Table 1.
Summary of studies reporting the efficacy of first-generation EGFR TKIs in patients with NSCLC and CNS metastases
| EGFR TKI | Publication | Study description | Treatments | Patient characteristics | Results | |
|---|---|---|---|---|---|---|
| Name/type | Phase | |||||
| Gefitinib | Iuchi et al. [39] | II | Gefitinib (250 mg QD) | N = 41; EGFR mutation-positive, TKI-naïve patients with brain metastases; surgical resection of the brain did not preclude participation | • ORR: 87.8% • Median PFS: 14.5 months; Del19 was associated with improved PFS vs. L858R (17.5 vs. 10.2 months, respectively; P = 0.003) • Median OS: 21.9 months; Del19 was associated with improved survival vs. L858R (30.3 vs. 19.8, respectively; P = 0.025) |
|
| Ceresoli et al. [50] | Prospective trial | Gefitinib (250 mg QD) with or without prior WBRT | N = 41 (18 with prior WBRT, 37 with prior chemotherapy); patients with NSCLC and brain metastases | • ORR: PR, 10%; SD, 17% • DCR: 27%; higher DCR in patients with prior WBRT • Median PFS: 3 months |
||
| Erlotinib | Deng et al. [32] | Erlotinib (150 mg QD), following first- or second-line chemotherapy | N = 6 (n = 4 with EGFR mutations); patients with NSCLC and brain metastases | • ORR: WT EGFR, 33.3%; mutant EGFR, 50% • Brain metastases response: PR, 33.3%; SD, 33.3% • Median PFS: overall, 2.8 months; mutant EGFR, 5.6 months |
||
| Porta et al. [103] | Retrospective analysis of patients from the Spanish Lung Adenocarcinoma Data Base (SLADB) study | First- and second-line erlotinib (150 mg QD) | N = 69 (n = 17 with EGFR mutations); patients with NSCLC and brain metastases | • OR: 14 patients, all of whom had EGFR mutations (14/17; 82.4%) • In patients with EGFR mutations: PR, 35.3%; CR, 47.1%; SD, 17.6% • In patients with EGFR mutations, median PFS: 11.7 months |
||
| Ohara et al. [104] | Case report | Fourth-line erlotinib (150 mg QD), following progression after gefitinib, chemotherapy, and RT | Female, Japanese patient with T790M-positive NSCLC and brain metastasis | • Neurological symptoms (disorientation) resolved • Brain metastases disappeared, but extracranial (lung) primary lesion progressed, resulting in treatment discontinuation |
||
| Ruppert et al. [105] | Case report | Third-line erlotinib (150 mg QD), following gefitinib and chemotherapy | Male with del19 mutant NSCLC with brain metastasis; secondary T790M mutation was identified after stopping EGFR TKI, consistent with development of resistance | • Prolonged disease control (4 months), until liver metastases were detected | ||
| Katayama et al. [106] | Retrospective analysis | Erlotinib (150 mg QD), following prior gefitinib therapy | N = 7; 6 patients with EGFR mutation-positive NSCLC (1 patient EGFR mutational status not available) with brain metastases or LMD; 6 patients had prior WBRT or radiosurgery | • ORR: PR, 3 patients; SD, 3 patients • ECOG PS score improved in 3 patients • Neurological symptoms improved in 5 patients |
||
| Gefitinib or erlotinib | Park et al. [36] | Prospective study of first-line EGFR TKI | II | First-line gefitinib (250 mg QD) or erlotinib (150 mg QD) | 28; patients with common EGFR mutations and metastatic brain tumors | • ORR: PR, 83%; SD, 11% • Median PFS: 6.6 months • Median OS: 15.9 months; no differences in survival between gefitinib and erlotinib |
| Kim et al. [37] | II | First-line gefitinib (250 mg QD) or erlotinib (150 mg QD) | N = 23; Korean, never-smoking patients with brain metastases | • ORR: PR, 70%; SD, 13% • Median PFS: 7.1 months • Median OS: 18.8 months |
||
| Zhang et al. [38] | Retrospective analysis | First-line gefitinib (250 mg QD) or erlotinib (150 mg QD) | N = 81; patients with EGFR mutant NSCLC and brain metastases | • Median PFS: gefitinib, 9.5 months; erlotinib, 9.0 months • Median PFS (overall treatments): Del19, 10.4 months; L858R, 8.6 months (P = 0.408) |
||
| Gefitinib or erlotinib + RT | Zhu et al. [58] | Retrospective analysis | Gefitinib (250 mg QD) or erlotinib (150 mg QD) WBRT (30–40 Gy in 10–20 fractions, 5 days/week) or SRS (15–24 Gy) |
