The objective of maintenance therapy is to sustain response to first-line induction therapy further tumor growth rather than induce substantial tumor shrinkage.
The NSCLC maintenance therapy can be split into two basic concepts:
Continuing therapy in patients with no disease progression after firstline induction treatment by using one of the agents that formed part of that induction regimen, so-called continuation maintenance; or Switching to another agent that has known efficacy as second-line treatment immediately following initial response to or disease stabilization after induction treatment, so-called switch maintenance or early second-line treatment.
Maintenance treatment may be administered until disease progression. In practice, it’s usually administered for an average of five to six cycles, although EGFR TKI maintenance may be given for longer, especially in patients with mutant EGFR.
Generally the oncologists prefer continuation maintenance over switch maintenance therapy because it allows patients to remain on a treatment that they are familiar with and does not exhaust a patient’s treatment options. In the moment, the oncologist has different maintenance schemes. For example, if a patient receives bevacizumab in the first-line treatment, he will receive bevacizumab maintenance. If somebody receives a platinum agent plus pemetrexed, he will continue pemetrexed at least for a while as a kind of maintenance.
But for some cases the oncologist will move to a switch maintenance. That means that somebody gets carboplatin and gemcitabine and is then put on erlotinib or pemetrexed as switch maintenance, because most of the patients need a drug holiday.
Continuation Maintenance with Chemotherapy
The first Phase III trial to present the idea that maintenance was a viable and useful concept was a continuation maintenance trial of gemcitabine, carried out by the Central European Cooperative Oncology Group (CECOG) and published in 2006 (Brodowicz T, 2006). The study met its primary end point of significantly increasing TTP but failed to show significant improvement. However, the E4599 trial and, later, the AVAiL study successfully continued bevacizumab as maintenance monotherapy in patients achieving response or SD after induction treatment with bevacizumab plus chemotherapy (Sandler A, 2006; Reck M, 2009). These results sparked new interest in this area of research. Since then, several trials have investigated the role of maintenance therapy in advanced NSCLC, with varying degrees of success.
The CECOG trial randomized patients with stage IIIB with PE/stage IV NSCLC who achieved response or SD after four cycles of induction therapy with gemcitabine/cisplatin 2:1 to continuation maintenance monotherapy with gemcitabine or to BSC following gemcitabine/cisplatin induction therapy. Results showed that, for the maintenance period, patients receiving gemcitabine had a near doubling of TTP compared with those receiving BSC, as well as a significantly longer TTP for the study’s entire duration The increase in responders in the maintenance gemcitabine arm suggests that maintenance therapy can induce substantial tumor shrinkage, and the improvements in survival, though not significant in the case of OS, were encouraging. Of note, this study was limited by its size.
The PARAMOUNT trial for pemetrexed as continuation maintenance were presented at the ASCO annual meeting. Patients in the PARAMOUNT trial (non-squamous-cell NSCLC; ECOG PS = 0-1) (n = 539) initially received four cycles of firstline treatment with pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Those patients who achieved a response or had disease stabilization after completion of first-line therapy were randomized to continuation maintenance therapy with pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) and BSC or to placebo/BSC. All patients received concomitant folic acid and vitamin B12 supplementation. Both treatment arms were equally matched. More patients in the pemetrexed arm (23%)
completed more than six cycles of treatment compared with the placebo arm (14%). Median PFS (investigator-assessed; primary end point) for patients in the pemetrexed maintenance arm was longer (4.1 months) compared with mPFS for patients in the placebo arm (2.8 months) (HR = 0.62; P = 0.00006). Subgroup analysis revealed that pemetrexed maintenance appeared better for female patients, never-smokers, and treatment responders to firstline treatment. Independent review of the data show that mPFS for patients in the pemetrexed maintenance arm was longer (3.9 months) compared with the placebo arm (2.6 months) (HR = 0.64; P = 0.0002). When PFS is considered for the complete duration of treatment from first-line therapy through the maintenance period, mPFS for patients receiving continuation maintenance with pemetrexed is longer (6.9 months) compared with patients
who received placebo during the maintenance phase (5.59 months) (HR = 0.59; P < 0.00001) (investigator-assessed). Not surprisingly, more patients in the pemetrexed arm (5.3%) discontinued treatment as a result of adverse events compared with patients in the placebo arm (3.3%). More patients in the pemetrexed maintenance arm experienced serious adverse events (8.9%) compared with patients in the placebo arm (2.8%) (a statistically significant result). The most frequently occurring grade 3/4 adverse events includedfatigue (pemetrexed arm: 4.2%, placebo arm: 0.6%), anemia (pemetrexed arm: 4.5%, placebo arm: 0.6%), and neutropenia (pemetrexed arm: 3.6%, placebo arm: 0%).
