Personalized maintenance therapy in advanced non-small cell lung cancer

Lung cancer is the leading cause of cancer-related death worldwide (1). Efforts to improve the survival of non-small cell lung cancer (NSCLC) patients are currently focused on the development of innovative personalized treatment options, particularly with molecular targeted therapy or maintenance therapy.

The accepted standard first-line treatment for patients with unselected advanced NSCLC is a platinum-based agent in combination with gemcitabine, vinorelbine, irinotecan, docetaxel, or paclitaxel (2-5). Recent studies demonstrated that cisplatin or carboplatin plus pemetrexed and carboplatin plus paclitaxel plus bevacizumab conferred a survival advantage compared to other regimens in a limited number of NSCLC patients with non-squamous cell histology (6,7). Currently, personalized therapy may contribute to improved survival through identification of specific genotypic anomalies and histologic subtypes in each patient.

Both gefitinib and erlotinib are reversible inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Erlotinib led to prolonged survival in a group of previously treated NSCLC patients who were not selected for EGFR mutations, whereas gefitinib did not improve survival in a similar population (8,9). Erlotinib and docetaxel are recommended for previously treated NSCLC patients according to American Society of Clinical Oncology (ASCO) guidelines. In a recent randomized phase III trial (DELTA) in unselected, previously treated NSCLC patients, erlotinib failed to result in better progression-free survival (PFS) than docetaxel (10). However, significantly longer PFS was seen in EGFR-wild type patients treated with docetaxel. Several prospective studies of gefitinib and erlotinib demonstrated significantly increased response rates and marked improvement in PFS compared to standard chemotherapy in selected populations harboring activating EGFR mutations including exon 19 deletion and L858R point mutation (11-14). According to these results, first-generation EGFR-TKIs are most effective in specific patients with NSCLC who have activating EGFR mutations.

Maintenance therapy is the continued treatment of a tumor that has not progressed after initial induction chemotherapy. Previous studies have demonstrated the utility and safety of switch or continuation maintenance chemotherapy after induction treatment with platinum-based combination chemotherapy (15,16). The AVAiL study (17), FLEX study (18), and ECOG 4599 study (7), large randomized phase III trials of continuation therapy with bevacizumab (AVAiL, ECOG 4599) or cetuximab (FLEX) after first-line chemotherapy, met their primary endpoints with significantly longer overall survival (OS) or PFS. The AVAiL and ECOG 4599 studies enrolled patients with non-squamous cell histology, and the FLEX study selected patients with EGFR positivity by immunohistochemistry. The first-line treatment differed between the control group and the treatment group in these studies. The chemotherapy regimen used for first-line therapy in each trial may influence survival. Therefore, it is difficult to draw conclusions about the benefits of continuation treatment after first-line therapy from these studies. Given this limitation, it is unclear whether bevacizumab and cetuximab, which were continually administered after first-line chemotherapy in these studies, are effective agents for maintenance therapy.

The AVAPERL study was a randomized phase III trial of maintenance bevacizumab with or without pemetrexed administered after first-line induction chemotherapy with cisplatin plus pemetrexed and bevacizumab in advanced NSCLC patients with non-squamous cell histology. In this study, patients treated with maintenance pemetrexed plus bevacizumab had a longer PFS (19). Given the results of the previous large phase III studies as well as AVAPERL, pemetrexed plus bevacizumab may currently be the most highly recommended maintenance regimen in NSCLC patients with non-squamous cell histology. The ECOG 5508 study, which is an ongoing randomized phase III trial, compares maintenance with bevacizumab alone to maintenance with bevacizumab plus pemetrexed or pemetrexed alone after treatment with carboplatin, paclitaxel, and bevacizumab in selected NSCLC patients with non-squamous cell histology (20). The results of this trial will allow confirmation of the most appropriate maintenance therapy.

There are two randomized phase III trials of maintenance therapy that demonstrated longer PFS and OS in selected patients with advanced NSCLC. The PARAMOUNT study assessed the efficacy of maintenance therapy with pemetrexed after completion of cisplatin plus pemetrexed in patients with advanced non-squamous NSCLC (21,22). The SATURN trial assessed the efficacy of erlotinib as maintenance therapy after completion of first-line platinum-doublet chemotherapy (23). These studies demonstrated longer PFS and OS with maintenance therapy than in a placebo control group. Given these results, the current recommendation is continuation maintenance therapy with pemetrexed for patients with advanced NSCLC with non-squamous cell histology, and switch maintenance therapy with erlotinib for patients with unselected advanced NSCLC. The latter regimen is especially recommended for patients who showed response with stable disease to induction platinum-doublet chemotherapy (24).

