Continuation maintenance, meanwhile, is standard in the disease with bevacizumab, cetuximab, and erlotinib, and there is growing evidence of value with gemcitabine, and possibly with pemetrexed, Wakelee said.
When oncologists don’t intend to continue a specific drug regimen after induction therapy, Wakelee noted, they often face a choice of giving a patient either switch maintenance or a treatment holiday, followed by second-line therapy. While many patients would fare as well with either approach, she said, there is a strong rationale for choosing continuous treatment.
“Forty percent of patients who go onto first-line trials and are then eligible for second-line therapy never get it,” Wakelee said. “They do OK, have a chemotherapy holiday, and never get to the next line of therapy. [Ultimately,] these patients don’t do as well. Studies show that this is true around the world, even at the top centers.”
In Fidias et al’s trial that favored docetaxel as MT rather than second-line treatment, 95% of patients eligible for MT received it, while only 63% of patients eligible for second-line therapy received treatment, Wakelee pointed out.
Despite those data, Langer said, when “patients have a cushion of time before they need additional treatment, a lot just want to take a break. They have a low disease burden and they want time to reconstitute themselves, go on vacation, and recover from platinum-based toxicities.” And oncologists, he said, are often comfortable going along with that.
But by choosing that route, patients risk losing their chance to get second-line treatment due to “variations in performance status, the frequency and nature of clinical and radiographic follow-up, local practice patterns, and the possibility of rapid clinical decline precluding further treatment,” wrote David E. Gerber and Joan H. Schiller in their 2013 paper on MT in NSCLC.8
The authors added that continuation maintenance chemotherapy is preferable to second-line chemotherapy because the early use of non–cross-resistant therapies may kill more cancer cells prior to the development of resistance, and because continuous, low-dose chemotherapy has antiangiogenic and immunomodulatory effects.
“We never stop second- or third-line therapy while it’s working,” Wakelee argued, “so why do we ever think about stopping first-line?”
She added that there isn’t much to gain by giving patients a treatment break.
“The argument that patients need a chemotherapy holiday to feel better is not a strong one,” she said. “Patients tend to feel better when they’re on a chemotherapy that’s working.”
Evidence in NSCLC Questioned
Offering a counterpoint during the debate at the Lung Cancer Congress was Glenwood Goss, MD, FCPSA, FRCPC, professor of Medicine and director of Clinical and Translational Research at the Ottawa Hospital Cancer Centre at the University of Ottawa.
Glenwood Goss, MD
Goss noted that, in trials of MT in NSCLC, there are many patients who never make it to the maintenance phase.
In studies of MT for NSCLC, he said, just 30% to 60% of patients who underwent induction therapy were then deemed eligible to receive maintenance. Of those patients, the ones randomized to placebo were more likely, after the study was over, to be eligible for treatment upon progression, Goss said, “meaning that maintenance therapy comes at a cost.”
Goss added that he hasn’t seen convincing evidence that MT works in the disease. In continuation maintenance, he said, PARAMOUNT was the only trial among six large, recent studies to demonstrate a statistically significant survival advantage associated with that approach. Similarly, he said, among three trials of chemotherapy switch maintenance in NSCLC, the JMEN study was the only one to show a statistically significant survival advantage, and SATURN stood alone among six phase III trials of targeted MTs in NSCLC in demonstrating a statistically significant improvement in OS.
In the PARAMOUNT study, which Goss described as “our most recent, and one of our best,” just half of the 1000 patients screened went on to get MT, he said. Then, he said, the treatment didn’t do as much as he would have liked to bolster OS.
“The median survival in the pemetrexed arm was 16.9 months, and the median survival in the placebo arm was 14 months, so what the patient undergoes is 3 months of treatment for 2.9 months of improvement in survival—they get treated longer than the increase in survival,” he said.
Moreover, of four meta-analyses that assessed the success of trials of MT in NSCLC,9,10,11,12
only one showed a statistically significant increase in PFS regardless of maintenance type, and in that case the hazard ratio was 0.92, Goss said—“rather minimal, if you ask me.”