Table 2.
Summary of studies reporting the efficacy of second-generation EGFR TKIs in patients with NSCLC and CNS metastases
| EGFR TKI | Publication | Study description | Treatments | Patient characteristics | Results | |
|---|---|---|---|---|---|---|
| Name/type | Phase | |||||
| Afatinib | Schuler et al. [71] | LUX-Lung 3 | III | First-line afatinib (40 mg QD) vs. cisplatin/pemetrexed (75 mg/m2 and 500 mg/m2 once every 21 days, up to a maximum of 6 cycles) | N = 345 (n = 42 with brain metastases [afatinib, n = 27; cisplatin/pemetrexed, n = 15], of which n = 35 also harbor common EGFR mutations [afatinib, n = 20; cisplatin/pemetrexed, n = 15]); patients with EGFR mutation-positive NSCLC and brain metastases | In patients with common EGFR mutations: • Median PFS: afatinib, 11.1 months; cisplatin/pemetrexed, 5.4 months • Median OS: afatinib, 19.8 months; cisplatin/pemetrexed, 33.2 months • Rate of CNS progression: afatinib, 45.0%; cisplatin/pemetrexed, 33.3% • Time to CNS progression: afatinib, 15.2 months; cisplatin/pemetrexed, 5.7 months • ORR: afatinib, 70.0%; cisplatin/pemetrexed, 20.0% (P = 0.0058) • DCR: afatinib, 95.0%; cisplatin/pemetrexed, 80.0% |
| Schuler et al. [71] | LUX-Lung 6 | III | First-line afatinib (40 mg QD) vs. cisplatin (75 mg/m2 every 21 days, up to 6 cycles) and gemcitabine (1000 mg/m2 on day 1 and day 8) | N = 364 (n = 49 with brain metastases [afatinib, n = 30; cisplatin/gemcitabine, n = 19], of which n = 46 harbor common EGFR mutations [afatinib, n = 28; cisplatin/gemcitabine, n = 18]); patients with EGFR mutation-positive NSCLC and brain metastases | In patients with common EGFR mutations: • Median PFS: afatinib, 8.2 months; cisplatin/gemcitabine, 4.7 months • Median OS: afatinib, 22.4 months; cisplatin/gemcitabine, 24.7 months • Rate of CNS progression: afatinib, 21.4%; cisplatin/gemcitabine, 27.8% • Time to CNS progression: afatinib, 15.2 months; cisplatin/gemcitabine, 7.3 months • ORR: afatinib, 75.0%; cisplatin/gemcitabine, 27.8% (P = 0.0027) • DCR: afatinib, 89.3%; cisplatin/gemcitabine, 72.2% |
|
| Schuler et al. [71] | Combined analysis of LUX-Lung 3 and LUX-Lung 6 | III | LUX-Lung 3: First-line afatinib (40 mg QD) vs. cisplatin/pemetrexed (75 mg/m2 and 500 mg/m2 once every 21 days, up to a maximum of 6 cycles) LUX-Lung 6: First-line afatinib (40 mg QD) vs. cisplatin (75 mg/m2 every 21 days, up to 6 cycles) and gemcitabine (1000 mg/m2 on day 1 and day 8) |
N = 91 (n = 81 harbor common EGFR mutations); patients with EGFR mutation-positive NSCLC and brain metastases | In patients with common EGFR mutations: • Median PFS: afatinib, 8.2 months; chemotherapy, 5.4 months (P = 0.0297) • Median PFS was higher with afatinib vs. chemotherapy in patients with Del19 mutation (9.5 vs. 4.7 months, respectively; P = 0.0012); there were no significant differences between treatments in patients with L858R (afatinib, 6.9 months; chemotherapy, 9.7 months) • PFS benefit was higher with afatinib compared to chemotherapy in patients who received prior WBRT (13.8 vs. 4.7 months) than in those who did not (6.9 vs. 5.4 months) • Median OS: afatinib, 22.4 months; chemotherapy, 25.0 months; no significant differences were seen between treatments among patients harboring Del19 or L8585R mutations |
|
| Park et al. [77] | LUX-Lung 7 | IIb | First-line afatinib (40 mg QD) vs. gefitinib (250 mg QD) | N = 319 (n = 50 with brain metastases: afatinib, n = 26; gefitinib, n = 24); patients with common EGFR mutation-positive NSCLC and brain metastases | • Median PFS: afatinib, 7.2 months; gefitinib, 7.4 months • Median TTF: afatinib, 8.4 months; gefitinib, 9.3 months |
|
| Hoffknecht et al. [4] | CUP and case report | Afatinib (50 mg/day); all patients pretreated with chemotherapy and erlotinib/gefitinib Case report: fourth-line afatinib (50 mg/day) |
N = 100 patients with brain metastases or LMD; 74% had EGFR mutations (77% of which were Del19 or L858R) Case report: Female patient; age: 59 years; ECOG PS: 3/4; L858R-positive NSCLC with LMD |
