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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

The PARAMOUNT Trial Shows a Survival Benefit: Putting Continuation Maintenance Therapy into Context
Fri, 07/13/2012 - 09:11
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Last year, the PARAMOUNT trial was one of the highlight presentations in lung cancer from ASCO 2011, an important landmark study of continuation maintenance therapy with Alimta (pemetrexed). To review briefly, the concept of maintenance therapy -- using a lower-intensity, ongoing therapy after first line treatment in order to maintain an achieved response for as long as possible with acceptable side effects -- can effectively be divided into switch maintenance therapy, in which all of the first line agents are discontinued and a person switches to one or more different agents, and continuation maintenance therapy, in which one or more agents from first line is discontinued, and the person continues on one or more of the same treatments on an ongoing basis.

The first trials that demonstrated a significant benefit for maintenance therapy employed a switch maintenance strategy. These were designed to switch patients to either Alimta in one trial (called JMEN) or Tarceva (erlotinib) in another (called SATURN), and both demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS) (another trial with Taxotere (doxetaxel) showed a significantly superior PFS but not OS with early Taxotere). Though both trials suffered from a design that ended up not giving the active drug at any time to about 80% of the patients assigned to the placebo arm (which compromises the interpretation of the importance of maintenance therapy -- perhaps it's just a question of whether you can ever get these active therapies or not), they led to both Alimta and Tarceva being approved as maintenance therapies for patients who hadn't progressed on first line chemotherapy.

The PARAMOUNT trial looked at continuation maintenance, so it was designed similarly to the 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). The difference between JMEN and PARAMOUNT was that whereas the former had patients receive four cycles of first line platinum-based chemo that didn't include Alimta (making the maintenance Alimta a switch maintenance strategy), the PARAMOUNT trial gave all patients cisplatin/Alimta for up to four cycles before randomizing non-progressing patients to continuation maintenance or not.

Last year's result was notable for a very significant increase in PFS with continuation maintenance. However, no OS data were presented. At this year's ASCO, Dr. Paz-Arez, who led the trial, presented data that demonstrated that the PFS benefit continued to hold up with the same magnitude of benefit with more time for follow up, with the "hazard ratio" for PFS going from 0.62 to 0.60 over time (which means that it was 40% better for recipients of maintenance Alimta).

But maintenance therapy really didn't become integrated as a leading option for advanced NSCLC until trials, initially all with a switch maintenance approach, demonstrated a benefit in overall survival. However, the design of all of the positive trials didn’t provide the active drug to the people on the placebo arm at any time, creating two variables of timing of treatment (is it important to give treatment as maintenance, right after first line treatment, without a break?) or access to an effective drug (these drugs prolong survival in patients who haven’t progressed through first line therapy, but only if you get them…and most of the patients on the observation arm never got the active drug)? That question hasn’t been answered yet, but maintenance therapy has enough momentum that it has become a standard of care (one of a few options), though certainly not a mandate for all patients.

This year, we saw the results of overall survival for patients on the PARAMOUNT trial, which was significantly longer for patients assigned to continuation maintenance with Alimta, a 3 month difference in median survival that is very comparable to the absolute numbers seen on the positive switch maintenance therapy trials (median 11.0 vs. 13.9 months from randomization at maintenance, or 14 vs. ~17 months from start of all treatment). Notably, pretty much all patient subgroups experienced the same degree of survival benefit: it wasn’t far more pronounced in patients who experienced significant tumor shrinkage vs. initial stable disease.

These results are impressive to me, even if they still don’t translate to a mandate to treat every eligible patient with maintenance therapy. We don’t have great directly comparative trial results suggesting that continuation or switch maintenance therapy is a meaningfully better approach, but the PARAMOUNT data look every bit as good as the results from switch maintenance trials (and this conclusion that continuation maintenance is every bit as good as, if not better than, switch maintenance is also supported by the results from a French maintenance therapy trial reported a couple of years ago). The positive results from these continuation maintenance therapy trials also convincingly demonstrate that the benefit of well-tolerated treatments on which a patient hasn’t progressed aren’t necessarily exhausted after four cycles of platinum-based doublet chemo.

However, this doesn’t mean that the treatment must necessarily be given immediately and without a break. I think it’s extremely likely that a patient will receive the exact same benefit if they resume a treatment like single agent Alimta after a limited treatment break, whether that is defined by a fixed period of maybe 1-2 months, or close follow-up with prompt re-initiation of treatment at an early sign of progression.

To me, the real 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. It’s possible for patients to progress faster than anticipated and miss an opportunity to receive subsequent therapy, but that doesn’t happen with a maintenance approach. But a treatment break may still be a very acceptable choice for individual patients.

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.

We’ll need to see how practice patterns shift in the wake of these survival results from the PARAMOUNT trial. But since continuation maintenance therapy with Alimta was already a popular strategy, I think we’ll just see more confidence in this approach and likely a gradual further shift toward more use of this approach.

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