Maintenance Therapy in NSCLC: Personalized Perspectives

Maintenance therapy has begun to emerge as a treatment standard for patients with non–small cell lung cancer (NSCLC) whose disease has not progressed after 4 to 6 cycles of frontline chemotherapy. But some caveats still apply. Although it may be suitable for fit, motivated patients who are highly symptomatic at the time of presentation, it is not yet clear if maintenance therapy should be routine.

Based on the phase 3 data, use of pemetrexed is certainly justified in patients whose advanced NSCLC has stabilized or improved after 4 or more cycles of frontline therapy with a platinating agent, plus either gemcitabine or a taxane. Pemetrexed is particularly well tolerated and convenient, al though its “maintenance” benefits are confined to nonsquamous histology and its utility is as yet unproven in patients who have received pemetrexed and/or bevacizumab as part of their first-line treatment. Similarly, erlotinib has yielded a survival advantage compared with placebo in the maintenance setting, although the extent of its benefit seems less pronounced compared with pemetrexed.

Prolonged Initial Chemotherapy

Prolonged treatment with initial chemotherapy (eg, 6 vs 3 cycles or indefinite treatment vs 4 cycles) has shown no overall survival (OS) benefit^1-3; neither have prior maintenance studies of attenuated dosing or single agents yielded a survival benefit, although “intriguing trends” in time to progression have been observed in underpowered efforts.^4,5

Switching to a new compound for maintenance therapy demonstrated some benefit in the welldesigned study by Fidias and colleagues, which evaluated immediate versus delayed docetaxel upon disease progression after first-line carboplatin/ gemcitabine.⁶ Pro gres sion-free survival (PFS) improved from 2.7 months in the delayed arm to 5.7 months with maintenance (P <.001), and median OS trended better (12.3 vs 9.7 months; P = .085). In addition, a recent metaanalysis documented a 30% reduction in disease progression using maintenance therapy with a third-generation regimen compared with maintenance with older regimens.⁷

Determining the Optimal Maintenance Therapy Agent

The study by Fidias and colleagues laid the groundwork for pemetrexed as maintenance after chemotherapy,⁶ which was evaluated in a recent phase 3 study by Ciuleanu and colleagues.⁸ Patients were randomized 2:1 to pemetrexed or intravenous placebo. Disease progression was reduced by 40% (P <.001) overall and by 53% in patients with nonsquamous histology (P <.001), and deaths were reduced by 21% (P = .012) and 30% (P = .002), respectively. Pemetrexed was reasonably well-tolerated and devoid of cumulative toxicity. Benefits were particularly pronounced in patients with nonsquamous histology (they had a more than 5-month survival advantage); there was no PFS or OS advantage in those with squamous histology.⁸

Although this was the first randomized, doubleblind, placebo-controlled trial to show a significant survival benefit for maintenance treatment, one still needs to exercise caution in basing clinical decisions on this study.

Maintenance therapy is unrealistic for many patients due to early disease progression, comorbidities, and patient desire to stop treatment. Pemetrexed is of no value to patients with squamous histology and is unproven in patients who have received first-line pemetrexed or bevacizumab. Furthermore, the survival improvement in the Ciuleanu study would be more impressive had there been mandatory crossover to pemetrexed at the time of disease progression in the control arm; unlike the Fidias trial, mandatory crossover was not instituted in this trial. It is noteworthy that <20% of enrollees in the control arm received pemetrexed at the time of disease progression, although a majority received a standard secondline treatment.

Many patients look forward to the prospect of a therapeutic holiday. If patients are closely monitored once they have completed first-line therapy, there is often enough time to implement secondline treatment when disease progresses before symptoms have taken over. Finally, cost is the 800lb gorilla in the room. Recent analyses of pemetrexed maintenance suggest a minimum incremental cost of >$120,000 per life-year saved.⁹

A recent phase 2 study evaluated pemetrexed plus bevacizumab for maintenance after 6 initial cycles of carboplatin, pemetrexed, and bevacizu - mab.⁹ Median PFS was 9.3 months and median OS was 14 months.¹⁰ Many practitioners are using this regimen increasingly in bevacizumabeligible patients. These encouraging findings have led to a large, planned randomized phase 3 trial in the Eastern Cooperative Oncology Group (ECOG) 5508, which just opened and will randomize 1282 patients to bevacizumab, pemetrexed, or to a combination of bevacizumab and pemetrexed after 4 cycles of initial therapy with paclitaxel/carboplatin/bevacizumab. In addition, a separate phase 3 trial, POINT-BREAK, will compare this regimen to the “winning” arm of ECOG 4599 (a combination of paclitaxel, carboplatin, and bevacizumab), which yielded a significant and clinically meaningful survival advantage in this setting compared with chemotherapy alone. Finally, in Europe, pemetrexed maintenance is being compared with “observation” in patients who have stabilized or responded to a “standard” pemetrexed/cisplatin regimen.

Erlotinib Maintenance

Erlotinib has shown value as a maintenance agent in 2 key studies. The Sequential Tarceva® in Unresectable NSCLC (SATURN) trial found that erlotinib reduced the risk of progression by 29% (P <.001) and offered a 1-month OS benefit (P = .0088).¹¹ In the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial, maintenance therapy with erlotinib plus bevacizumab improved PFS by 39%, or by approximately 1 month (P = .0012), but no OS difference was shown.¹² Moreover, toxicity associated with this approach is not trivial.

Conclusions

Docetaxel, pemetrexed, and erlotinib are each approved in the second-line setting, and all have shown a PFS benefit as maintenance therapy and at least a trend toward improved survival, if not a statistically significant increase in survival. To date, both pemetrexed and erlotinib are US Food and Drug Administration–approved for maintenance therapy. At the end of the day, treatment should be individualized for all patients, taking into account not only clinical outcomes but patients’ personal preferences, disease burden, and comorbidities.

References

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8. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non–small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440.
9. Klein R, Wielage R, Muehlenbein C, et al. Cost-effectiveness of pemetrexed as first-line maintenance therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol. 2010;5:1263-1272.
10. Patel JD, Hensing TA, Rademaker F, et al. Phase II study of pemetrexed and carboplatin plus bevacizu mab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer. J Clin Oncol. 2009;27:3284-3289.