARAMOUNT

Efficacy Parameter	Pemetrexed (N=359)	Placebo (N=180)
Overall survival
Median (months) (95% CI)	13.9(12.8-16)	11(10-12.5)
Hazard ratio (HR)a (95% CI)	0.78(0.64-0.96)
p-value	p=0.02
Progression-free survivalb
Median (months) (95% CI)	4.1(3.2-4.6)	2.8(2.6-3.1)
Hazard ratio (HR)a (95% CI)	0.62(0.49-0.79)
p-value	p<0.0001

^a Hazard ratios are adjusted for multiplicity but not for stratification variables.

^b Based on investigator’s assessment.

Figure 8: Kaplan-Meier Curves for Overall Survival in PARAMOUNT