As highlighted in the previous paragraphs, evidence on the continued (maintenance) use of the same third-generation agent employed in the induction regimen remains inconclusive with respect to gemcitabine and frankly negative in terms of cost/benefit ratio with respect to weekly paclitaxel [
20‐
22,
34]. Nowadays, available data about pemetrexed in maintenance setting do not answer to the question if this approach could be useful in those patients responding to a first line with platinum compound and pemetrexed and the answer will be available soon from a randomized trial comparing pemetrexed versus placebo in patients who do not progress following four cycles of pemetrexed plus cisplatin [
35]. Positive data in terms of cost-effectiveness switching to pemetrexed, which employment in non-squamous NSCLC is really cost-effective, are driven by its impact on PFS and OS [
36]. This is indeed a crucial point: resources use and costs involved with this new paradigm in the clinic, would all argue for a meaningful improvement in survival as a critical necessity from a practical standpoint. As a consequence, the usefulness of maintenance therapy has to be based on a clearly defined, reproducible and measurable endpoint. Using PFS as the basis for the adoption of a new therapeutic approach, may be considered as a limitation due to the variability in the definition of progression and frequency of response assessment across studies; in this context, it seems very relevant to standardize PFS measurement in definitive phase III trials. For example, in the Fidias trial, patients on the immediate docetaxel arm underwent radiologic assessment after cycles two, four and six, while patients in the delayed docetaxel arm the evaluation was performed every three months. Timing and the type of imaging studies used in the control arm has been considered one of the main limitations of this study, as unfavorably delaying detection of possible disease progression [
37]. As it happens in routine daily practice, only about two thirds of patients on the control arm was able to receive second-line docetaxel, as opposed to 95% of patients who received the study drug in the immediate, maintenance arm; thus, the true benefit with "immediate" docetaxel in this study could be entirely attributed to the higher proportion of patients receiving active therapy in the maintenance setting. Indeed, a post-hoc analysis documented an identical OS duration of 12.5 months for patients who received docetaxel on either arm of the study, clearly indicating that when patients stop first-line chemotherapy, they should be followed closely to detect progression early and at a time when they remain fit for further treatment [
24].
Even if a bevacizumab maintenance in patients receiving bevacizumab combined with chemotherapy in the context of their first-line regimen is considered common practice on the basis of the registration trials, both of which maintained bevacizumab until progression after the completion of the assigned first-line regimen, with the notable exception of the recently-presented ovarian cancer trial clearly supporting the use of maintenance bevacizumab, this specific issue has never been assessed in
ad hoc designed randomized trials [
4,
5,
38]. Currently there are at least two trials designed to clarify its role in maintenance: the ECOG three-arm, phase III study of Paclitaxel/Carboplatin/Bevacizumab followed by randomization to pemetrexed versus bevacizumab versus pemetrexed/bevacizumab in non-squamous carcinoma and a study with Pemetrexed/Cisplatin/Bevacizumab followed by Pemetrexed/Bevacizumab versus Bevacizumab alone [
39]. The approximately 4-month median PFS with single-agent erlotinib maintenance in the SATURN trial and 4.76 months with the combination of erlotinib and bevacizumab in the ATLAS trial, highlights the importance of establishing the relative contribution of each agent when a combination therapy strategy is being evaluated in the maintenance setting [
31,
32]. Another related question is whether subgroups of patients with specific clinico-pathological and/or molecular characteristics would especially benefit from the choice of a particular maintenance agent, among those currently available. Within the limits imposed by such methodological considerations, the only biomarker that clearly showed a statistically significant, quantitative interaction with the treatment assigned (erlotinib or placebo) was the presence of sensitizing EGFR mutations (p for interaction <.001); indeed, although even EGFR M- patients derive a small, but statistically significant, benefit in PFS from erlotinib maintenance (HR: 0.78, 95% CI: 0.63-0.96, p = 0.0185), the PFS gain of EGFR M+ patients is exceptionally wide (HR: 0.10, 95% CI: 0.04-0.25, p < 0.0001). The potential benefits of the inclusion of erlotinib in the maintenance treatment of EGFR M+ patients were consistent in the ATLAS trial, where erlotinib was combined with bevacizumab. However, at the moment there are no survival data and no further analyses of OS are planned, due to loss of patients to follow up [
32]. In routine clinical practice obtaining information on EGFR mutational status is not always easy and time-consuming, being not exceptional that such information becomes available only when the patient is already receiving a standard first-line chemotherapy treatment: should this be the case, EGFR M+ patients have now the option to receive TKI right after the induction. The impact of erlotinib maintenance on OS of EGFR M+ patients, however, is currently uncertain. Survival data in EGFR M+ patients included in SATURN trial are not yet mature although the low number of EGFR M+ patients and the shape of the survival curves, make it unlikely that a statistically significant benefit will become apparent with longer follow up. It is true that EGFR TKI are effective in advanced NSCLC even when administered late in the course of the disease, but recent data document that about 50% of NSCLC patients treated with EGFR-TKIs will develop resistance-inducing EGFR mutations (such as the T790M) implying the possibility that resistant clones may expand as disease progresses [
