Continuation maintenance therapy with pemetrexed (Alimta, Eli Lilly) offers a survival benefit in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC), compared with placebo, according to the final survival analysis of the PARAMOUNT trial.
For patients alive at the median follow-up of 24.3 months, pemetrexed therapy resulted in a significant 22% reduction in the risk for death (hazard ratio [HR], 0.78; P = .0195).
Continuation maintenance pemetrexed also led to significantly longer median overall survival than placebo (13.9 vs 11.0 months; unadjusted HR, 0.78; log-rank P = .0195). The survival benefit was consistent across all patient subgroups.
In addition, 1-year survival rates were significantly longer with pemetrexed than with placebo (58% vs 45%), as were 2-year survival rates (32% vs 21%).
The study was published online July 8 in the Journal of Clinical Oncology.
In an accompanying editorial, Howard (Jack) West, MD, from the Swedish Cancer Institute in Seattle, notes that "by incorporating our thoughtful judgment, the available data should now lead us to overcome our historical biases and recognize instead a cost-effective and well-supported means by which to improve the survival of a large, clinically defined subgroup of patients with lung cancer by several months — even without a new molecular marker and pricey novel therapy."
"Sometimes our biggest gains can be realized by determining how best to use the tools we already have," he writes.
Improved Progression-Free Survival
The PARAMOUNT study was the first large trial to demonstrate that continuation maintenance therapy can increase progression-free survival in the setting of advanced nonsquamous NSCLC. The results of the study were initially presented at the 2011 annual meeting of the American Society of Clinical Oncology, as reported at that time by Medscape Medical News.
The researchers, led by Luis G. Paz-Ares, MD, PhD, from the University Hospital Virgen del Rocío in Seville, Spain, evaluated 939 patients with advanced nonsquamous NSCLC. All participants received the standard 4 courses of first-line induction therapy with pemetrexed and cisplatin to induce disease remission. Nonprogressers with a good performance status (ECOG 0 or 1) were then randomized to either maintenance pemetrexed 500 mg/m² on day 1 of 21-day cycles (n = 359) or placebo (n = 180).
Median progression-free survival was 4.1 months in the pemetrexed group and 2.8 months in the placebo group. Continuation maintenance therapy with pemetrexed resulted in a significant 38% reduction in the risk for disease progression (HR, 0.62; P = .00006).
"Some may have significant toxicity during induction treatment, and it may be worth having a treatment break," Dr. Paz-Ares said in a press statement when the results were originally presented. However, "a patient who is having a good response in the absence of significant toxicity may be a good candidate for maintenance therapy," he added.
In their report of the final overall survival and updated safety data, the researchers explain that some studies of NSCLC maintenance therapy use a different drug for the maintenance phase than the one used for induction (switch maintenance), whereas others use a drug effective during the induction regimen for the maintenance phase (continuation maintenance).
Although the primary end point of the PARAMOUNT study was progression-free survival in the maintenance groups, it was fully powered to analyze the secondary objective of overall survival.
Of the 939 patients enrolled in the induction phase (from November 2008 to April 2010), 700 patients (75%) achieved disease control (tumor response or stable disease) and 637 (68%) completed 4 cycles of pemetrexed and cisplatin. Of this group, 539 were randomly assigned to maintenance treatment.
There were 256 deaths (71.3%) in the pemetrexed group and 141 (78.3%) in the placebo group. Most of the patients in the pemetrexed and placebo groups received at least 1 maintenance cycle before halting treatment (99.4% vs 98.9%). In addition, a median of 4 maintenance cycles was achieved in both groups (range, 1 to 44 for pemetrexed and 1 to 38 for placebo).
The researchers found overall survival from the start of induction therapy, as opposed to randomization to maintenance therapy, to be consistent with the primary analysis. There was no change in the hazard ratio, and the median overall survival measured from induction was 16.9 months for pemetrexed and 14.0 months for placebo.
Updated Safety Analysis
The updated safety analysis was conducted on data collected for 7 months (July 1, 2010 to February 7, 2011) after the primary end-point analysis. The rates of drug-related grade 3/4 anemia, neutropenia, and fatigue were significantly higher with pemetrexed than placebo, although were less than 7% in each case.
The rates of some low-grade adverse events, including anemia, neutropenia, fatigue, nausea, vomiting, mucositis/stomatitis, anorexia, and watery eye, were significantly higher in the pemetrexed group.
The study was supported by Eli Lilly. Several of the study authors have declared relationships with industry, including Eli Lilly, as noted in the paper. Dr. West has disclosed no relevant financial relationships.
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