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Lung Cancer Health Center

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Non-Small Cell Lung Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV NSCLC Treatment


EGFR tyrosine kinase inhibitors (first line)

Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Evidence (EGFR tyrosine kinase inhibitors):

  1. A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[36]
    1. The study met its primary objective of demonstrating the superiority of gefitinib as compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65-0.85; P < .001).
    2. The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[36][Level of evidence: 1iDiii]
    3. Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
      • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
    4. More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36-0.64; P < .001), whereas, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05-3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).[36]
    5. OS was similar for gefitinib and carboplatin/paclitaxel, with no significant difference between treatments overall (HR, 0.90; 95% CI, 0.79-1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76- 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86-1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34-0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09-7.09).
  2. Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.[37,38]
    1. In the first trial, 230 chemotherapy-naïve patients with metastatic, NSCLC, and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[37]
      • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
      • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22-0.41; P < .001).[37][Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = .31).
    2. In the second trial, the West Japanese Oncology Group conducted a phase 3 study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).[38]
      • Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.
      • The gefitinib group had significantly longer PFS compared with the cisplatin plus docetaxel group, with a median PFS time of 9.2 months (95% CI, 8.0-13.9) versus 6.3 months (5.8-7.8; HR, 0.489; 95% CI, 0.336-0.710, log-rank, P < .0001).[38][Level of evidence: 1iiDiii]
  3. Similar benefit may be achieved with erlotinib.
    1. In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[39]
      • Median PFS was significantly longer in erlotinib-treated patients than in those treated with chemotherapy (13.1 [95% CI, 10.58-16.53] vs. 4.6 [4.21-5.42] months; HR, 0.16; 95% CI, 0.10-0.26; P < .0001).[39][Level of evidence: 1iiDiii]
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