CHICAGO -- Survival in advanced lung cancer improved significantly in patients who received who received maintenance chemotherapy after induction with a platinum-based regimen, investigators reported here.
Final results of the multinational PARAMOUNT trial showed a median overall survival of 13.9 months in patients with nonsquamous non-small cell lung cancer (NSCLC) who received maintenance therapy with pemetrexed (Alimta) and 11.0 months with placebo (P=0.0195).
The results provided additional support for pemetrexed maintenance therapy, which had already demonstrated a beneficial effect on the risk of progression.
"The survival results were internally consistent across all subgroups, including response to induction therapy -- complete or partial response versus stable disease," Luis Paz-Ares, MD, of the Biomedicine Institute of Seville in Spain, said at the conclusion of a presentation at the American Society of Clinical Oncology.
"PARAMOUNT is the first study to show that continuation maintenance has an impact on the disease course of advanced NSCLC, including progression-free and overall survival, supporting a change in the treatment paradigm in this setting."
Conducted in Europe and India, the PARAMOUNT trial evaluated the impact of maintenance therapy after induction with a chemotherapy doublet consisting of two drugs with proven efficacy in NSCLC: pemetrexed and cisplatin.
The trial involved patients with stage IIIB/IV NSCLC treated with four cycles of the induction regimen. Patients who had stable disease or objective response were then randomized to pemetrexed or placebo, plus best supportive care, administered every 21 days until progression.
The primary endpoint was PFS, which was significantly better in patients randomized to maintenance therapy, as Paz-Ares reported at the 2011 ASCO meeting. At that point the data were not mature enough to permit an analysis of overall survival, which was a secondary endpoint of the trial.
The 539 patients who qualified for the randomized phase of the trial were allocated 2:1 to pemetrexed or placebo. The patients had a median age of about 61, 75% to 80% were current or former smokers, 90% had stage IV disease, and 40% to 45% had objective responses to induction therapy.
The trial had a median follow-up of 12.5 months, including 24.3 months for patients who remained alive at the end of the study.
The 2.9-month improvement in median survival with pemetrexed translated into a 22% reduction in the mortality hazard (95% CI 0.64 to 0.96). The results showed that the pemetrexed maintenance arm had a 1-year survival of 58% and 2-year survival of 32%. Corresponding figures for the placebo group were 45% and 21%.
The primary survival analysis was the time from randomization. When assessed from the end of induction therapy, an identical difference emerged between the groups: 16.9 months with pemetrexed and 14.0 months with placebo (P=0.0191).
The survival benefit with pemetrexed maintenance therapy was similar in patients who had objective responses to induction therapy and those who had stable disease as best response, said Paz-Ares.
The most frequent adverse events in the pemetrexed maintenance arm were fatigue (17.5%), nausea (13.4%), and anemia (11.7%). The most common grade 3/4 adverse events were anemia (6.4%), neutropenia (5.8%), fatigue (4.7%), and leukopenia (2.2%).
Invited discussant Gregory P. Kalemkerian, MD, of the University of Michigan in Ann Arbor, said that continuation maintenance therapy has two primary goals for patients with advanced NSCLC: prolong survival and improve or maintain quality of life.
An optimal agent for maintenance therapy should improve a clinically relevant outcome, be well tolerated, have minimal cumulative toxicity, and be cost-effective.
Pemetrexed met one of the goals and exhibited three of the four qualities of an optimal maintenance agent, Kalemkerian continued.
A previous report of PFS results from PARAMOUNT showed that pemetrexed-treated patients had quality of life similar to that of the placebo group, an observation that "doesn't exactly arouse support." Cost-effectiveness remains unclear.
"We know that continuation maintenance therapy with pemetrexed prolongs overall survival," said Kalemkerian. "We know that continuation maintenance therapy with bevacizumab (Avastin) is standard of care, but we do not know if it is beneficial. There is no statistically or clinically significant survival benefit for continuation maintenance therapy with other agents or regimens."
"There is no evidence that continuation maintenance therapy improves quality of life," Kalemkerian continued. "Everyone does not need maintenance therapy. In the PARAMOUNT trial, one patient received 38 cycles of placebo, so clearly, some patients do well without maintenance therapy."
The study was supported by Eli Lilly, whose employees were among co-investigators.
Paz-Ares disclosed relationships with Bayer, Lilly, Pfizer, and Roche.
Kalemkerian had no relevant disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
American Society of Clinical OncologySource Reference: Paz-Ares L, et al "PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC for advanced nonsquamous non-small cell lung cancer" ASCO 2012; Abstract LBA7507.