• ORR: PR, 42%; SD, 39% • TTF: overall, 3.6 months; EGFR-mutation-positive vs. WT, 4.0 vs. 1.3 months • Median OS: 9.8 months Case report: • Neurological symptoms diminished • ECOG PS improved to 1/2 |
||
| Tamiya et al. [80] | Multicenter trial | Third-line or later afatinib (40 mg/day) | N = 11; patients with EGFR-mutations and LMD | • ORR 27.3% • Median PFS 2.0 months • Median OS 3.8 months • Survival outcomes superior in patients with G719X mutation-positive tumors (median PFS 5.6 months; median OS 7.0 months) |
||
| Saijo et al. [89] | Case series | Third-line afatinib (40 mg/day) or afatinib (40 mg/day) following RT | N = 3; Japanese female patients with EGFR common mutations and LMD | Third-line afatinib, n = 2 patients with Del19: • Reduction in LMD-associated symptoms after 2 weeks • Improvement in ECOG PS to 1; disappearance of evidence of LMD/brain metastases Afatinib after RT, n = 1 patient with L858R: • No improvement in ECOG PS, but levels of consciousness improved • LMD under control after 11 months |
||
| Kuiper et al. [14] | Retrospective cohort analysis | Afatinib with/without cetuximab | N = 3; male patients with Del19 mutation and LMD | • Survival following LMD diagnosis was variable: 4.6, 8.7, and 0.2 months in the 3 patients | ||
| Lin et al. [87] | Case report | Afatinib (40 mg/day) plus cetuximab (250 mg/m2 biweekly) | Female patient with Del19 and LMD | • Regression of brain lesions on MRI and reduction of LMD-associated symptoms after 1 month • PD of the lung after 4 months, but no suggestion of relapse of LMD |
||
| Kawaguchi et al. [86] | Case report | Eight-line afatinib (40 mg/day) | Female patient with L858R and LMD | • Regression of neurological symptoms after 1 week of afatinib treatment • Symptom free after 1 month with ECOG PS improved to 1 • Progression free at 7 months |
||
| Ghosn et al. [85] | Case report | Third-line afatinib (50 mg/day) | Male patient with Del19 and LMD | • Disappearance of meningeal enhancement on brain MRI 10 months after the start of afatinib therapy • Patient alive with no evidence of neurological relapse at 35 months |
||
| Afatinib + RT | Baird et al. [81] | Cambridge Brain Mets Trial 1 (CamBMT1); Phase 2 of study is currently ongoing (NCT02768337) | Ib | Afatinib (20 mg QD, escalated to 30 mg and 40 mg) + 2 Gy or 4 Gy targeted RT | N = 10; patients with NSCLC (n = 6) or breast tumors (n = 4) with operable brain metastases | • Phase I (dose defining) of study completed: afatinib 40 mg QD will be used in phase II which compares efficacy • Afatinib dose in resected brain metastases was not correlated with RT dose • No dose-limiting toxicities were identified |
| Li et al. [84] | Retrospective analysis | Afatinib (30 or 40 mg/day initial or maintenance dose) + WBRT (mean dose of 2805.9 ± 405.4 cGy) | N = 28; EGFR mutation-positive, treatment-naive NSCLC patients receiving afatinib monotherapy (n = 11) or afatinib with WBRT (n = 17) | • ORR: afatinib monotherapy, 81.8%; afatinib + WBRT, 88.2% • Intracranial CR: afatinib monotherapy, 63.6%; afatinib + WBRT, 17.6% (p = 0.02) • No significant differences in OS between treatments |
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| Dacomitinib | NCT02047747 [66] | II | Dacomitinib (45 mg/day) | Patients with lung cancer, melanoma, HER2-amplified breast cancer, or HER2-amplified gastric cancer with brain metastases or LMD | Study terminated after 4 patients | |
CNS central nervous system, DCR disease control rate, ECOG PS Eastern Cooperative Oncology Group performance status, EGFR epidermal growth factor receptor, HER2 human epidermal growth factor receptor 2, LMD leptomeningeal disease, MRI magnetic resonance imaging, NSCLC non-small cell lung cancer, ORR overall response rate, OS overall survival, PD progressive disease, PFS progression-free survival, PR partial response, QD once daily, RT radiation therapy, SD stable disease, TKI tyrosine kinase inhibitor, TTF time to failure, WBRT whole-brain radiation therapy, WT wild-type