An interesting finding from the PARAMOUNT trial was that there was no statistical difference between the two treatment arms in health-related quality of life as measured by the EQ-5D index or the visual analog scale. These data may help convince some oncologists or patients who insist that a treatment holiday is needed before receiving second-line therapy because they think that maintenance therapy compromises quality of life.
Switch Maintenance with Chemotherapy
The trial of note that focused on switch maintenance therapy in advanced NSCLC compared the efficacy and safety of docetaxel given immediately after gemcitabine/cisplatin induction therapy or upon disease progression.
Results were first presented at ASCO 2007 and final results were published in 2009 (Fidias P, 2007; Fidias P, 2009). OS was the primary end point. OS for the ITT population trended in favor of immediate docetaxel therapy, but the difference was not statistically significant
There was a statistically significant more than doubling of PFS, a secondary end point, in the immediate docetaxel arm.
Several aspects of this trial are interesting. For example, it seems welldesigned in that the intention was to directly compare survival in patients receiving docetaxel before progression (maintenance) as opposed to after progression (second line), thereby allowing any improvement in survival in the immediate docetaxel arm to be attributed to the drug’s administration as maintenance per se, as opposed to its administration at all. However, what actually occurred is that more than one-third of the patients in the delayed arm—37%—never received docetaxel therapy because of symptomatic deterioration by the time they progressed. When survival was adjusted to account for the differing rates of docetaxel treatment in each arm, there was absolutely no difference. Therefore, it appears that the trend toward improved survival in the immediate docetaxel arm was simply because more people in that arm received docetaxel at all, not because they received it as maintenance. Furthermore, in their assessment of patients in each treatment arm who did receive docetaxel, the study investigators discovered no difference in quality of life (QOL) between treatment arms.
These results seem to suggest that although docetaxel monotherapy is beneficial, there is no increased benefit from giving it immediately after induction treatment, as opposed to following progression. The fact that so many patients in the delayed docetaxel arm were not fit to receive the drug following progression does support, to some degree, the concept that certain patients may benefit from immediate secondline/maintenance treatment following induction.
Switch Maintenance with an EGFR TKI
In April 2010, the EGFR TKI erlotinib was approved in both the USA and Europe as a first-line switch maintenance treatment.
Erlotinib’s approval as maintenance therapy is based on the Phase III SATURN trial, a placebo-controlled study whose primary end points were PFS in all analyzable patients regardless of EGFR protein status and PFS in patients with EGFR protein-expressing (IHC-positive) tumors. As with pemetrexed in the H3E-MC-JMEN trial, erlotinib was given immediately following four cycles of induction platinum-based doublet chemotherapy.
Results, given in terms of HR, were presented at both ASCO and the World Conference on Lung Cancer 2009 (Cappuzzo F, 2009a; Cappuzzo F, 2009b; Brugger W, 2009a; Brugger W, 2009b), and final results were published in 2010 (Cappuzzo F, 2010). PFS was significantly prolonged with erlotinib as opposed to placebo in both the ITT population and those patients with EGFR-expressing tumors (HR = 0.71 and 0.69, respectively), although it translated to an increase in median PFS of just 1.2 weeks in both populations. A significant OS benefit (secondary end point) was also seen with erlotinib in both the ITT and IHC-positive populations (HR = 0.81 and 0.77, respectively). MOS in the ITT population increased by one month in erlotinib-treated patients compared with placebo-treated patients. Of note, patients achieving SD following induction therapy experienced a more pronounced benefit in survival from erlotinib than those experiencing a response; MOS was 2.3 months longer for SD patients following treatment with erlotinib than with placebo (HR = 0.72) and just 0.5 months longer for patients with response (HR = 0.94).
