CHICAGO – Final results of the phase III PARAMOUNT trial support continued use of pemetrexed after pemetrexed-plus-cisplatin induction therapy for advanced, nonsquamous non-small cell lung cancer.
More patients on pemetrexed (Alimta) maintenance were alive at 1 year (58% vs. 45% of the control group) and 2 years (32% vs. 21%), investigators reported. With nearly all patients off study treatment, median overall survival from randomization was 13.9 months with pemetrexed maintenance plus best supportive care (BSC) vs. 11.0 months with BSC plus placebo.
This translates into a 22% reduction in the risk of death (HR, 0.78; log-rank P = .0195). An analysis of overall survival from the start of induction yielded the same risk reduction with the median reaching 16.9 months in patients maintained on pemetrexed vs. 14.0 months in the control group (HR 0.78; log-rank P = .0191).
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Dr. Luis Paz-Ares
The benefit of pemetrexed maintenance was consistent across all subgroups, including patients with a complete or partial response (HR 0.81) and those with stable disease (HR 0.76) after induction therapy, Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.
"This is the first study to show that continuation maintenance had a clear impact on the natural course of the disease in advanced non–small cell lung cancer, including an improvement in [progression-free survival] and [overall survival], and may support a change in the treatment paradigm in this clinical setting," said Dr. Paz-Ares of University Hospital Virgen del Rocio in Seville, Spain.
"I think we should share with our patients the information about the role of maintenance treatment, but it doesn’t mean that every single patient should be treated in this way," he said.
At last year’s ASCO meeting, the investigators reported that pemetrexed maintenance significantly reduced the study’s primary end point, the risk of disease progression (HR 0.62). Results were subsequently published in Lancet Oncology (Lancet Oncol. 2012;13:247-55).
The overall survival data were not mature at the time, leaving some clinicians to question the overall efficacy of pemetrexed maintenance and whether the delay in progression was enough to justify the potential increased toxicity with continued therapy.
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Dr. Gregory Kalemkerian
Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said the strength of the trial was the selection of a tolerable maintenance drug, although chronic fatigue with pemetrexed maintenance can be bothersome and quality of life appears similar with placebo. He also pointed out that pemetrexed and placebo patients received a median of four cycles, suggesting that most patients do not benefit.
Everyone Received Pemetrexed Induction
In the PARAMOUNT trial, 939 chemotherapy-naive patients with advanced nonsquamous NSCLC, at least one measurable lesion, and an ECOG performance status of 0 or 1 received four cycles of induction pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 of a 21-day cycle. The 539 patients who responded were then stratified by disease stage, performance status, and induction response and randomly assigned to maintenance with pemetrexed 500 mg/m2 every 21 days plus BSC or to BSC and placebo. All patients received folic acid and vitamin B12.
The median age was 61 years, about 90% of patients had stage IV disease, 86%-89% had adenocarcinoma histology, and 42%-44% had a complete or partial response to induction therapy. The mean number of maintenance cycles was 7.9 (range 1-44) for the 359 pemetrexed patients and 5 cycles for the 180 placebo patients (range 1-38).
Median follow-up for all patients was 12.5 months, and reached 24.3 months among all patients still alive.
Reassessment of progression-free survival at the time of the final analysis once again favored pemetrexed (HR 0.60), confirming the robustness of the results, Dr. Paz-Ares said of the late-breaking abstract.
The pemetrexed maintenance arm had more grade 3/4 events than did the placebo arm, notably fatigue (4.7% vs. 1.1%), anemia (6.4% vs. 0.6%), and neutropenia (5.8% vs. 0%).
Most Treated After Stopping Maintenance
In all, 64% of the pemetrexed arm and 72% of the placebo arm received postdiscontinuation therapy, mainly erlotinib (Tarceva) (40% of the pemetrexed arm and 43% of the control group). Only docetaxel (Taxotere) usage differed significantly between arms (32% vs. 43%; P = .013), he said.
During a discussion of the study, an attendee asked whether the estimate of the benefit of pemetrexed would be more credible if the study had mandated an established second-line treatment for controls.
Dr. Paz-Ares said the percentage of patients receiving second- and third-line treatment is in the high range compared with other trials and exceeds what occurs in normal practice. He called the 72% of controls receiving postdiscontinuation therapy "quite remarkable," and said he interprets the 64% of pemetrexed patients receiving additional therapy as proof these patients are "not losing any further chance of having second or third-line treatment."