Results of a pivotal phase III trial that led to approval of pemetrexed as the first maintenance therapy in locally advanced or metastatic nonsquamous non–small cell lung cancer are being published online Sept. 19 by the Lancet.
Pemetrexed maintenance improved median overall survival by 2.8 months and median progression-free survival by 1.7 months in the placebo-controlled, 663-patient trial, according to the paper by lead author Dr. Tudor Ciuleanu of the Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania, and his coinvestigators in the 20-country study (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61497-5]).
An accompanying comment by two oncologists says the strategy “merits being considered as a strong option,” as reflected by the approvals of maintenance pemetrexed in the United States and Europe. The authors of the comment raise questions about the poststudy treatment of patients who progressed, however, and call for caution in interpreting the results (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61598-1]).
“We cannot assume that the survival benefit observed in today’s trial is entirely a function of the timing of maintenance therapy,” explain Dr. Thomas E. Stinchcombe of the University of North Carolina at Chapel Hill and Dr. Howard L. West of the Swedish Cancer Institute in Seattle.
Eli Lilly and Co. sponsored the trial, which was conducted at 83 centers. The principal investigator, Dr. Chandra P. Belani of Penn State Cancer Institute in Hershey, Pennsylvania., presented the results earlier this year at the American Society of Clinical Oncology’s annual meeting.
Starting in March 2005, investigators enrolled 745 adult patients with advanced stage IIIB or IV non–small cell lung cancer (NSCLC) that had not progressed during four cycles of platinum-based chemotherapies. After exclusions of 82 patients, mostly for not meeting study criteria, 663 patients were randomized on a 2:1 basis (441 to pemetrexed and 222 to placebo).
Pemetrexed was delivered intravenously at 500 mg/m2 on day 1 of 21-day cycles until disease progression. Both study arms also received best supportive care. Intent-to-treat analyses were based on all 663 patients at a median follow-up from randomization of 11.2 months.
Median progression-free survival, the primary end point, lasted significantly longer in the pemetrexed arm than the placebo arm (4.3 months vs. 2.6 months, respectively; hazard ratio, 0.50; P = less than .0001) by investigator assessment. The improvement in median overall survival also favored pemetrexed significantly (13.4 months vs. 10.6 months; HR, 0.79; P = .12). Response and disease-control rates were reported to be better in the pemetrexed arm as well.
An independent review of scans from 581 patients produced slightly shorter survival advantages, but the differences remained statistically significant, according to the report. As with previous pemetrexed trials, the benefits were observed mainly in patients with nonsquamous histology.
Although grade 3 or higher adverse events were more common with pemetrexed (16% vs. 4%), as were drug-related discontinuations (5% vs. 1%), the investigators found the drug to be well tolerated and not the cause of any treatment-related deaths.
What concerned Dr. Stinchcombe and Dr. West in their comment was a “striking difference” in the treatments that patients in the two arms of the trial received after disease progression. Just over half of the pemetrexed group (227 patients, or 51%) received systemic therapy vs. about two-thirds of the placebo arm (149 patients, or 67%). The treatments were at the choice of the investigator, and only 41 patients (18%) of the placebo arm crossed over to pemetrexed.
The trial investigators concluded that poststudy therapy probably did not affect survival results “in view of the higher rate of follow-up treatment in the placebo group than in the pemetrexed group, low rate of crossover, and the balanced selection of therapies between groups.”
Dr. Stinchcombe and Dr. West were not so sure. They noted that about a third of the control arm had a period of stable disease, whereas 40% of those given maintenance pemetrexed had disease progression and possible side effects from the treatment. Until the timing of maintenance therapy can be dissociated from differences in access to effective second-line therapies, they suggested the following:
“For patients who have a response or stable disease with first-line chemotherapy, who tolerated platinum-based therapy without limiting toxicity while maintaining a good performance status, and who desire to continue therapy, maintenance therapy is an appealing consideration. However, if patients have had substantial toxicity with first-line therapy or desire a treatment-free interval, close monitoring and starting timely second-line therapy at disease progression remains an appropriate alternative.”
Some trial investigators, including Dr. Ciuleanu and Dr. Belani, disclosed relationships with Eli Lilly; four of the study authors were company employees with stock ownership. Dr. Stinchcombe and Dr. West disclosed serving on the speakers bureau of Lilly Oncology.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
