ASCO 2009: One Way or the Other — Pemetrexed Extends Survival in Advanced Lung Cancer

Nick Mulcahy

June 03, 2009

June 3, 2009 (Orlando, Florida) — Pemetrexed (Alimta, Eli Lilly) following standard chemotherapy improves overall survival in patients with advanced nonsmall-cell lung cancer (NSCLC), according to study results presented here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

The study also confirms that this benefit is primarily limited to those with the nonsquamous subtype of NSCLC.

"This is the first single-agent maintenance therapy to show significant survival benefit in advanced nonsmall-cell lung cancer. Other studies of maintenance therapies have not shown this benefit," said the study's lead author, Chandra P. Belani, MD, from the Penn State Cancer Institute in Hershey, Pennsylvania, at a press conference.

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In the study, among the 482 patients with nonsquamous NSCLC, pemetrexed resulted in significantly better overall survival than placebo (15.5 vs 10.3 months; = .002).

Pemetrexed maintenance therapy is a new treatment paradigm.

"Pemetrexed maintenance therapy is a new treatment paradigm for patients with advanced nonsmall-cell lung cancer who respond to initial chemotherapy," said Dr. Belani.

However, other lung cancer experts attending the meeting differed on the appropriateness of using the drug as a maintenance therapy.

I don't think we have the answer as to when it is best to start pemetrexed.

"I don't think we have the answer as to when it is best to start pemetrexed. Should we start immediately after standard chemotherapy, or later on? All you can say is that it improves survival in nonsquamous-cell patients. In my clinic, I will present maintenance therapy as an option," said Julie Brahmer, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.

I don't think that all patients need immediate maintenance therapy following first-line treatment.

"I endorse the use of pemetrexed as a second-line therapy for advanced nonsmall-cell lung cancer, but I don't think that all patients need immediate maintenance therapy following first-line treatment," said Nasser H. Hanna, MD, from the Department of Medicine at Indiana University in Indianapolis, adding that the trial design did not allow it to definitively establish pemetrexed as a maintenance therapy.

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Drs. Brahmer and Hanna were both interviewed by Medscape Oncology.

Dr. Hanna was a discussant at a session in which the study was presented. He was also lead author of a study comparing pemetrexed with docetaxel that was presented at ASCO in 2003, which served as the basis for the drug's approval by the US Food and Drug Administration, he said. Dr. Hanna pointed out that the drug is not indicated as a maintenance therapy, but is for use either in combination with cisplatin for the initial treatment of advanced nonsquamous NSCLC or as a second-line single agent.

I think we should be adopting this in our practices.

Another lung cancer expert at the meeting was more enthusiastic. "I think we should be adopting this in our practices in patients with the nonsquamous-cell histology that is responsive," said Bruce Johnson, MD, director of the Dana-Farber/Harvard Cancer Center Lung Cancer Program in Boston, Massachusetts, who was speaking at a Highlights of the Day session.

Dr. Johnson's advice was in contrast with his comments on 2 other maintenance-therapy studies presented at the meeting involving nonchemotherapy targeted agents—the ATLAS and SATURN trials. Both showed that the impact of these agents was limited to progression-free survival and, unlike the pemetrexed trial, the 2 trials had no data on overall survival, as reported by Medscape Oncology. "It's not clear yet that the patients in these 2 trials are living longer and better," he said.

Maintenance Therapy or Second-Line Therapy: Why It Matters

The distinction between maintenance and second-line therapy is important because the latter means that patients will receive a treatment break after initial chemotherapy, said Dr. Hanna. That, in turn, allows clinicians to find out which patients with advanced disease will immediately progress (that is, within 2 to 3 months), and which will not.

"About 30% of patients will not progress for quite some time. If you give maintenance therapy following initial chemotherapy to everyone, you will overtreat the group of patients who do not progress immediately," he said.

Dr. Hanna believes that this overtreatment is detrimental because pemetrexed has adverse events, including 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. He also acknowledged that a quality-of-life analysis of patients on pemetrexed, presented at ASCO in 2008, concluded that there was "no deterioration of quality of life" with the drug. However, for patients with severely limited life spans, Dr. Hanna believes quality of life is especially important. "I want to see improved quality of life," he emphasized.

He also said that the trial was not designed to indicate whether maintenance therapy was superior to using pemetrexed at time of disease progression. "Only 19 patients who were on placebo received pemetrexed at time of disease progression because, in part, the drug was not available at all of the centers involved in the study. In short, we know the drug improves survival but not that maintenance therapy is the best way to use it," he said.

Despite his objections about pemetrexed maintenance therapy, Dr. Hanna believes "some patients do benefit from it."

So how does a clinician decide which patients should immediately get pemetrexed maintenance therapy?

According to Dr. Hanna, the approach is "especially well-suited" for patients who are "troubled" by their lung cancer symptoms and who have "pretty well-tolerated" chemotherapy. In other words, for such patients, starting pemetrexed immediately after the completion of initial chemotherapy will prolong the interval of progression-free survival. That is a "good thing" because such patients get very upset about their symptoms, he explained. However, for most patients who have completed initial chemotherapy, starting maintenance therapy immediately afterward is probably unnecessary, said Dr. Hanna.

He explained that most patients will have stabilized disease for a few months after initial chemotherapy. "If they take maintenance therapy, it's hard to tell what is at work: Is it maintenance therapy, or a durable response to chemotherapy, or is it indolent disease?," he wondered.

Study Details

In this randomized double-blind multicenter phase 3 study, patients received either pemetrexed (n = 441) or placebo (n = 222), along with the best supportive care. Patients had advanced or metastatic (stage 3B or 4) NSCLC (both squamous and nonsquamous subtypes) that had not progressed after 4 cycles of initial platinum-based chemotherapy. In a previous report, the investigators indicated that pemetrexed had better progression-free survival (< .00001) than placebo.

For all patients in the study, the pemetrexed treatment group had an overall survival of 13.4 months, compared with 10.6 months for the placebo group. As noted above, for the nonsquamous subgroup (482 patients), overall survival was 15.5 months for patients taking pemetrexed and 10.3 months for patients taking placebo.

Severe adverse effects (grade 3 or 4) were more common in the pemetrexed than in the placebo group, including fatigue (5% vs 0.5%) and low white blood cell counts (2.9% vs 0%).

Dr. Belani is a consultant to Eli Lilly, the manufacturer of pemetrexed, and has received honoraria from the company. Some of his coauthors are employees of Eli Lilly. Dr. Johnson has acted as a consultant to Genzyme; holds stock ownership in Boston Scientific, Celgene, and Johnson & Johnson; and receives royalty payments on a license to Genzyme for carrying out EGFR mutation testing. Dr. Brahmer has acted as an adviser to AstraZeneca, Eli Lilly, and ImClone. Dr. Hanna has received honoraria from Eli Lilly and Genentech.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA8000. Presented May 31, 2009.