Previously, the WJTOG0203 study showed significantly long PFS in Japanese patients with NSCLC who were treated with continuation gefitinib after completion of first-line platinum-doublet chemotherapy (25). However, patients enrolled in this study randomly received either platinum-doublet chemotherapy for up to six cycles or platinum-doublet chemotherapy for three cycles followed by gefitinib. The number of treatment cycles given during first-line chemotherapy was different between the treatment and control groups in this study. Therefore, it is difficult to draw conclusions about the efficacy of gefitinib as switch maintenance therapy in these unselected NSCLC patients. The INFORM trial, which was a phase III study of gefitinib as switch maintenance treatment in patients who completed first-line platinum-based chemotherapy during induction, showed significantly longer PFS in patients with advanced NSCLC (26). This study is the first phase III trial to assess the efficacy of gefitinib as maintenance treatment in Asian patients with advanced NSCLC who achieved disease control with platinum-based induction chemotherapy. This study met its primary endpoint, with significantly increased PFS in patients who received gefitinib, as indicated by histology analysis and biomarker measurement, compared to the placebo group in unselected patients. This study strongly suggests that maintenance therapy with gefitinib conferred considerable survival benefit on specific patients who had activating EGFR mutations, including exon 
19 deletion and L858R point mutation, but no PFS benefit on patients who had wild-type EGFR.

While both gefitinib and erlotinib have potential for maintenance therapy in EGFR-mutated NSCLC patients, the efficacy of each agent was determined by subset analysis of randomized phase III studies including the INFORM and SATURN trials. These studies demonstrated the important fact that first-generation EGFR-TKIs used as switch maintenance therapy may produce a significant improvement in PFS for a limited group of NSCLC patients who harbor EGFR mutations and who achieve disease control after first-line platinum-doublet chemotherapy when compared to the placebo group. However, EGFR-TKIs need to undergo more thorough assessment as switch maintenance therapy before they are fully accepted as a standard treatment. First, studies must analyze whether these switch maintenance regimens would show increased PFS and/or OS benefits compared to a strategy in which treatment would not begin until after the disease is progressive (watch and wait) in NSCLC patients harboring EGFR mutations. Second, the efficacy of first-generation EGFR-TKIs as first-line therapy should be examined to determine whether their use in maintenance therapy is really the best way to increase survival. Finally, studies must determine whether gefitinib or erlotinib is the most promising agent for switch maintenance therapy.

The most recommended first-line chemotherapy regimen as induction treatment in patients with advanced NSCLC is unclear. Large prospective phase III trials comparing first-line chemotherapy regimens as induction treatments are lacking. According to previous studies, platinum-based chemotherapy including pemetrexed is considered the best treatment chemotherapy regimen in patients with non-squamous cell NSCLC. The POINTBREAK study (27), which was a randomized phase III study, was designed to assess whether pemetrexed plus carboplatin plus bevacizumab followed by pemetrexed plus bevacizumab was superior to paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab for advanced non-squamous cell NSCLC. However, no significant difference was observed in terms of the primary endpoint of OS in either group, and this study failed to show a positive outcome. Additionally, Zinner et al. reported at the 2013 ASCO annual meeting that the PRONOUNCE study, which was a randomized phase III trial of carboplatin plus pemetrexed (plus maintenance pemetrexed), found no significant difference in PFS or OS compared to carboplatin plus paclitaxel plus bevacizumab (plus maintenance bevacizumab) according to subset analysis (28). Platinum-based combination chemotherapy with pemetrexed or paclitaxel (with bevacizumab) is recommended as induction chemotherapy for non-squamous cell NSCLC.

In summary, platinum-based combination chemotherapy with pemetrexed or carboplatin plus paclitaxel plus bevacizumab is recommended as the induction chemotherapy regimen in patients with non-squamous cell NSCLC. Pemetrexed plus bevacizumab is potentially more effective as a continuation or switch maintenance regimen than pemetrexed in this same population. First-generation EGFR-TKIs including gefitinib and erlotinib as switch maintenance therapies may prominently prolong PFS in patients harboring activating EGFR mutations. However, several prospective studies are needed to assess the efficacy of those molecular agents as maintenance therapy in selected patients with activating EGFR mutations. Since no trials have compared maintenance therapy with cytotoxic agents versus targeted agents in EGFR-mutated patients, data about the advantage of these maintenance therapies are inconclusive. Recently, the FASTACT-2 study (29), which was randomized phase III trial of chemotherapy plus erlotinib followed by erlotinib, demonstrated longer PFS and OS in unselected NSCLC patients. The difference was particularly large in patients harboring activating EGFR mutations. Chemotherapy plus EGFR-TKIs followed by EGFR-TKIs may come to be a new strategy for EGFR-mutated NSCLC. In the future, specific clinical studies are needed to establish new strategies for maintenance therapy in EGFR-mutated patients and in patients with squamous cell histology without activating EGFR mutations.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

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