Should maintenance therapy serve as the standard of care in metastatic non-small-cell lung cancer?

The current treatment regimen for non–small–cell lung cancer calls for patients to undergo four to six cycles of platinum–based doublet therapy, followed by clinical or imaging surveillance for signs of disease progression. If and when the latter occurs, second–line therapy is initiated. But recent studies have indicated that maintenance therapy, or starting second–line therapy in the absence of disease progression, can improve overall survival.

Major trials, such as SATURN and ATLAS, have investigated agents that are generally not used in first–line regimens but have proven effective as second–line treatment. Tracey L. Evans, MD, and Thomas E. Stinchcombe, MD, debated the relative merits of NSCLC maintenance therapy with Dr. Evans speaking in favor of its use as standard care and Dr. Stinchcombe speaking against it as a matter of routine practice.

Dr. Evans is an assistant professor of hematology/oncology in the department of medicine at Philadelphia’s Abramson Cancer Center, University of Pennsylvania. Dr. Stinchcombe is an associate professor in the department of medicine, multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.

Longer treatment time but with less toxicity
While standard NSCLC treatment regimens have demonstrated the ability to improve progression–free survival (PFS), boosting overall survival (OS) remained an elusive outcome-at least until multiple studies with bevacizumab (Avastin), cetuximab (Erbitux), and erlotinib (Tarceva) finally broke that losing streak (N Engl J Med 355:2542–2550, 2006; Lancet 373:1525–1531, 2009; N Engl J Med 353:123–132, 2005).

All three of these drugs offered improved OS over standard of care through chronic administration until disease progression, Dr. Evans pointed out. So using those regimens could be considered one form of maintenance chemotherapy, although the benefits were modest at one to two months.

Pemetrexed (Alimta) in the second–line setting was another boon to the NSCLC armamentarium, turning in noninferior OS and PFS compared with second–line docetaxel (Taxotere) and proving to be better tolerated by patients (J Clin Oncol 22:1589–1597, 2004).

How are these agents best used and combined as maintenance therapy, and what benefits do they offer? One option is to have the patient continue on a portion of standard treatment. The phase III JMEN trial led by Tudor Ciuleanu, MD, put patients on cisplatin–based or carboplatin–based chemotherapy paired with docetaxel, paclitaxel, or gemcitabine (Gemzar).

Patients who did not have progressive disease were immediately placed on pemetrexed or placebo, which was given every three weeks until disease progression (Lancet 374:1432–1440, 2009).

If disease progression occurred, then subsequent therapy was left to the discretion of the treating physician. As a result, those patients on the placebo arm were receiving the current standard of care, Dr. Evans said. According to the results, all patients on the pemetrexed arm had an improvement in median OS of 2.8 months while those patients with nonsquamous cell tumors had even better results at 5.2 months.

Did the OS extension come at the price of higher toxicity? No, Dr. Evans said. "If we look at the grade 3–4 toxicities [in the pemetrexed arm], we see they’re all in the single digits," she said. "The most common grade 3–4 toxicity was fatigue, which came in at 5%. You might then say, ‘Even minor toxicities are relevant when we’re talking about a treatment we’re going to have patients on indefinitely.’ And that’s true." Indeed, among patients in the pemetrexed group, there were more cases of nausea, neutropenia, and fatigue, she added.

"But why do we have to be such a glass–half–empty sort of society? I think we should be optimistic," Dr. Evans said. "Twenty–four percent of patients in the pemetrexed arm reported some element of fatigue, compared with 10% of the placebo arm. But 76% of the patients in the pemetrexed arm reported no fatigue. I think that’s pretty good. If we also look at discontinuation for toxicity, this was a pretty rare event for patients in the actual treatment arm: Only 5% of patients had to discontinue [treatment] because of toxicity compared with 1% in the placebo arm."

Dr. Evans then turned to the phase III SATURN study, which tested erlotinib as maintenance treatment in advanced NSCLC. Patients received four cycles of platinum–based doublet chemotherapy, she said, and in the absence of disease progression were randomized 1:1 to receive either erlotinib or placebo. "And they continued on treatment until progressive disease," Dr. Evans explained.