40‐
42]. Talking about costs in this specific context a recent retrospective cost-effectiveness analysis by Bradbury et al. reported the cost per year of life gained being not the most favorable in patients with sensitizing mutations in the EGFR gene. This was because these patients derived relatively greater benefit and stayed on treatment longer, thereby incurring considerably higher drug acquisition costs [
43]. Besides EGFR mutations, histology represents a potentially crucial decision factor for the choice of specific maintenance agents. Currently, no direct comparisons between different agents in histology-selected subgroups of patients have been reported. In the JMEN trial, the benefit of maintenance pemetrexed is clearly confined to patients with non-squamous histology: indeed, in patients with squamous histology OS on pemetrexed maintenance was indistinguishable from that on placebo; conversely, in non-squamous patients pemetrexed maintenance resulted in a reduction of the risk of death of approximately 30% and prolonged median survival from 10.3 to 15.5 months [
27]. In the SATURN trial, non-squamous patients on erlotinib maintenance experienced a 21% reduction in the risk of death and a prolongation of median survival from 10.5 to 13.7 months [
31]. Similar results were obtained in the IFCT-GFPC trial (for which only PFS data are available), where the benefit for erlotinib maintenance was also confined to adenocarcinoma patients [
21]. Conversely, in the ATLAS trial the benefit in OS gained from the addition of erlotinib to bevacizumab is very limited in both the adenocarcinoma and non-adenocarcinoma groups of patients (HR 0.91, 95% CI 0.74-1.12 and HR 0.98, 95% CI 0.64-1.49, respectively) [
32]. Overall, in patients with non-squamous histology pemetrexed maintenance appears to provide the greatest benefit in terms of both PFS (HR 0.44) and OS (HR 0.70). Erlotinib also represents a reasonable choice (HR 0.60 and 0.79 for PFS and OS respectively) and may possibly be preferable in selected subgroups, such as females (HR 0.64 for erlotinib vs. HR 0.83 for pemetrexed) and east Asians patients (HR 0.66 for erlotinib vs. HR 1.05 for pemetrexed). An improvement in PFS was obtained with either erlotinib in patients with squamous histology in the SATURN trial (HR 0.76, 95% CI 0.60-0.95) or gemcitabine in patients with non-adenocarcinoma histology in the IFCT-GFPC trial (HR 0.56, 95% CI 0.37-0.85)[
21,
32]. Many other phase II and III trials are currently ongoing looking at maintenance therapy in NSCLC (Tables
3 and
4) [
35,
39,
44,
45]. Modulating the immune response in lung cancer is a strategy that is being actively investigated also in maintenance approach. The L-BLP25 (Stimuvax; Biomira Alberta, CA) is a liposome vaccine targeted to the extracellular core peptide of mucine 1 (MUC 1), a transmembrane protein expressed on epithelial cells. In a phase IIb trial, patients in stage III NSCLC, who had disease control after induction therapy, were randomized to receive vaccination weekly for 8 weeks and then they had the option to proceed to maintenance therapy, consisting in vaccination every 6 weeks or BSC. The median OS (primary endpoint) was 17.4 months for the vaccinated patients versus 13.0 months for those on BSC arm (p = 0.66)[
46].
Table 3
New Phase II trials
NCT00867009
| Pemetrexed and Cisplatin Plus Cetuximab Followed by Pemetrexed and Cetuximab as Maintenance IIIB or IV Nonquamous NSCLC | ongoing, but not recruiting | |
NCT00687297
| Vandetanib (ZD6474)n With Docetaxel and Carboplatin Followed by Placebo or Vandetanib as Maintenance in IIIb, IV or Recurrent NSCLC | ongoing, but not recruiting | |
NCT01004250
| Pemetrexed, Cisplatin, and Bevacizumab as Induction, Followed by Pemetrexed and Bevacizumab as Maintenance, in First-Line Nonsquamous Advanced NSCLC | currently recruiting | |
NCT00425646
| Maintenance Strategy of Gleevce® (Imatinib Mesylate) and Bevacizumab in Advanced, Non-Squamous, NSCLC Following Completion of First-Line Chemotherapy With Bevacizumab | ongoing, but not recruiting | |
NCT00766246
| Docetaxel, Carboplatin and Bevacizumab as First-Line Treatment, Followed by Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Second-Line Treatment of Stage IIIB or IV NSCLC | currently recruiting | |
Table 4
Current PHASE III trials
NCT01107626 ECOG 5508
| Paclitaxel/Carboplatin/Bevacizumab, followed by pemetrexed vs bevacizumab vs pemetrexed/bevacizumab | not yet open for recruitment | |
NCT00789373 Paz-Ares LG
| Maintenance Pemetrexed/BSC Vs BSC Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced Nonsquamous NSCLC | currently recruiting | |
NCT00762034 Patel et al. | Pemetrexed/Carboplatin/Bevacizumab Followed by Maintenance Pemetrexed/Bevacizumab vs Paclitaxel/Carboplatin/Bevacizumab Followed by Maintenance Bevacizumab in IIIB or IV Nonsquamous NSCLC | currently recruiting | |
NCT00820755 NEXT
| Platinum-based chemotherapy plus cetuximab followed by cetuximab as maintenance with either 500 mg/m2 every 2 w or 250 mg/m2 every w | ongoing, not recruiting | |
NCT00948675 Zinner et al. | Pemetrexed/carboplatin with maintenance pemetrexed vs paclitaxel/carboplatin/bevacizumab with maintenance bevacizumab in IIIB or IV Nonsquamous NSCLC | currently recruiting | |
NCT00693992 CALGB 30607
| Sunitinib as maintenance therapy vs placebo in Non-Progressing Patients Following 4 Cycles of Platinum-Based Combination in IIIB/IV NSCLC | currently recruiting | |
NCT00961415 AVAPERL1
| Bevacizumab with or without pemetrexed as maintenance after 4 cycles Bevacizumab/Cisplatin/Pemetrexed | currently recruiting | |
NCT00676507 STOP
| Lucanix™ (Belagenpumatucel-L) as Maintenance III/IV NSCLC with SD or PR and Who Have Responded to or Have Stable Disease Following One Regimen of Front-line, Platinum-based Combination Chemotherapy | currently recruiting | |