N = 133 (EGFR TKI alone, n = 66; EGFR TKI + WBRT, n = 63; EGFR TKI + SRS, n = 4); patients with EGFR mutations and brain metastases | • Median intracranial PFS: TKI + RT, 16.0 months; TKI, 11.5 months (P = 0.017) • Median OS: TKI + RT, 22 months; TKI, 15 months (P = 0.015) • Exon 21 mutations: Median PFS and OS were longer with TKI + RT than TKI alone (PFS: 14 vs. 9.5 months, P = 0.001; OS: 22 vs. 13.5 months, P = 0.004) |
|
| Ma et al. [53] | II | Gefitinib (250 mg QD with WBRT (40 Gy/20f/4w) | N = 21; patients with NSCLC and brain metastases | • ORR: 81% • PR, 62%; CR, 19%; SD, 14% • Median PFS: 10.0 months • Median OS: 13.0 months |
||
| Welsh et al. [54] | II | Erlotinib (150 mg QD) + WBRT | N = 40; patients with NSCLC and brain metastases | • ORR: 86% • Median PFS: overall, 8.0 months; EGFR mutant, 12.3 months; EGFR WT, 5.2 months • Median OS: overall, 11.8 months; EGFR mutant, 19.1 months; EGFR WT, 9.3 months |
||
| Zeng et al. [57] | Retrospective analysis | Gefitinib (250 mg QD) with or without WBRT (40 Gy/20f/4w) | N = 90; patients with NSCLC and brain metastases | • ORR: 64.4% vs. 26.7% (P < 0.001) for gefitinib + WBRT vs. gefitinib • DCR for brain metastases: 71.1% vs. 42.2% (P = 0.006) for gefitinib + WBRT vs. gefitinib • Longer time to progression of brain metastases with gefitinib + WBRT vs. gefitinib (10.6 vs. 6.6 months) • Longer median OS with gefitinib + WBRT vs. gefitinib (23.4 vs. 14.8 months) |
||
| Olmez et al. [56] | Retrospective analysis | Erlotinib (150 mg QD) + WBRT | N = 7; patients with NSCLC and brain metastases | • All patients had intracranial disease control • In extracranial sites: PR, 3 patients; SD, 2 patients |
||
| Lee et al. [51] | II | Erlotinib (100 mg QD) + WBRT (20 Gy/5f), then erlotinib (150 mg QD) | N = 80 (erlotinib, n = 40; placebo, n = 40); patients with NSCLC and brain metastases | • Median neurological PFS: 1.6 months for erlotinib or placebo • Median OS: erlotinib, 3.4 months; placebo, 2.9 months |
||
| Lind et al. [52] | Dose-escalation study | I | Erlotinib (100 mg QD or 150 mg QD) + WBRT (30 Gy/10f) | N = 11; patients with NSCLC and brain metastases | • Only 1 patient had intracranial progression; 6 patients had extracranial progression • Median PFS: 4.6 months • Median OS: 4.4 months • In 7 patients with follow-up neuroimaging: PR, 5 patients; SD, 2 patients |
|
| Zhuang et al. [55] | Prospective cohort study | II | WBRT (30 Gy/10f) with or without second-line erlotinib (150 mg QD) following failure of chemotherapy | N = 54 (WBRT, n = 31; WBRT + erlotinib, n = 23); patients with NSCLC and brain metastases; patients treated with erlotinib had EGFR mutations | • ORR: WBRT, 54.8% (PR, 41.9%; CR, 12.9%; SD, 38.7%; WBRT + erlotinib, 95.7% (PR, 60.9%; CR, 34.8%; SD, 4.4%) • Median intracranial PFS: WBRT, 6.8 months; WBRT + erlotinib, 10.6 months • Median overall PFS: WBRT, 5.2 months; WBRT + erlotinib, 6.8 months • Median OS: WBRT, 8.9 months; WBRT + erlotinib, 10.7 months |
|
| AZD3759 | Ahn et al. [107] | BLOOM | I | Third-line and beyond, AZD3759 (50–500 mg BID) | N = 29 (BM, 21; LM, 5; non-measurable/non-BM or LM, 3); patients with EGFR mutations | Overall: • Among 20 patients with BM: tumor shrinkage, 8; confirmed PR, 3; unconfirmed PR, 3 • Among 5 LM patients, 1 patient had CSF clearance of tumor cells and improvement of brain MRI imaging and CNS symptoms |
| Ahn et al. [64] | BLOOM | I, expansion cohort | AZD3759 (200–300 mg BID) in TKI-naïve patients | N = 20 (BM, 16; LM, 4), TKI-naïve patients with EGFR mutations and CNS metastases | • Confirmed disease control: 90% • Confirmed OR: 65% • Best response: PR, 65%; SD, 25% |
|
| Cho et al. [63] | BLOOM | I, expansion cohort | AZD3759 (200–300 mg BID) in TKI-naïve patients | N = 18, patients with EGFR mutations and LMD | • Best response: PR, 4; SD, 9; CR, 1 • 6/18 patients with extracranial tumors had tumor shrinkage but no confirmed response |
|
CNS central nervous system, DCR disease control rate, ECOG PS Eastern Cooperative Oncology Group performance status, EGFR epidermal growth factor receptor, NSCLC non-small cell lung cancer, ORR overall response rate, OR overall response, OS overall survival, PFS progression-free survival, PR partial response, QD once daily, RT radiation therapy, SD stable disease, SRS stereotactic radiosurgery, TKI tyrosine kinase inhibitor, WBRT whole-brain radiation therapy, WT wild-type