Revisiting Doublet Maintenance Chemo in Advanced NSCLC

Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer: Results of the GOIRC 02-2006 Randomized Phase II Study and Pooled Analysis With the NVALT7 Trial

Ardizzoni A, Tiseo M, Boni L, et al
J Clin Oncol. 2102;30:4501-4507

Background

Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib -- each well-tested as single agents -- and evidence indicating a survival benefit in previously treated patients. Nevertheless, it is always tempting to consider whether if some is good, would more be better? For second-line therapy, this leads us to test the strategy of doublet chemotherapy in hopes of improving the typically modest benefits conferred by single-agent treatment.

Study Summary

A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and it provides more evidence that our current approach of sequential singlet therapy remains appropriate. This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.^[1] Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m² IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days. The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands.^[2] The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.

The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically, median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed. Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen (RR 12.6% vs 12.5%, median OS 9.2 vs 8.8 months, for pemetrexed and carboplatin/pemetrexed, respectively). Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone. Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint

What should we make of this work? Putting it in the context of previous data,^[3] these results only provide further confirmation that more is not better. Perhaps the larger question is why? Although the Ardizzoni trial provided very minimal reporting of adverse events, we know that combinations are associated with more toxicity than single-agent therapy, and this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced. As more data emerge to support sequential maintenance strategies, treatment on a long-term basis may prove to be beneficial, but it is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We are not at the point where we can envision management of advanced NSCLC as a marathon instead of a sprint, but we do need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.