June 8, 2011 (Chicago, Illinois) — Maintenance therapy with the chemotherapy drug pemetrexed (Alimta, Bristol-Myers Squibb) improves progression-free survival in patients with advanced nonsquamous nonsmall-cell lung cancer who received pemetrexed as part of their first-line chemotherapy regimen, according a phase 3 placebo-controlled trial.
The study, known as PARAMOUNT, is the first large trial to demonstrate that using "continuation maintenance" therapy can increase progression-free survival in this setting. The results were presented here at the American Society of Clinical Oncology 2011 Annual Meeting.
In an earlier study, pemetrexed was found to increase progression-free survival and overall survival, compared with placebo in this same patient population, when used in "switch maintenance," which refers to its use after induction with a regimen that did not include pemetrexed. However, whether pemetrexed was used as switch maintenance or second-line therapy was debated in that earlier study.
In PARAMOUNT, there is no debate about whether the trial fully included maintenance therapy. The 939 patients were all given the standard 4 courses of first-line induction treatment with pemetrexed and cisplatin to induce disease remission. Nonprogressers with a good performance status were then randomized (in a 2:1 ratio) to either maintenance pemetrexed (n = 359) or placebo (n = 180).
Median progression-free survival was 4.1 months in the pemetrexed group, compared with 2.8 months in the placebo group. Continuation maintenance therapy with pemetrexed resulted in a significant 38% reduction in the risk for disease progression (hazard ratio, 0.62; P = .00006).
"The results may support its use in this clinical context," said lead author Luis Paz-Ares, MD, PhD, from Seville University Hospital in Spain, referring to the use of pemetrexed in continuation maintenance therapy. He highlighted study results at a meeting press conference.
The study is powered to provide overall survival findings, but the data are not yet mature, said Dr. Paz-Ares.
The findings indicate that continuation maintenance with pemetrexed provides "an incremental benefit," said Mark Kris, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press conference.
The progression-free survival benefit is "not a discovery that will radically change a patient's life," he said.
The study answers the question of what clinicians should do with patients who start pemetrexed and do well, Dr. Kris added.
However, the results do not indicate that maintenance therapy is meant for every responsive patient, explained Dr. Paz-Ares.
"Some may have significant toxicity during induction treatment, and it may be worth having a treatment break. On the other hand, a patient who is having a good response in the absence of significant toxicity may be a good candidate for maintenance therapy," he said in a press statement.
Maintenance therapy for responders who have minimal toxicity is a good rule of thumb, said Roman Perez-Soler, MD, from Montefiore Medical Center and Albert Einstein College of Medicine in the Bronx, New York, who was not involved in the study.
However, Dr. Perez-Soler and another lung cancer expert, Martin Edelman, MD, from University of Maryland Greenebaum Cancer Center in Baltimore, look forward to learning the overall survival results before having firm opinions about pemetrexed maintenance.
"I hope survival will be impacted. . . . If not impacted, this [maintenance] is still an option, but many physicians may prefer to give a drug vacation and follow closely," Dr. Perez-Soler told Medscape Medical News.
Dr. Edelman, who acted as discussant for the study at its oral presentation, said that the findings "may mean that a treatment that is actually working should be continued somewhat longer."
But it will be "interesting" to see "how this holds up" when overall survival data are final, he added.
Novel Finding
Other trials in this setting, such as the SATURN trial, have not found that responders to first-line therapy have the "degree of benefit" with maintenance therapy that patients with stable disease have after first-line therapy, said Dr. Edelman.
PARAMOUNT found the opposite, he observed. Responders (complete and partial) to initial treatment with pemetrexed and cisplatin had a statistically significant improvement on continuation maintenance, whereas those who had stable disease did not. In other words, the first-line responders turned out to be better patients for maintenance therapy than patients with stable disease after initial treatment.
This begs a question: "Is there a benefit from [maintenance therapy] in patients who have an unequivocal response to initial treatment?," Dr. Edelman asked.
"Data are conflicting or not reported," he answered, referring to the body of literature on maintenance therapy, both continuation and switch.
Dr. Edelman also stated that the strategy of maintenance therapy, which he called "ever-contentious," is in need of a cost-effectiveness analysis — especially in light of the extra toxicity experienced with the additional treatment — to help determine its overall value.
However, Dr. Paz-Ares, reported that, in PARAMOUNT, there was no statistically significant difference in a quality-of-life measure between the treatment and placebo groups in the study.
Study Details
The induction phase of this study specified 4 cycles of induction pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients who had not progressed during pemetrexed and cisplatin induction and who had an Eastern Cooperative Oncology Group performance status of 0/1 were randomized (stratified for disease stage, performance status, and induction response) to maintenance pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (n = 359) or to placebo plus best supportive care (n = 180) until disease progression. All patients received vitamin B12, folic acid, and dexamethasone. Patient characteristics were balanced between the groups, report the authors. The median age was 61 years, 58% of participants were male, and 95% were white. Nearly a third had the best performance status possible (32% had a performance status of 0), 91% had stage IV disease, and 87% had adenocarcinomas. Nearly half of patients (45%) had a complete or partial response to induction.
"Pemetrexed was well tolerated," said Dr. Paz-Ares. The drug-related serious adverse event rate was 8.9% in the pemetrexed group, and 9.2% of patients had grade 3/4 adverse events. In the placebo group, the rates were 2.8% and 0.6%, respectively. Discontinuations because of adverse events were 5.3% in the pemetrexed group and 3.3% in the placebo group.