Preplanned subgroup analyses of the SATURN results revealed that patients benefited from erlotinib regardless of histology, although those with adenocarcinoma benefited most in terms of PFS (HR = 0.60 compared with 0.71 in ITT population and 0.76 in squamous-cell patients) and OS (HR = 0.77 compared with 0.81 in the ITT population and 0.86 in squamous-cell patients). Erlotinib’s PFS and OS benefits occurred regardless of smoking status, although never-smokers and former smokers derived greater benefit than current smokers (PFS HR = 0.56, 0.66, and 0.80, respectively; OS HR = 0.69, 0.75, 0.88, respectively) and regardless of gender, ethnicity, and PS. Furthermore, molecular subset analyses showed a significant PFS benefit of erlotinib in both EGFR-mutated as well as EGFR wild-type tumors. However, although this benefit was statistically significant in both groups, there was a highly significant interaction between treatment and mutational status; the HR was 0.10 in the group with EGFR-mutated tumors compared with 0.78 in those with EGFR-wild-type tumors.
Switch Maintenance with Erlotinib plus Continuation Maintenance with Bevacizumab
The ATLAS trial also investigated erlotinib as switch maintenance (Miller VA, 2009; Kabbinavar FF, 2010). The Phase III study compared erlotinib plus bevacizumab maintenance with bevacizumab plus placebo maintenance following first-line treatment with bevacizumab in combination with platinum-based chemotherapy. The primary end point was PFS. The trial was stopped early, in February 2009, on the recommendation of an independent data safety monitoring board after a preplanned interim analysis showed that the combination of bevacizumab and erlotinib significantly increased PFS compared with maintenance bevacizumab plus placebo. The data showed that PFS was significantly improved—by 4.4 weeks—in patients treated with erlotinib and bevacizumab as maintenance compared with those treated with bevacizumab alone.
Interestingly, the PFS in patients treated with the dual biologic combination as maintenance was 8.2 weeks longer than that of patients treated with erlotinib as maintenance in the SATURN trial.
The ATLAS trial results suggest that a subset of patients may benefit from maintenance treatment with erlotinib plus bevacizumab in combination, but whether the benefit outweighs the extreme expense of using not one but two premium-priced agents as maintenance therapy is open to debate.
Switch Maintenance with Erlotinib vs. Continuation Maintenance with Chemotherapy
Erlotinib as switch maintenance examined both switch and continuation maintenance but, unlike ATLAS, compared the two in different treatment arms. IFCT-GFPC 05.02 randomized patients achieving response or SD following induction gemcitabine/cisplatin treatment to continuation maintenance with gemcitabine, switch maintenance with erlotinib, or observation alone (Perol M, 2010). The study target was to investigate further if patients responding to first-line therapy do benefit from continuation maintenance as the Brodowicz trial (and subsequently the Belani trial) suggested, especially given that the switch maintenance studies seem to indicate that patients with SD following induction benefit most from this “early second-line” strategy.
Although, almost 40% of the patients enrolled in each arm of this study were never-smokers, and about two-thirds in each arm had adenocarcinoma. The primary end point was PFS, and results showed significant improvements for both maintenance therapies compared with observation alone, although greater improvement in PFS occurred with gemcitabine continuation maintenance (HR = 0.55) . Compared with observation only, the chances of being progression-free at three and six months improved by 25% and 13.5%, respectively, with gemcitabine maintenance but by just 5% and 7.7%, respectively, with erlotinib maintenance.
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