Non–Small Cell Lung Cancer Maintenance Therapy: None, Single Agent, Multiple Agents? 

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Barlesi et al have reported results of a randomized trial comparing bevacizumab (Avastin) vs pemetrexed (Alimta)/bevacizumab as maintenance therapy in patients with stage IV nonsquamous cell non–small cell lung cancer (NSCLC). It is important to consider their observations in relation to data from other maintenance trials and in relation to perceptions regarding maintenance therapy.

Currently, opinions regarding maintenance therapy range from strong advocacy to nihilism based on the premises that treatment holidays are good and that outcome will be similar providing second-line therapy is initiated immediately upon identification of tumor progression. Prior to addressing these divergent views, it is instructive to review data from the Barlesi et al study and from other ­trials.

Increasing Interest in Maintenance Chemotherapy

Prior to 2009, results of relatively small randomized trials in patients with stage IV NSCLC did not provide a clear answer regarding the role of maintenance chemotherapy. A meta-analysis that included 13 randomized maintenance therapy trials and 3,027 patients provided some clarification. This analysis showed superior progression-free survival (hazard ratio [HR] = 0.75, P = .0001) and superior overall survival (HR = 0.92, P = .03) in patients treated with maintenance chemotherapy. Comparison of newer treatments (third-generation regimens) vs older regimens revealed superior progression-free survival with third-generation regimens (P = .003).

Although the survival benefit was marginal and adverse events were more frequent in patients receiving maintenance chemotherapy, there was increased interest in studying maintenance therapy, particularly with newer chemotherapeutic agents. Docetaxel was the first drug tested in this setting.

The design of the docetaxel study was based on the hypothesis that switching to a different drug as maintenance therapy might be cytotoxic for tumor cells that were resistant to the induction regimen. Treatment-naive patients with stage IV NSCLC were randomly assigned to immediate vs delayed docetaxel following treatment with four cycles of first-line gemcitabine/cisplatin, providing disease was controlled at completion of first-line treatment. Progression-free survival was superior in patients treated with immediate docetaxel, and, despite a trend for superior overall survival in patients treated with immediate docetaxel, the survival difference was not significant.

Pemetrexed Trials

Subsequently, pemetrexed maintenance therapy was tested in two randomized studies. Like the docetaxel maintenance trial, the first pemetrexed study tested a switch maintenance strategy. In this trial, patients with stage IV NSCLC were treated initially with a nonpemetrexed platinum doublet. Patients who achieved objective tumor regression or stable disease after four cycles of first-line therapy were randomly assigned to pemetrexed maintenance or placebo.

Both progression-free survival (HR = 0.50, P = .001) and overall survival (HR = 0.79, P = .012) were significantly prolonged in patients receiving pemetrexed maintenance. Subset analysis revealed that the benefit was limited to patients with non–squamous cell lung cancer with hazard ratios of 0.44 (P < .0001) for progression-free survival and 0.70 (P = .002) for overall survival. In addition, there was a significant interaction difference for treatment by histology (P = .033).

The subsequent pemetrexed maintenance trial evaluated the concept of continuation maintenance. Based on the observation in the previous trial that treatment benefit was limited to patients with non–squamous cell cancers, patients with squamous cell histology were excluded. It is noteworthy that this is the largest maintenance trial in this setting and that the population of patients with nonsquamous disease constitutes a relatively large group of patients.

In the first study, 72% (481/663) of the patients had nonsquamous histology. In the second trial, 939 patients were enrolled and received four cycles of pemetrexed/carboplatin. Then, 539 patients were randomly assigned to maintenance pemetrexed vs placebo, providing there was no evidence of tumor progression. Outcomes were similar to results from the prior maintenance trial, with progression-free survival (HR = 0.50, P < .0001) and overall survival (HR = 0.79, P = .012) being longer in patients treated with pemetrexed continuation maintenance.

