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.

 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.

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.

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).

 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; 

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.

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.

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.

Ciuleanu and colleagues showed that immediate pemetrexed following 4 cycles of a platinum plus paclitaxel, docetaxel, or gemcitabine improved overall survival by nearly 3 months over placebo (13.4 v 10.6 months; 

 = .012) in a randomized trial of 663 patients.

 The survival benefit was noted despite the fact that 67% of patients in the placebo arm went on to receive subsequent systemic therapy (pemetrexed in 18%).

Coincident with this report, Scagliotti et al, showed that the combination of first-line pemetrexed/cisplatin produced significant improvement in overall survival versus gemcitabine/cisplatin in a randomized trial of over 1700 patients.

However, this improvement was only noted for patients with nonsquamous histology, while gemcitabine/cisplatin had superior efficacy in squamous histology. Therefore the maintenance indication for pemetrexed was limited to nonsquamous patients only. Given positive randomized trials of pemetrexed in the frontline as well as the switch maintenance settings, the next most relevant question pertained to the use of maintenance pemetrexed following frontline pemetrexed/platinum therapy.

trial of maintenance pemetrexed vs placebo following 4 cycles of induction pemetrexed/cisplatin showed significant improvement in PFS (4.1 vs 2.8 months) and OS (13.9 vs 11.0 months) remarkably similar to the Ciuleanu et al trial. Thus pemetrexed continuation maintenance has been validated after frontline pemetrexed/platinum doublet therapy.

The use of bevacizumab and pemetrexed as single agents in the maintenance setting has not surprisingly led to the investigation of doublet maintenance therapy, especially as these drugs are administered as short infusions and in general have non-overlapping toxicities (Table 2). Trials of doublet maintenance have taken different forms. In the wake of promising phase II results of combination bevacizumab/pemetrexed maintenance following 6 cycles of bevacizumab plus pemetrexed/carboplatin, this strategy was compared to standard bevacizumab alone after bevacizumab plus paclitaxel/carboplatin in the phase III PointBreak trial of over 900 patients.

No difference in overall survival with doublet maintenance was noted (12.6 vs 13.4 months, HR, 1.00; 

Results from the 253 patient phase III AVAPERL trial also indicated no survival benefit (19.8 versus 15.9 months, HR, 0.88, 

 = 0.32) to bevacizumab/pemetrexed maintenance over bevacizumab alone following 4 cycles of bevacizumab plus pemetrexed/cisplatin, despite significant improvement in PFS noted at the time the trial was initially reported.

One criticism of these studies is that they did not include maintenance pemetrexed alone as a treatment arm. A large randomized trial (ECOG 5508) of maintenance bevacizumab versus pemetrexed versus bevacizumab/pemetrexed following frontline bevacizumab/paclitaxel/carboplatin is currently open across cooperative groups and should provide useful evidence regarding optimal maintenance therapy following bevacizumab-containing frontline treatment.

The role of bevacizumab in induction and maintenance when pemetrexed is used is also a question of interest. Overall survival times from randomized trials of frontline pemetrexed plus cisplatin as described above are comparable to trials of platinum combinations plus bevacizumab. Zinner and colleagues recently published the results of a 361 patient randomized trial (PRONOUNCE) of 4 cycles of pemetrexed/carboplatin followed by maintenance pemetrexed versus 4 cycles of bevacizumab plus paclitaxel/carboplatin with maintenance bevacizumab.

 Overall survival was noted to be similar in both arms (10.5 versus 11.7 months, HR, 1.07; 

Significantly less hematologic and neurologic toxicity was noted in the patients receiving pemetrexed, as well as less grade 2 alopecia. This has led some to favor the use of pemetrexed-based induction and maintenance therapy without bevacizumab in nonsquamous patients; there are also favorable cost-effectiveness data to support the use of pemetrexed plus platinum in this setting.

