James P. Stevenson, MD
The paradigm of observation alone following 4-6 cycles of frontline platinum-based combination chemotherapy has become obsolete for patients with nonsquamous non-small cell lung cancer (NSCLC), while no clinically significant breakthroughs in “continuation,” or “maintenance,” therapy have occurred to date for patients with squamous NSCLC.
Agents that have been shown to improve survival when administered as maintenance therapy include bevacizumab and pemetrexed, although questions have been raised regarding the design of the randomized trials that led to their approval in this setting. Doublet maintenance has not been proved to be superior to single-agent therapy, although this question is currently being addressed in a large randomized trial.
Quality of life and cost considerations clearly become important for patients receiving prolonged intravenous therapy for durations ranging from months to years; therefore optimization of drug and patient selection for maintenance therapies will continue to be a research focus in today’s environment of value-based care.
Despite the discovery of oncogenic driver mutations and corresponding targeted agents with clinical activity in a small percentage of non-small cell lung cancers (NSCLCs), the majority of patients with advanced disease will receive cytotoxic agents as frontline therapy, most commonly in the form of a platinum-based doublet.1
Traditional treatment paradigms with platinum combinations consisted of 6 cycles of therapy in patients with response/disease stability followed by observation, with consideration of second-line therapy initiation at the time of disease progression.2
Unfortunately, the typical survival time for an advanced NSCLC patient only approached 10 months with this strategy.
Continuation, or “maintenance,” therapy in advanced NSCLC is not a new concept; however early tests of the hypothesis have proved disappointing. Socinski and colleagues found that 6 cycles of paclitaxel plus carboplatin produced the similar response rate, survival benefit, and quality of life as continuation of combination therapy past 4 cycles, with greater neurotoxicity occurring in the continuation arm.3
Proceeding with single-agent maintenance therapy as an alternative to the continuation of more toxic doublet therapy also failed to show survival benefit in multiple trials of agents including gemcitabine and docetaxel (Table 1).4-6
A subsequent meta-analysis published in 2009 revealed that continuation therapy produced significant improvement in PFS, however, overall survival was only slightly improved (HR, 0.92; P
These findings did not generate further enthusiasm in the thoracic oncology community for maintenance therapy with the cytotoxic agents evaluated in the trials included in the meta-analysis (with the exception of pemetrexed), especially given the reported increase in associated adverse events.
The landmark ECOG 4599 trial established the continuation of bevacizumab until progression following 6 cycles of combination bevacizumab plus paclitaxel/carboplatin as a new standard of care for patients with nonsquamous disease who were otherwise candidates for bevacizumab, making bevacizumab the first agent to garner such an indication.8
Patients receiving bevacizumab survived a median of 12.3 months, significantly improved by 2 months over chemotherapy alone, as were response rates (35% vs 15%) and PFS (6.2 vs 4.5 months).
Of note is that a third arm of bevacizumab plus chemotherapy without bevacizumab maintenance was not included in this trial, raising questions that persist to this day regarding the contribution of continuation therapy to the overall survival improvement.
The restriction of the approval of bevacizumab to nonsquamous patients because of an increased incidence of fatal hemoptysis in those with squamous histology, as well as the initial exclusion of patients with hemoptysis, brain metastases, or those receiving anticoagulation limited the initial use of bevacizumab in the clinic for NSCLC patients, as did concerns about rare but life-threatening toxicities. While bevacizumab has since been shown to be safe in patients with treated brain metastases and can as well be given concurrent with anticoagulants, subsequent retrospective analyses have called into question the efficacy of bevacizumab in elderly NSCLC patients (older than 65 years in 1 study) as well as its cost-effectiveness.9-11
The initial finding of the effectiveness and tolerability of pemetrexed in the second-line setting for advanced NSCLC patients led investigators to study its use earlier in the disease course as “switch” maintenance following platinum doublet therapy.