PARAMOUNT

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Paz-Ares LG, et al. "PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non-Small-Cell Lung Cancer". Journal of Clinical Oncology. 2013. 31(23):2895-902.
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Clinical Question

Among patients with advanced or metastatic nonsquamous NSCLC who have received induction cisplatin/pemetrexed, does maintenance pemetrexed improve PFS and OS compared to placebo?

Bottom Line

Among patients with advanced or metastatic nonsquamous NSCLC who have received induction cisplatin/pemetrexed, maintenance pemetrexed improves PFS and OS compared to placebo.

Major Points

First-line therapy for advanced or metastatic NSCLC typically includes systemic chemotherapy with a platinum-based doublet, and cisplatin-pemetrexed is a standard regimen for those with nonsquamous histology. Following 4-6 cycles of first-line therapy, nonprogressors may proceed to maintenance therapy with one of the agents given as first-line therapy (so-called "continuation maintenance") or with a second-line agent ("switch maintenance"). Prior to PARAMOUNT, SATURN and JMEN (2009)[1] demonstrated both PFS and/or OS benefits to switch maintenance therapy. PARAMOUNT was undertaken to study the efficacy of continuation maintenance with pemetrexed.

Published in 2013, PARAMOUNT randomized 539 patients with stage IIIB or IV nonsquamous NSCLC to either maintenance pemetrexed or maintenance placebo. All patients had completed induction chemotherapy with four cycles of cisplatin/pemetrexed given on day 1 of each 21-day cycle, with concomitant folic acid, vitamin B12, and dexamethasone. With a median follow-up of 2 years, maintenance pemetrexed was associated with improved PFS (4.4 vs. 2.8 months) and overall survival (13.9 vs. 11 months) when compared to maintenance placebo. Pemetrexed was associated with more grade 3-4 anemia, neutropenia, and fatigue than placebo but was generally well tolerated.

Guidelines

NCCN Non-Small-Cell Lung Cancer (2013, adapted)[2]

  • Continuation maintenance pemetrexed in nonsquamous NSCLC after 4-6 cycles of induction cisplatin/pemetrexed. (Category 1)

Design

  • Randomized, double-blind, phase III, placebo-controlled trial
  • N=539
    • Maintenance pemetrexed (n=359)
    • Placebo (n=180)
  • Setting: 83 primarily European centers
  • Enrollment: 2008-2010
  • Median follow-up: 2 years
  • Analysis: Intention-to-treat
  • Primary outcome: PFS

Population

Inclusion Criteria

  • Age ≥18 years
  • ECOG PS 0-1
  • Stage IIIB-IV nonsquamous NSCLC
  • Prior radiation to <25% of bone marrow if completed and patient has recovered 30 days before enrollment
  • ≥1 measurable lesion per RECIST 1.0
  • No prior systemic chemotherapy
  • Estimated life expectancy ≥12 weeks
  • Contraceptive use by males and females with reproductive potential
  • Negative pregnancy test within 7 days of study enrollment for women with reproductive potential

Exclusion Criteria

  • Squamous and/or mixed small cell, non-small cell histology
  • Prior systemic chemotherapy for lung cancer
  • Concurrent administration of any other anti tumor therapy
  • Treatment within last 30 days with drug that has not received regulatory approval
  • Prior participation in a pemetrexed study
  • Serious cardiac condition
  • Prior serious malignancy
  • CNS metastases unless patient has completed successful local therapy and has been off corticosteroids for ?4 weeks
  • Clinically significant third space fluid collection that cannot be controlled by drainage or other procedure
  • Inability to interrupt aspirin or other NSAIDs, other than aspirin ?1.3 g/day for a 5-day period

Baseline Characteristics

  • Median age: 61 years
  • Male: 59%
  • White 94%
  • ECOG PS 0: 32%
  • Stage IV: 91%
  • Adenocarcinoma: 86%
  • CR/PR induction response: 43%

Interventions

  • All patients had undergone the induction phase of the trial, consisting of four cycles of pemetrexed 500mg/m2 and cisplatin 75mg/m2 given on day 1 of each 21-day cycle.
  • Those with ECOG PS 0-1, completion of four cycles of induction therapy, and radiologic PR, CR, or SD, proceeded to the maintenance phase.
  • The maintenance phase consisted of random 2:1 assignment to maintenance pemetrexed 500mg/m2 or maintenance placebo (normal saline) on day 1 of each 21-day cycle.
  • Maintenance therapy was continued until disease progression, patient-physician decision, or unacceptable toxicity.
  • All patients received folic acid, vitamin B12, and prophylactic dexamethasone.
  • Cycle delays ?42 days and dose adjustments were permitted for toxicity management.

Outcomes

Comparisons are maintenance pemetrexed vs. maintenance placebo.

Primary Outcome

Progression-free survival, median
4.4 vs. 2.8 months (HR 0.60; 95% CI 0.5-0.73; P<0.001)

Secondary Outcomes

Overall survival, median
13.9 vs. 11 months (HR 0.78; 95% CI 0.64-0.96; P<0.02)
1-year survival
58% vs. 45% (P<0.01)
2-year survival
32% vs. 21% (P<0.02)

Adverse Events

Anemia, grade 3-4
6.4% vs. 0.6%
Neutropenia, grade 3-4
5.8% vs. 0%
Fatigue, grade 3-4
4.7% vs. 1.1%
Febrile neutropenia, grade 3-4
1.9% vs. 0%

Criticisms

  • Only 72% of patients receiving placebo received post-discontinuation therapy; thus it is impossible to know whether the observed benefit of maintenance pemetrexed was due to the timing of therapy or to the provision of second-line therapy at all.

Funding

Eli Lily

Further Reading

  1. 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(9699):1432-40
  2. NCCN Non-small cell lung cancer guidelines, version 2.2013