Mark A. Socinski, MD
The ATLAS trial was unique in that it included a bevacizumab (Avastin)-eligible population of first-line patients, who received 4 cycles of bevacizumab combined with a choice of platinum-based doublets that included a taxane or gemcitabine.10
Following 4 cycles of therapy, patients were randomized to continue the bevacizumab with placebo or erlotinib. Of the 1160 patients initially registered, only 768 (66%) were randomized. The primary endpoint was median PFS, which was met. Erlotinib combined with bevacizumab significantly improved PFS compared with bevacizumab plus placebo (4.8 mo vs 3.7 mo, respectively; HR, 0.72; 95% CI, 0.59-0.88; P
= .0012). Data were cut off in June 2009, and median OS for patients in the bevacizumab plus erlotinib arm was reported as 15.9 months compared with 13.9 months for patients in the bevacizumab plus placebo group (HR, 0.90; 95% CI, 0.74-1.09; P
This 10% improvement over the duration of treatment was not statistically significant. Only 55% of the placebo arm received second-line therapy, and only 40% of these patients received a regimen containing an EGFR TKI. Neither SATURN nor ATLAS revealed new safety signals for erlotinib alone or in combination with bevacizumab.DISCUSSION
In looking at these 4 trials together (Table 1), we see that a significant number of patients dropped out during the 4 cycles of first-line therapy. This occurrence was greatest in the SATURN trial, where 54% of registered patients did not get randomized to either cohort. Though no explanations have been given, this dilutes the applicability of the data to the potential effect of maintenance therapy on the advanced NSCLC population as a whole. As expected, maintenance therapy produced responses; however, the response rates were low, which is typical of second-line treatment with the agents used. The impact of maintenance chemotherapy with docetaxel or pemetrexed on PFS and OS seemed to be greater than that seen with erlotinib, though one must be very careful in making this comparison across trials. All 4 trials affirmed that these agents can be tolerated well following first-line chemotherapy, at least when they are limited to 4 cycles.
The important question now is how these trials should influence management of patients with advanced NSCLC. Is maintenance therapy now a new standard of care? The answer is no, in my opinion, but the results of these 4 trials should be considered in the overall management strategy for patients with advanced NSCLC.
The best-designed trial was that of Fidias and colleagues,11
where patients were supposed to receive docetaxel either immediately following 4 cycles of carboplatin-gemcitabine or at the time of objective progression. The 3 placebo-controlled trials8-10 allowed physicians to treat at their discretion, which produced imbalanced exposure to the maintenance agent. In Fidias,11
the survival of patients who received delayed docetaxel was identical to that of patients getting immediate docetaxel. This suggests treatment with an effective second-line agent is important, but the exact timing of dose administration may be less significant. Delaying treatment until objective disease progression creates major risks because many patients have disease- or comorbidity-related events that rapidly erode PS and preclude further therapy.
One way to increase exposure is using a maintenance strategy that ensures treatment-sensitive patients (those with a lack of progression during the 4 cycles of first-line therapy) are given effective therapy more often. Table 2 shows the rates of exposure to multiple lines of therapy in the 3 placebo-controlled trials.8-10
Second-line therapy is synonymous with maintenance therapy in Table 2, which shows that patients randomized to the maintenance arm of these 3 trials were more often exposed to an agent in the “second-line” setting.
Based on the results of BR.216 and the Hanna trial,7
it is known or believed that both erlotinib and pemetrexed improve survival, and they have been approved by the FDA for second-line treatment. Considering the increased exposure to these agents in the SATURN9 trial and in the study by Ciuleanu and colleagues,8
it is not surprising, therefore, that these trials showed improved survival.
Most of the patients randomized to the maintenance arms of these trials also received third-line therapy, but these data were not presented for patients randomized to the placebo arms (Table 2). Given the drop-off in patients from the placebo arms who went on to receive second-line therapy, it is likely a similar drop-off occurred between second- and third-line therapies, resulting in lower exposure to effective therapies in these arms.