The results showed a significant PFS benefit for 443 patients on maintenance erlotinib (12.3 weeks) vs 445 patients on placebo (11.1 weeks). The median OS benefit was a little less impressive, inching from 11 months to 12 months in the erlotinib arm, but it was statistically significant (Lancet Oncol 11:521–529, 2010; 2009 World Conference on Lung Cancer abstract A2.1).

"There was a biomarker companion to this study, and it showed that patients who were chemically positive for [epidermal growth factor receptor] did a little better," Dr. Evans said. "The EGFR mutation patients actually had the best PFS benefit from maintenance erlotinib, but they did not have an OS benefit. Once again the toxicities are relevant: The toxicities were generally pretty manageable and very much in line with what we know about erlotinib," she said, with the most serious adverse event being pneumonia (2% in erlotinib arm vs < 1% for placebo arm). The most common grade 3 or higher adverse events were rash (9% in erlotinib group vs none in placebo group) and diarrhea (2% in erlotinib arm vs none in placebo arm).

Similar to SATURN was the ATLAS study, which compared bevacizumab plus erlotinib to bevacizumab plus placebo as maintenance therapy after four cycles of bevacizumab plus platinum–containing doublet chemotherapy in patients with stage IIIb/IV NSCLC (American Society of Clinical Oncology [ASCO] abstract LBA 8002).

The results showed a non–statistically significant improvement in PFS: 4.8 months for bevacizumab plus erlotinib vs 3.7 months for bevacizumab plus placebo. In a poster presentation at ASCO 2010, the ATLAS investigators offered OS results, which came in at 15.9 months for the experimental arm vs 13.9 months for the placebo arm, but these results did not reach statistical significance (abstract 7526).

"It turns out that the FDA is on my side, which should count for something," Dr. Evans said. "On July 2, 2009, pemetrexed was approved for maintenance therapy and on April 16, 2010, erlotinib was approved for maintenance therapy."

That leaves docetaxel, which is currently approved only for first– and second–line use. Dr. Evans cited results from a new study led by Panos Fidias, MD, and colleagues that looked at second–line therapy with immediate delivery of docetaxel compared with delayed docetaxel after first–line therapy with gemcitabine plus carboplatin in advanced NSCLC.

They found that the median PFS with immediate docetaxel was 5.7 months vs 2.7 months with delayed treatment. The OS did not reach statistical significance, but there was a trend toward a better outcome with immediate (12.3 months) vs delayed (9.7 months) treatment (J Clin Oncol 27:591–598, 2009).

"This study demonstrates what I really want to hit home about maintenance therapy," Dr. Evans said. The [authors] did an analysis to show that, even though it looks like the patients who get the immediate docetaxel do better than [those who get] delayed docetaxel, if you focus in on just those patients who actually received [docetaxel] treatment, there was no difference in the median survival. So you can make the argument that it doesn’t matter if the patient gets [second–line therapy] later or earlier, [he] just has to get it. As long as we make sure patients get it, then we’re fine. We may not even need maintenance therapy."

One of many options for an incurable disease
Dr. Stinchcombe agreed that patients should receive second–line therapy at some point during their treatment period. But the magnitude of benefit with maintenance therapy has been overestimated, mainly because in the major trials, patients in the placebo arm received therapy at a lower rate. "Unfortunately, only 56% of the patients we see in the clinic will be eligible for [maintenance] therapy," he said. For his argument, Dr. Stinchcombe cited the same trials as Dr. Evans but interpreted the results more cautiously.

In SATURN, ATLAS, JMEN, and the trial led by Dr. Fidias, the rates at which patients in the placebo arm received post–study therapy ranged from 55.5% to 72%. Reasons for this lower rate of second–line therapy may have included variations in access to care, the expense of additional therapy, physician preference, and disease progression. The question is: Do patients who received second–line therapy derive the same benefits as those who are on maintenance therapy?

