Table 6.

Factors Predicting Benefit From Maintenance Chemotherapy

Factor	Examples
Response to first-line therapy	In clinical trials of switch maintenance therapy with pemetrexed (JMEN) and erlotinib (SATURN), the survival benefit of maintenance therapy was limited to patients who had stable disease (in contrast to responding disease) after induction chemotherapy. In JMEN, the OS HR was 0.68 for patients with stable disease v 0.90 for patients with responding disease. In SATURN, the OS HR was 0.72 for patients with stable disease v 0.94 for patients with responding disease. In contrast, in the clinical trial of switch maintenance therapy with docetaxel, the survival benefit of maintenance therapy was limited to patients who had responding disease (HR, 0.61 v 1.02 for patients with stable disease).16,17,58
Performance status	In the CECOG trial of continuation maintenance with gemcitabine, a survival benefit for maintenance therapy was observed only in patients with good performance status. For KPS > 80 (n = 99), median OS was 8.3 months with BSC and 22.9 months with gemcitabine (HR, 2.1; 95% CI, 1.2 to 3.8). For KPS ≤ 80 (n = 120), median OS was 7.7 months with BSC and 7.0 months with gemcitabine (HR, 0.8; 95% CI, 0.5 to 1.3).40
Likelihood of therapy at progression	The clinical trial of switch maintenance therapy with docetaxel demonstrated that OS is similar between patients who received immediate docetaxel after completion of four cycles of carboplatin-gemcitabine and patients who received delayed docetaxel at time of progression. Therefore, factors associated with lower likelihood of receipt of second-line chemotherapy may predict patients most likely to benefit from maintenance therapy. Two single-center retrospective studies have evaluated factors predicting receipt of second-line chemotherapy among patients with advanced NSCLC. In a US study, these factors included socioeconomic status (by insurance type) and a surrogate marker of disease burden (prechemotherapy palliative radiation therapy). Second-line chemotherapy administration was not associated with age, sex, race, histology, or year of diagnosis. In a Korean study, poor performance status, larger initial target lesions, and smaller decrease in target lesions after first-line therapy were associated with a lower likelihood of second-line chemotherapy administration.16,31,32
Histology	In certain clinical trials of switch maintenance therapy with EGFR inhibitors, clinical benefit seems greater in patients with adenocarcinoma histology. In SATURN, the OS benefit from erlotinib was significant in patients with adenocarcinoma (HR, 0.77; 95% CI, 0.61 to 0.97) but not in patients with squamous cell histology (HR, 0.86; 95% CI, 0.68 to 1.10). In WJTOG 0203, which did not demonstrate a significant survival advantage with gefitinib in the overall study population, a subset analysis of patients with adenocarcinoma demonstrated a significant OS difference (HR, 0.79; P = .03). However, there was no treatment-histology interaction in the IFCT-GFCP-052 trial of switch maintenance therapy with erlotinib. As noted in other clinical trials of pemetrexed, the clinical benefit of switch maintenance therapy with pemetrexed is limited to patients with nonsquamous histology. In the JMEN trial, for nonsquamous histology in the pemetrexed and placebo arms, PFS was 4.4 v 1.8 months, respectively (HR, 0.47; P < .001), and OS was 15.5 v 10.3 months, respectively (HR, 0.7; P = .002); for squamous histology, PFS was 2.2 v 2.5 months, respectively (HR, 1.03), and OS was 9.9 v 10.8 months, respectively (HR, 1.07). Subsequent maintenance therapy trials incorporating pemetrexed have restricted enrollment to patients with nonsquamous tumors.17,33,43,58,61,71,72
Molecular characteristics	As noted in other clinical trials of EGFR inhibitors, the clinical benefit of maintenance therapy with erlotinib or gefitinib is greatest for patients with tumors harboring activating EGFR mutations. In SATURN, for EGFR mutant tumors, the PFS HR was 0.10 (95% CI, 0.04 to 0.25; P < .001); for EGFR wild-type tumors, the PFS HR was 0.78 (95% CI, 0.63 to 0.96; P = .0185). In WJTOG 0203, patients with EGFR mutant tumors had a median PFS of 16.6 months with gefitinib v 2.8 months with placebo (HR, 0.17; 95% CI, 0.07 to 0.42); patients with EGFR wild-type tumors had a median PFS of 2.7 months with gefitinib v 1.5 months with placebo (HR, 0.86; 95% CI, 0.48 to 1.51). Also consistent with clinical trials of EGFR inhibitors in other settings, KRAS mutations seem to be associated with lack of benefit from maintenance therapy with EGFR inhibitors. In the ATLAS trial, the PFS HR was 0.67 (95% CI, 0.49 to 0.9) for KRAS wild-type tumors. For KRAS mutant tumors, the PFS HR was 0.93 (95% CI, 0.55 to 1.56).58,59,63,71

Abbreviations: BSC, best supportive care; CECOG, Central European Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; IFCT-GFPC, Intergroupe Francophone de Cancerologie Thoracique–Groupe Francais de Pneumo-Cancerologie; KPS, Karnofsky performance score; NSCLC, non–small-cell lung cancer; OS, overall survival; PFS, progression-free survival; SATURN, Sequential Tarceva in Unresectable NSCLC; WJTOG, West Japan Thoracic Oncology Group.