Bevacizumab vs Pemetrexed/Bevacizumab Maintenance

Barlesi et al designed a randomized trial in which patients with nonsquamous NSCLC and disease control after four cycles of pemetrexed/cisplatin plus bevacizumab were randomly assigned to bevacizumab vs pemetrexed/bevacizumab maintenance. The induction regimen was given to 376 patients, and 253 were subsequently randomly assigned to maintenance therapy. Progression-free survival was significantly longer in patients who received pemetrexed/bevacizumab maintenance (HR = 0.66, P < .001). Although there was a trend for superior overall survival with pemetrexed/bevacizumab (HR = 0.75, P = .219), the study was not powered to to address overall survival.

Role of Pemetrexed/Carboplatin/Bevacizumab

If Barlesi et al’s trial design had compared maintenance pemetrexed vs pemetrexed/carboplatin, it would have provided important information regarding the role of bevacizumab maintenance. In a large trial comparing paclitaxel/carboplatin/bevacizumab followed by bevacizumab maintenance vs paclitaxel/carboplatin, superior survival was observed in patients treated with the bevacizumab regimen. It has been assumed that bevacizumab maintenance contributed to the survival advantage of the triplet regimen. However, the survival impact of maintenance bevacizumab has not been addressed in a randomized trial.

In addition to the maintenance question, the role of bevacizumab with nonpaclitaxel regimens is not clear. While a recent meta-analysis suggested that adding bevacizumab to platinum doublets improves overall survival, the accompanying editorial contended that survival benefit is limited to the combination of bevacizumab with paclitaxel/carboplatin.

The triplet regimen consisting of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab has been evaluated by Barlesi et al and two additional groups of investigators. Each group observed acceptable toxicity during induction and maintenance phases with this regimen.

Patel et al’s trial compared pemetrexed/carboplatin/ bevacizumab followed by pemetrexed/bevacizumab maintenance vs paclitaxel/carboplatin/bevacizumab followed by bevacizumab maintenance. Survival was the primary endpoint of this study. While superior progression-free survival was observed with the pemetrexed regimen, overall survival was not significantly different. These results suggested that inclusion of bevacizumab maintenance might be necessary for the pemetrexed regimen to achieve similar efficacy to the paclitaxel/bevacizumab regimen.

However, results from a smaller randomized trial presented at the 2013 ASCO meeting showed similar survival with pemetrexed/carboplatin followed by maintenance pemetrexed compared to paclitaxel/carboplatin/bevacizumab followed by bevacizumab maintenance. Although not powered to address survival, the study suggests that combining bevacizumab with pemetrexed/carboplatin may not add benefit.

Closing Thoughts

In summary, the objective of maintenance therapy in patients with stage IV NSCLC should be improved overall survival without excessive toxicity and with acceptable cost. Maintenance pemetrexed alone, bevacizumab alone, and pemetrexed/bevacizumab are associated with acceptable toxicity. Although some physicians do not embrace maintenance pemetrexed because mandatory crossover to pemetrexed was not required in the two trials discussed, these large randomized placebo-controlled trials provide convincing evidence that switch or continuation pemetrexed maintenance after a platinum doublet significantly prolongs overall survival.

Does adding bevacizumab to pemetrexed maintenance improve survival? The Barlesi et al trial comparing bevacizumab vs pemetrexed/bevacizumab maintenance and another study testing bevacizumab vs pemetrexed maintenance were not powered to address overall survival. In addition, interpretation of maintenance treatment effect in two trials that tested a paclitaxel/bevacizumab–containing regimen vs a pemetrexed regimen might be confounded by a potentially more favorable interaction of bevacizumab with paclitaxel.

The ongoing Eastern Cooperative Oncology Group (ECOG) E5508 trial, in which non–squamous cell NSCLC patients are randomly assigned to bevacizumab vs pemetrexed vs pemetrexed/bevacizumab after completion of four cycles of paclitaxel/carboplatin/bevacizumab, will have important clinical and economic implications for maintenance therapy. ■

Dr. Bonomi is Director of the Division of Hematology and Oncology at Rush University Medical Center, Chicago.

Disclosure: Dr. Bonomi reported no potential conflicts of interest.

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