The third agent to have an indication for maintenance therapy is erlotinib, which was approved based on the large, randomized SATURN trial of erlotinib versus placebo following 4 cycles of frontline platinum-based therapy in 889 NSCLC patients of any histology.

Erlotinib produced significant improvement in overall survival (12.0 versus 11.0 months, HR, 0.81; 

 = .0088) that was also evident in patients without epidermal growth factor receptor (EGFR)-mutated tumors (HR, 0.77; 

 = .0243), although testing was completed only on approximately half of the randomized patients and there was no pre-specified stratification based on this marker.

Other investigations of EGFR tyrosine kinase inhibitors (TKIs) as maintenance therapy in unselected NSCLC patients following frontline platinum-based treatment have not duplicated these results. Four trials employing this strategy (2 with erlotinib, 2 with gefitinib) showed no statistically significant improvement in survival with maintenance EGFR TKI therapy.

 Therefore, despite the approval of erlotinib as a maintenance therapy for NSCLC, it has not been widely employed in the clinic in such a fashion.

Another EGFR targeted agent to be studied in the maintenance setting is the monoclonal antibody cetuximab. Two large randomized trials of continuation cetuximab following the addition of cetuximab to frontline platinum-based therapy have been reported. The FLEX trial involved cetuximab added to vinorelbine plus cisplatin followed by maintenance cetuximab versus vinorelbine plus cisplatin alone in 1125 patients with EGFR immunohistochemistry (IHC) positive NSCLC.

These data were not considered robust enough to elicit FDA approval for an NSCLC indication, and this decision was perhaps informed by the negative result of the second randomized trial, reported by Lynch and colleagues.

 In that study of 676 unselected NSCLC patients, cetuximab produced no improvement in PFS or OS when added to up to 6 cycles of frontline paclitaxel/carboplatin and then continued as a single agent.

As noted here, the results of maintenance trials in NSCLC as well as other malignancies underscore the need to better define the clinical meaningfulness of significantly improved survival endpoints: these costly therapies may be continued for months to years in patients who do not progress. In the current value-based medical environment, survival improvement benchmarks and cost-effectiveness analyses will play an increasing role in approvals by regulatory agencies, acceptance by payers, and the day-to-day decisions of individual practitioners.

 Trials showing marginal benefit in unselected histologic or genomic tumor subtypes are unlikely to find their way to the clinic or the patient.

Continuation maintenance therapy with either pemetrexed or bevacizumab has become a widely accepted standard of care, and this strategy has significantly impacted the prognosis for nonsquamous NSCLC patients, although questions remain regarding the use of bevacizumab in the elderly, and there is an unmet need in patients with squamous histology. There are currently no compelling data to support the use of these drugs in combination, although a large ongoing randomized trial (ECOG 5508) examines this and is expected to complete accrual in late 2015.

It otherwise appears unlikely that further refinement and improvements in maintenance treatment following frontline platinum-based chemotherapy will come from available cytotoxic agents. The promise of immunotherapy has become real for patients with malignant melanoma, and agents that target the PD-1 receptor, including nivolumab and pembrolizumab, have shown hopeful and sometimes striking results in pretreated nonsquamous and squamous NSCLC patients.

The CheckMate (nivolumab) and KEYNOTE (pembrolizumab) series of ongoing clinical trials involve the use of these agents in different manners as frontline and maintenance therapies: alone versus platinum chemotherapy, or in combination with platinum doublets and then continued as monotherapy in patients showing benefit. Positive results from trials such as these could dramatically change the landscape of current initial treatment paradigms for patients with advanced NSCLC.

James P. Stevenson, MD, Cleveland Clinic Foundation — Taussig Cancer Institute, 9500 Euclid Ave, R-35, Cleveland, OH 44195, phone: 216-636-6888, fax: 216-636-2498. E-mail: stevenj5@ccf.org.

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Articles

James P. Stevenson, MD, discusses optimization of drug and patient selection for maintenance therapies in NSCLC, and how it will continue to be a research focus in today's environment of value-based care.

James P. Stevenson, MD

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