1. Belani CP et al. ASCO 2009; Abstract CRA8000. (Oral Presentation)
Maintenance Pemetrexed Plus Best Supportive Care (BSC) versus Placebo Plus BSC: A Phase III Study in NSCLC
Belani CP et al.
ASCO 2009; Abstract CRA8000. (Oral Presentation)

2. Introduction
Optimal duration of treatment with 1st-line platinum-doublet is 4-6 cycles
Treatment guidelines recommend waiting until disease progression to administer 2nd- and 3rd-line regimens
Recent studies of maintenance therapy (sequential, consolidation, “switch” to a new agent), following 1st-line therapy, have not demonstrated a survival benefit
Current study objectives:
Evaluate pemetrexed, a multitargeted antifolate, as maintenance therapy in patients with advanced NSCLC who have not progressed on 4 cycles of first-line platinum-based chemotherapy
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

3. Phase III Randomized, Double-Blind Placebo-Controlled Trial
Pemetrexed 500 mg/m2 (d1 q3wks) + best supportive care (BSC)
(N = 441)*
Eligibility
Stage IIIB/IV NSCLC
4 prior cycles of platinum + taxane or gemcitabine, with complete or partial response (CR or PR) or stable disease (SD) 2 R
Placebo (d1 q3wks) + BSC
(N = 222)* 1
*B12, folate, and dexamethasone
administered in both arms
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

4. Efficacy: Progression-Free and Overall Survival (N = 663)
Placebo
Pemetrexed
Hazard ratio
P value
Progression-free survival
2.0 mos
4.0 mos
0.60
<
Non-squamous (n = 481)
Squamous (n = 182)
1.8 mos
2.5 mos
4.4 mos
2.4 mos
0.47
1.03
0.896
Overall survival (ITT)
10.6 mos
13.4 mos
0.79
0.012
10.3 mos
10.8 mos
15.5 mos
9.9 mos
0.70
1.07
0.002
0.678
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

5. Efficacy: Response Rate and Disease Control Rate*
Placebo
Pemetrexed
P value
Response rate
(CR + PR)*
0.5%
3.4%
0.042
Disease control rate
(CR + PR + SD)*
28.9%
49.1%
<0.001
*Tumor response based on independently reviewed population (N = 581)
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

6. Post-Study Systemic Therapy
Placebo
(n = 222)
Pemetrexed
(n = 441)
Patients with post-study therapy
67%
52%
EGFR TKI (erlotinib or gefitinib)
31%
35%
Taxane (docetaxel or paclitaxel)
26%
Vinorelbine
17%
13%
Platinum agent (cis- or carboplatin)
16%
12%
Gemcitabine
14% 9%
19% 1%
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

7. Summary and Conclusions
The use of pemetrexed in this study is the first randomized, double-blind, placebo-controlled study demonstrating a significant OS benefit with maintenance therapy in advanced NSCLC (13.4 mos vs 10.6 mos, HR = 0.79, p = 0.012)
Non-squamous histology predictive of improved efficacy with pemetrexed (OS of 15.5 mos vs 10.3 mos, HR = 0.70, p = 0.002)
No OS benefit for patients with squamous histology
Pemetrexed is well tolerated and devoid of cumulative toxicity
Grade III/IV AEs in ≤ 5% of patients with pemetrexed
Increased Grade III/IV fatigue (5% vs 1%) and neutropenia (3% vs 0%) with pemetrexed
Source: Belani CP et al. ASCO 2009; Abstract CRA8000.

8. Implications for Pemetrexed Trial
Only 19% of patients on the placebo arm received pemetrexed
Would survival benefit be preserved if more patients received pemetrexed after progression, as delayed 2nd-line therapy?
The current study does not definitively prove that a maintenance strategy improves survival
Do any patients need maintenance treatment prior to disease progression? Yes, some would benefit
Do all patients require it? Definitely not. Many patients will be unnecessarily overtreated
~30% of patients can still enjoy a treatment holiday for 3-6 months
Frequent, close follow-up is necessary to avoid losing the opportunity to treat patients
Source: Hanna NJ. ASCO 2009; Lung Oral Metastatic Discussion.