"Let’s talk about the [SATURN] erlotinib trial," he said. "There was a run–in phase where 1,900 patients initiated platinum–based therapy and only 889 were eligible for randomization at stable disease or response. In the placebo arm, 21% of the patients received post–study erlotinib therapy at the time of disease progression. This post–study therapy was at the discretion of the investigator and many patients actually received second–line therapy. If, in the post–study period, placebo patients had been given the same treatment as the maintenance arm and an improvement in OS were observed, then the results of maintenance would have been more reliable."

In the ATLAS trial, patients on bevacizumab continued to receive the drug post–therapy, even though the benefit of bevacizumab as second–line therapy is unproven, he said. "Forty percent of patients on bevacizumab and placebo continued to receive bevacizumab post–therapy and 25% of people in the bevacizumab plus erlotinib arm continued to receive bevacizumab therapy. Interestingly, 40% of patients in the bevacizumab/erlotinib arm continued to receive erlotinib. I think this does not undermine the efficacy of the second–line therapy the patients did receive," he said.

In the JMEN trial, only 18% of the patients in the placebo arm received post–study therapy with pemetrexed and it was not clear how many received the drug as third–line therapy. "So there’s really not a trial of pemetrexed now vs pemetrexed later," he said.

In the docetaxel trial led by Dr. Fidias, the median OS was 12.5 months in the immediate and delayed therapy arms for patients who actually received docetaxel treatment, suggesting that close observation and the initiation of second–line therapy upon disease progression offers a similar benefit to maintenance therapy.Dr. Stinchcombe pointed out several issues that he has with all of these trials. First, PFS was used as the primary endpoint in many of them, but improvements in PFS don’t necessarily translate into improvements in quality of life or a delay in time–to–deterioration as reported by patients.

Second, the toxicities associated with these regimens were acceptable, but they were not inconsequential. Finally, the burden of starting maintenance therapy on the heels of platinum–based therapy needs to be considered.

"I think it’s clear from these trials that starting chemotherapy immediately after four cycles of platinum–based therapy will increase the rate at which the patients receive the chemotherapy," Dr. Stinchcombe said. "Why, in the placebo arm, did patients receive chemotherapy at a lower rate? Disease progression is inevitable. There’s an inherent risk that if you put someone on a treatment–free interval, that patient will have disease progression and will not respond to therapy. There is also patient preference. Ultimately, this is an incurable disease, and some patients may have elected not to pursue further therapy."

Physician preference is another factor that needs to be taken into account when interpreting trial results for clinical practice. Dr. Stinchcombe said that in his experience, "there is varied enthusiasm for the benefits of second–line chemotherapy [among] physicians. Some of the physicians on the placebo arm may not have been the most enthusiastic supporters of it."

Third, the subset of patients who actually benefit from maintenance therapy may represent a small portion of the overall NSCLC population. The patients enrolled in the experimental arms of ATLAS or SATURN may have represented a group who had a better prognosis than is generally found in the NSCLC population. This could be especially true for patients with EGFR mutations, he said. "Increasingly, we are testing for [EGFR mutations] at the time of diagnosis. I think most of us use the EGFR–tyrosine kinase inhibitor therapy in the first–line setting. And this is the group that had the most robust benefit from maintenance therapy of all the trials discussed today."

Despite advances in NSCLC treatment, there is currently no reliable way to employ clinical and molecular markers to identify which patients can be safely observed and which patients should go immediately to more therapy.

"I consider maintenance therapy to be a treatment option," Dr. Stinchcombe said. "We need to consider the disease burden, the patient’s symptoms, toxicity associated with first–line therapy, and performance status. Ultimately, I think that patient preference needs to be considered. The problem with maintenance therapy is you commit the patient to continuous treatment in a palliative setting. There are no treatment breaks and that means less chance of recovering from toxicity and more trips to the doctor’s office. I think treatment reprieve intervals are still an option for this incurable disease."