Pemetrexed Continuation Maintenance Slows NSCLC Progression

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.

CHICAGO – Pemetrexed maintenance therapy following pemetrexed plus cisplatin induction reduced the risk of progression by 38% in patients with advanced nonsquamous non–small cell lung cancer in the phase III PARAMOUNT trial.

The study’s primary end point of investigator-assessed progression-free survival was 4.1 months for pemetrexed (Alimta) plus best supportive care and 2.8 months for placebo plus best supportive care (log rank P = .00006; unadjusted hazard ratio, 0.62).

Independent review, completed in 88% of patients, confirmed the robustness of the primary end point, revealing a progression-free survival of 3.9 months for pemetrexed vs. 2.6 months for placebo (log rank P = .0002; HR, 0.64), lead author Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data were not mature enough at the time of the analysis, with just 16 deaths.

"The magnitude of the benefit shown on progression-free survival, a 38% decrease in the risk of progression, is in favor of saying this is an effective treatment for patients with advanced nonsquamous non–small cell lung cancer," he said.

A previous trial (Lancet 2009;374:1432-40) showed that switching patients to pemetrexed maintenance improved the time free of cancer, but until now, it was unclear whether patients initially treated with pemetrexed would benefit from maintenance.

"This trial answers that," Dr. Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York, told reporters in a press briefing at the meeting. "I think it’s very important in that it’s an example of how we can achieve an incremental benefit in our patients by the optimal use of drugs that are already available."

Pemetrexed (Eli Lilly) is approved in combination with cisplatin as first-line therapy for advanced nonsquamous non–small cell lung cancer (NSCLC) and in the second line as maintenance therapy in patients initially treated with chemotherapy.

Standard treatment for nonsquamous NSCLC is to continue bevacizumab until disease progression, but on the basis of these results, clinicians will likely give bevacizumab with pemetrexed, Dr. Kris said in an interview.

"The guidelines don’t say that because they didn’t have any data, but this will be the data that I’m pretty confident will change the guidelines," said Dr. Kris, who also is the William and Joy Ruane Chair in Thoracic Oncology at Sloan-Kettering.

During the formal presentation of the data, invited discussant Dr. Martin Edelman, director of solid tumor oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, described the use of maintenance therapy as a contentious issue. He noted that many questions remain regarding maintenance trials, including the value of progression-free survival as an end point, how and when control patients are crossed over to active treatment, and whether the RECIST criteria should be used to determine progression.

Dr. Edelman described progression-free survival as an arbitrary end point subject to testing interval and considerable bias. To the credit of the PARAMOUNT investigators, he pointed out that there was use of independent review for this end point, but he said it still does not answer the question of overall survival.

"If one is supposed to change practice based on progression-free survival, we really need to know if particularly small differences are really beneficial," Dr. Edelman said. "That is where quality of life analysis can help us."

The PARAMOUNT investigators assessed health-related quality of life using the EuroQol-5D at baseline, day 1 of each cycle of induction or maintenance therapy, and at the 30-day postdiscontinuation visit. Compliance at all time points during the maintenance phase was more than 80%, but no statistical differences in the EQ-5D index score or its visual analog scale were observed between treatment arms, said Dr. Paz-Ares of the Hospital Universitario Virgen del Rocío, Seville, Spain.

A total of 939 patients were enrolled in the trial. They received pemetrexed 500 mg/m² on day 1 of a 21-day cycle plus cisplatin 75 mg/m² induction. In all, 539 patients whose disease had not progressed and had a performance status of 0-2 were then randomized to pemetrexed maintenance 500 mg/m² on day 1 of a 21-day cycle plus best supportive care or placebo plus best supportive care until disease progression.

Dr. Paz-Ares said pemetrexed had a well-tolerated safety profile, similar to that seen in the previous pemetrexed switch maintenance trial. The pemetrexed and placebo groups had similar drug-related deaths (0.6% for both), drug-related serious adverse events (9% vs. 3%, respectively), and discontinuations due to adverse events (5.3% vs. 3.3%). Patients in the pemetrexed arm had significantly more grade 3/4 adverse fatigue (4.2% vs. 0.6%), anemia (4.5% vs. 0.6%), and neutropenia (3.6% vs. 0%). There was one on-study death with pemetrexed (pneumonia) and placebo (not otherwise specified), and one death within 30 days with pemetrexed (endocarditis), Dr. Paz-Ares reported.

"While overall very reasonable, this still comes at a cost in terms of significant toxicity, not to mention the cost of additional treatment," Dr. Edelman observed. "We really need a cost-effectiveness analysis in this era to follow strategies of frequent visits and scanning with early institution of second-line therapy versus the maintenance approach."

Eli Lilly funded the study. Dr. Paz-Ares disclosed no relevant relationships. Several coauthors reported relationships with industry, including employment, stock ownership, honoraria, and consultancy with Lilly, which markets pemetrexed.