Some of the authors report financial relationships or employment with Eli Lilly, sponsor of the trial.
American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract CRA7510. Presented June 5, 2011.
The study, known as PARAMOUNT, is the first large trial to demonstrate that using "continuation maintenance" therapy can increase progression-free survival in this setting. The results were presented here at the American Society of Clinical Oncology 2011 Annual Meeting.
In an earlier study, pemetrexed was found to increase progression-free survival and overall survival, compared with placebo in this same patient population, when used in "switch maintenance," which refers to its use after induction with a regimen that did not include pemetrexed. However, whether pemetrexed was used as switch maintenance or second-line therapy was debated in that earlier study.
In PARAMOUNT, there is no debate about whether the trial fully included maintenance therapy. The 939 patients were all given the standard 4 courses of first-line induction treatment with pemetrexed and cisplatin to induce disease remission. Nonprogressers with a good performance status were then randomized (in a 2:1 ratio) to either maintenance pemetrexed (n = 359) or placebo (n = 180).
Median progression-free survival was 4.1 months in the pemetrexed group, compared with 2.8 months in the placebo group. Continuation maintenance therapy with pemetrexed resulted in a significant 38% reduction in the risk for disease progression (hazard ratio, 0.62; P = .00006).
"The results may support its use in this clinical context," said lead author Luis Paz-Ares, MD, PhD, from Seville University Hospital in Spain, referring to the use of pemetrexed in continuation maintenance therapy. He highlighted study results at a meeting press conference.
The study is powered to provide overall survival findings, but the data are not yet mature, said Dr. Paz-Ares.
The findings indicate that continuation maintenance with pemetrexed provides "an incremental benefit," said Mark Kris, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press conference.
The progression-free survival benefit is "not a discovery that will radically change a patient's life," he said.
The study answers the question of what clinicians should do with patients who start pemetrexed and do well, Dr. Kris added.
However, the results do not indicate that maintenance therapy is meant for every responsive patient, explained Dr. Paz-Ares.
"Some may have significant toxicity during induction treatment, and it may be worth having a treatment break. On the other hand, a patient who is having a good response in the absence of significant toxicity may be a good candidate for maintenance therapy," he said in a press statement.
Maintenance therapy for responders who have minimal toxicity is a good rule of thumb, said Roman Perez-Soler, MD, from Montefiore Medical Center and Albert Einstein College of Medicine in the Bronx, New York, who was not involved in the study.
However, Dr. Perez-Soler and another lung cancer expert, Martin Edelman, MD, from University of Maryland Greenebaum Cancer Center in Baltimore, look forward to learning the overall survival results before having firm opinions about pemetrexed maintenance.
"I hope survival will be impacted. . . . If not impacted, this [maintenance] is still an option, but many physicians may prefer to give a drug vacation and follow closely," Dr. Perez-Soler told Medscape Medical News.
Dr. Edelman, who acted as discussant for the study at its oral presentation, said that the findings "may mean that a treatment that is actually working should be continued somewhat longer."
But it will be "interesting" to see "how this holds up" when overall survival data are final, he added.
Novel Finding
Other trials in this setting, such as the SATURN trial, have not found that responders to first-line therapy have the "degree of benefit" with maintenance therapy that patients with stable disease have after first-line therapy, said Dr. Edelman.
PARAMOUNT found the opposite, he observed. Responders (complete and partial) to initial treatment with pemetrexed and cisplatin had a statistically significant improvement on continuation maintenance, whereas those who had stable disease did not. In other words, the first-line responders turned out to be better patients for maintenance therapy than patients with stable disease after initial treatment.
This begs a question: "Is there a benefit from [maintenance therapy] in patients who have an unequivocal response to initial treatment?," Dr. Edelman asked.
"Data are conflicting or not reported," he answered, referring to the body of literature on maintenance therapy, both continuation and switch.
Dr. Edelman also stated that the strategy of maintenance therapy, which he called "ever-contentious," is in need of a cost-effectiveness analysis — especially in light of the extra toxicity experienced with the additional treatment — to help determine its overall value.
However, Dr. Paz-Ares, reported that, in PARAMOUNT, there was no statistically significant difference in a quality-of-life measure between the treatment and placebo groups in the study.
Study Details
The induction phase of this study specified 4 cycles of induction pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients who had not progressed during pemetrexed and cisplatin induction and who had an Eastern Cooperative Oncology Group performance status of 0/1 were randomized (stratified for disease stage, performance status, and induction response) to maintenance pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (n = 359) or to placebo plus best supportive care (n = 180) until disease progression. All patients received vitamin B12, folic acid, and dexamethasone. Patient characteristics were balanced between the groups, report the authors. The median age was 61 years, 58% of participants were male, and 95% were white. Nearly a third had the best performance status possible (32% had a performance status of 0), 91% had stage IV disease, and 87% had adenocarcinomas. Nearly half of patients (45%) had a complete or partial response to induction.
"Pemetrexed was well tolerated," said Dr. Paz-Ares. The drug-related serious adverse event rate was 8.9% in the pemetrexed group, and 9.2% of patients had grade 3/4 adverse events. In the placebo group, the rates were 2.8% and 0.6%, respectively. Discontinuations because of adverse events were 5.3% in the pemetrexed group and 3.3% in the placebo group.
Some of the authors report financial relationships or employment with Eli Lilly, sponsor of the trial.
American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract CRA7510. Presented June 5, 2011.
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