Advice on Timing of Pemetrexed in Advanced Lung Cancer
By Nick Mulcahy
Medscape Medical News
October 29, 2009 – The clinical trial that served as the basis for the approval of pemetrexed (Alimta, Eli Lilly) in the United States and Europe as a maintenance therapy for patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) appears in the October 24 issue of the Lancet.
Pemetrexed is limited for use in patients who have not progressed after platinum treatment. It is not indicated for patients who receive pemetrexed as part of an initial therapy.
In the new trial, pemetrexed, an intravenous chemotherapy, showed a statistically significant improvement in overall survival.
The study data were presented at the American Society of Clinical Oncology (ASCO) meeting in June. At the time, pemetrexed maintenance therapy was described as a "new treatment paradigm" for lung cancer patients by presenter Chandra P. Belani, MD, from the Penn State Cancer Institute in Hershey, Pennsylvania. Dr. Belani is also the senior author of the newly published study.
However, at ASCO, 2 lung cancer experts approached by Medscape Oncology disagreed with Dr. Belani and said that it was not clear when to start pemetrexed — immediately after initial treatment (maintenance therapy) or when progression occurred (second-line therapy).
"I don't think that all patients need immediate maintenance therapy following first-line treatment," Nasser H. Hanna, MD, commented at the time.
Dr. Hanna, who is from Indiana University in Indianapolis, also pointed out that the trial was not designed to test whether maintenance therapy was superior to using pemetrexed at time of disease progression.
Now, an editorial accompanying the newly published study echoes these concerns about treatment timing.
The new data have not "conclusively shown that the timing of subsequent therapy is crucial," write editorialists Thomas E. Stinchcombe, MD, from the University of North Carolina at Chapel Hill, and Howard J. West, MD, from the Swedish Cancer Institute in Seattle, Washington. However, they also reiterate the point that pemetrexed "can significantly improve survival."
Timing Is a Patient Choice
The editorialists suggest that using pemetrexed as a maintenance therapy is very much a patient choice.
"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," they write.
However, using pemetrexed as a second-line therapy may be preferred by other patients. "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," write Drs. Stinchcombe and West.
However, Dr. West, writing in his Medscape blog on lung cancer, expressed doubt about just how many oncologists are interested in recommending maintenance therapy, with either pemetrexed or erlotinib (OSI Pharmaceuticals). A statistically significant improvement in overall survival in this setting has recently been shown with erlotinib.
There isn't a sea change happening in the wake of these positive trials.
"From my conversations with various medical oncologists, ranging from broad community-based practice to thoracic oncology specialists, there isn't a sea change happening in the wake of these positive trials," he wrote in his Blowing Smoke blog.
If not maintenance therapy, what are clinicians more likely to use in patients with nonprogressing disease? "Many oncologists seem far more inclined to extend 1 or more agents from first line until progression than to switch to a new treatment after 4 lines of therapy," Dr. West writes.
Why Maintenance Therapy Is Not an Automatic Choice
In the new multicenter international study, NSCLC patients received standard chemotherapy; those who did not have disease progression were then randomly assigned (2:1 ratio) to receive pemetrexed plus best supportive care or placebo plus the same care.
Among the trial's 481 patients with nonsquamous NSCLC, pemetrexed resulted in statistically significantly better overall survival than placebo (15.5 vs 10.3 months; P = .002).
The editorialists also highlighted another outcome — that of disease control. They point out that the disease control rate in the patients with nonsquamous NSCLC was 58% in the pemetrexed group and 33% in the placebo group.
This is important because it shows that about one third of these lung cancer patients have a period of disease stability after initial chemotherapy — without any additional therapy — and thus would be overtreated by maintenance therapy, they note.
There is clearly a subset of patients with relatively indolent disease who would effectively be overtreated.
"There is clearly a subset of patients with relatively indolent disease who would effectively be overtreated by an immediate transition to further treatment after first-line therapy; however, we cannot reliably identify these patients," write the editorialists.
Clinicians should also evaluate the adverse effects of pemetrexed in making their recommendations about maintenance therapy, the editorialists suggest. They note that the rates of severe toxicity were low, with only 5% of patients on maintenance pemetrexed discontinuing treatment because of drug-related toxicity and only 5% requiring a dose reduction. However, concerns remain. "Mild toxicity can adversely affect a patient's quality of life," they write.
At ASCO, Dr. Hanna from Indiana University noted the same thing, citing the chemotherapy's grade 1 and 2 nonhematologic toxicities, such as diarrhea, rash, and fatigue. "We must be careful not to trivialize these," he said, noting that they affect quality of life.
Dr. Belani is a consultant to Eli Lilly, which sponsored the trial.
