Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:
Squamous cell carcinoma (25% of lung cancers).
Adenocarcinoma (40% of lung cancers).
Large cell carcinoma (10% of lung cancers).
There are numerous additional subtypes of decreasing frequency.
EGFR inhibitors in patients with or without EGFR mutations.
EML4-ALK inhibitors in patients with EML-ALK translocations.
Surgical resection of isolated cerebral metastasis (for highly selected patients).
Laser therapy or interstitial radiation therapy (for endobronchial lesions).
Stereotactic radiation surgery (for highly selected patients).[10,11]
Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.
The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[13,14] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.
Evidence (chemotherapy and targeted therapy):
Two prospective, randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[2,15] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.
A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported. In that analysis the following was shown:
Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
Significantly less-severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.
A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel and those with nonsquamous histologies appeared to benefit more from pemetrexed.
Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared to placebo [19,20] but does not improve survival compared to standard second-line chemotherapy with docetaxel or pemetrexed.
The trial of erlotinib versus best supportive care included 731 patients; 49% had received two prior chemotherapy regimens and 93% had received platinum-based chemotherapy.
OS was 6.7 months among those who had received two prior chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[Level of evidence: 1iiA]
In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy following progression on first-line platinum combination therapy, 424 patients were randomly assigned.
There was no difference in the primary endpoint of OS (median OS survival, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[Level of evidence: 1iiA]
A randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed the following:
Gefitinib does not improve OS.
Median survival did not differ significantly between the groups in the overall population (5.6 mo for gefitinib and 5.1 mo for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 mo vs. 5.4 mo; HR, 0.84; CI, 0.68–1.03; P = .089).
Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 mo vs. 6.1 mo) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 mo vs. 5.5 mo).[Level of evidence: 1iiA]
In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy. The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m2 intravenously every 3 weeks; n = 733).
Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.
A study (NCT00585195) that screened 1,500 patients with NSCLC for ALK rearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual MET and ALK inhibitor of 250 mg twice daily in 28-day cycles. Most of the patients had received previous treatment.
At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and 1 confirmed complete response); 27 patients (33%) had stable disease.[Level of evidence: 3iiiD]
The estimated probability of 6-month PFS was 72%.
1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [CI 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [23–64], and 2-year OS 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[Level of evidence: 3iiiD]
Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas.