What does the PARAMOUNT Trial Teach Us About Maintenance Therapy for Advanced NSCLC?
July 20th, 2012 - by Dr. Jack Westhttp://blog.lungevity.org/2012/07/20/pa ... -maint-rx/
The PARAMOUNT trial is a key study of continuation maintenance therapy with Alimta (pemetrexed) vs. placebo. To review, maintenance therapy is the idea of employing a low-intensity, longitudinal treatment after first line therapy in order to maintain an achieved response, or at least stable disease, for as long as possible with acceptable side effects. This concept can effectively be divided into switch maintenance therapy, where a person switches to one or more different agents after discontinuing all of the agents from the first line setting, and continuation maintenance therapy, in which the person continues on an ongoing bases on one or more of the same treatments from first line after dropping some.
The first trials in maintenance therapy that that revealed a benefit followed an approach of switch maintenance; specifically, patients started maintenance Alimta in one trial (called JMEN) or Tarceva (erlotinib) in another (called SATURN) after having not been on these agents previously. Each of these studies demonstrated a significant improvement in progression-free survival (PFS) as well as overall survival (OS) (in contrast, an earlier trial with Taxotere (doxetaxel) given as maintenance or at progression demonstrated significantly superior PFS but not OS with early Taxotere). Though both of the positive trials really tested access to drug more than timing because they ended up not giving the active drug at any time to about 80% of the patients assigned to the placebo arm, they led to both Alimta and Tarceva being approved as maintenance therapies for patients who hadn’t progressed on first line chemotherapy.
In this context, the PARAMOUNT trial is important for now testing the potential value of continuation maintenance. It was designed similarly to the switch maintenance “JMEN” trial, with advanced NSCLC patients who hadn’t progressed after four cycles of first line chemotherapy randomized to either single agent maintenance Alimta (2/3 of patients) or placebo as maintenance therapy (1/3 of patients). However, while the patients on JMEN received 4 cycles of first line platinum-based chemo that didn’t include Alimta (making the maintenance Alimta a switch maintenance strategy), the patients on the PARAMOUNT trial all started with 4 cycles of first line cisplatin/Alimta and then randomized non-progressing patients to continue on Alimta (2/3) of placebo (1/3).
We got some early information about the trial from ASC 2011, when Dr. Paz-Arez reported that patients receiving maintenance Alimta experienced a significant increase in PFS with continuation maintenance. Overall survival results, however, weren’t reported. But because the finding of a survival benefit has really been critical in determining whether maintenance therapy is continued truly valuable or not, the report of this information at this year’s ASCO was of great interest. First, we saw that the PFS benefit continued to hold up with the same magnitude of benefit with more time for follow up (as shown on the right), with the “hazard ratio” for PFS going from 0.62 to 0.60 over time (in other words, the time before progression was 40% longer for recipients of maintenance Alimta).
We also saw the survival results, which were significantly better for patients assigned to continuation maintenance with Alimta. Specifically, there was a 3 month difference in median survival (median 11.0 vs. 13.9 months from randomization at maintenance, or 14 vs. ~17 months from start of all treatment) that is quite comparable to the absolute numbers on the positive switch maintenance therapy trials.
I’m certainly impressed by these results, though I would submit that there still isn’t a mandate to treat every eligible patient with maintenance therapy, since these trials don’t show that you really need to give more therapy immediate after first line therapy. Instead, we might envision that patients who have access to more Alimta can do just as well if they get it at the first evidence of progression as they would if they continue on it as a maintenance therapy. This study clearly demonstrates that getting more of an effective treatment is better than getting less of it. But it doesn’t speak to the optimal timing of that treatment. It does highlight that the benefit of well-tolerated treatments on which a patient hasn’t progressed aren’t exhausted after four cycles of platinum-based doublet chemo.
If we want to compare continuation maintenance therapy to switch maintenance, we really don’t have good studies to prove that one is better than other. Overall, the outcomes appear quite comparable, and I’d consider either to be completely acceptable. Much depends on how a person is tolerating first line therapy and whether they are on treatments that lend themselves easily to ongoing treatment. Several agents have cumulative side effects that make it challenging to continue on them for month after month after month.
To me, the clearest advantage of a maintenance approach is that it is the most reliable way to ensure that a patient actually receives the maximal benefit from the treatments available. Though we hope and expect that nearly all of our patients being monitored off of therapy will be able to promptly resume treatment, there’s always a chance for people to progress faster than anticipated and miss an opportunity to receive subsequent therapy. That doesn’t happen with a maintenance approach. But a treatment break may still be a very acceptable, appropriate option for individual patients, and I would say that the evidence supports that they’ll do just as well if they can jump back into treatment readily, when the time is right.
My personal view is that if continuation maintenance therapy is with an agent that is well tolerated, like Alimta or potentially Gemzar (gemcitabine) often is, then continuation maintenance therapy provides a way to maximize the benefit of further treatment without discarding a valuable therapy too early, and without initiating another treatment before it’s really needed. I’d be more inclined to pursue switch maintenance therapy for people who haven’t progressed, want or are felt to need maintenance therapy, but have experienced problematic, likely cumulative side effects from the first line therapy. But there’s not enough evidence for anyone to be dogmatic about the “right” way to pursue maintenance therapy, or even whether to do it at all.