Table 1. Characteristics of studies included in meta-analysis.
| Author | Published year | Study type | Characteristic of subjects | Previous treatments with ALK inhibitor | Treatment regimen | Overall patients enrolled | Patients with BMs (measureable disease/measureable or non-measureable disease) | iORR (%) |
|---|---|---|---|---|---|---|---|---|
| Costa et al. | 2015 | Retrospective | Histologically or cytologically proven diagnosis of NSCLC; positive for the ALK fusion gene; must have had disease progression after only one prior platinum-based chemotherapy; tumors must be measurable | None | Oral crizotinib, 250 mg twice per day | 888 | 22/109 (no prior brain radiotherapy) | 18 |
| 18/166 (received prior brain radiotherapy) | 33 | |||||||
| Crinò et al. | 2016 | Phase 2 | Locally advanced/metastatic ALK-rearranged NSCLC; have received prior treatment with at least one platinum-based chemotherapy regimen; prior treatment with any ALK inhibitor other than crizotinib was not permitted | 1 | Oral ceritinib, 750 mg once daily | 140 | 20/NR | 45 |
| Drilon et al. | 2017 | Phase 1 | Histologically- or cytologically-confirmed, relapsed or refractory advanced/metastatic solid tumor without alternative effective standard therapy; positive NTRK1/2/3, ROS1, or ALK molecular alterations; ECOG PS 0–2; patients with stable asymptomatic CNS involvement were eligible | None to 2 or more | Oral entrectinib, 100–1,600 mg/m2, once daily; 600 mg once daily | 25 | 8/NR | 63 |
| Gadgeel et al. | 2014 | Phase 1/2 | ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib; no previous treatment with ALK inhibitors other than crizotinib; measurable disease per RECIST v1.1; ECOG PS 0–2; patients with asymptomatic CNS metastases, including leptomeningeal carcinomatosis were eligible | none | Oral alectinib, 300–900 mg twice a day | 47 | 9/21 | 55.6 |
| Gettinger et al. | 2016 | Phase 1/2 | Histologically or cytologically confirmed NSCLC; ALK rearrangements (required for phase 2 study); measurable disease per RECIST v1.1; ECOG PS 0–2; previous ALK inhibitors was not allowed with the exception of crizotinib | None to 1 | Oral brigatinib, 30–300 mg once daily | 137 | 15/46 | 53 |
| Horn et al. | 2018 | Phase 2 | Eligible patients in dose escalation had advanced solid tumors. Dose expansion was limited to patients with ALK-rearranged, advanced NSCLC; prior therapy with crizotinib and/or second-generation ALK TKIs was allowed | None to 2 or more | Oral ensartinib, 25–250 mg once daily | 97 | 14/NR | 64.3 |
| Kim et al. | 2016 | Phase 1 | ALK-rearranged, locally advanced or metastatic NSCLC that had progressed despite standard therapy (including chemotherapy or ALK inhibitor); ECOG PS 0–2; at least one measurable disease per RECIST v1.0; patients with untreated or locally treated asymptomatic and stable (>4 weeks) CNS disease were eligible | None to 1 | Oral ceritinib, 750 mg once daily | 246 | 36/94 | 42 |
| Kim et al. | 2017 | Phase 2 | Locally advanced or metastatic ALK-positive NSCLC; disease progression while receiving crizotinib; at least one measurable lesion per RECIST v1.1; ECOG PS ≤2. Patients must not have received any prior ALK inhibitor other than crizotinib; other exclusions included a history or presence of pulmonary interstitial disease or drug-related pneumonitis, or symptomatic CNS metastases | 1 | Oral brigatinib, 90 mg once daily | 112 | 26/54 | 42.3 |
| Kiura et al. | 2018 | Phase 3 | ALK-rearranged, locally advanced or metastatic NSCLC (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression; patients with asymptomatic or stable CNS disease were eligible | 1 | Experimental arm: oral ceritinib, 750 mg once daily; control arm: pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 | 11 | NR/5 | 20 |
| Metro et al. | 2016 | Observational | Histologically-proven ALK-positive NSCLC; newly diagnosed or progressive CNS metastases; prior treatment with an ALK-TKI other than alectinib was allowed | None to 2 | Oral alectinib, 600 mg twice daily | 11 | 7/11 | 85.7 |
| Novello et al. | 2018 | Phase 3 | Histologically/cytologically confirmed advanced, recurrent, or metastatic ALK-positive NSCLC; two prior lines of systemic therapy (including one line of PDC and one of crizotinib); PS 0–2. Patients with CNS metastases were allowed if asymptomatic, or symptomatic and ineligible for radiotherapy | 1 | Experimental arm: oral alectinib, 600 mg twice daily; control arm: pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, every 3 weeks | 107 | 24/50 | 54.2 |
| Ou et al. | 2016 | Phase 2 | Locally advanced or metastatic NSCLC harboring an ALK rearrangement and had progressed on crizotinib. Patients could be chemotherapy naive or could have received prior platinum-based chemotherapy | 1 | Oral alectinib, 600 mg twice daily | 138 | 35/84 | 57.1 |
| Shaw et al. | 2016 | Phase 2 | Locally advanced or metastatic ALK-positive NSCLC; have progressed on crizotinib, and may have had prior chemotherapy; patients with untreated or treated, asymptomatic and neurologically stable brain or leptomeningeal metastases were eligible; exclusion criteria included prior treatment with an ALK inhibitor other than crizotinib | 1 | Oral alectinib, 600 mg twice daily | 87 | 16/52 | 75 |
| Shaw et al. | 2017 | Phase 1 | Locally advanced or metastatic NSCLC with ALK or ROS1 rearrangements; age 18 years or older; ECOG PS 0 or 1; patients who had received previous ALK or ROS1 TKIs or had asymptomatic untreated or treated CNS metastases were eligible | None to 2 or more | Oral lorlatinib, 10–400 mg once daily | 54 | 24/32 | 45.8 |
| Shaw et al. | 2017 | Phase 3 | ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression | 1 | Experimental arm: oral ceritinib, 750 mg once daily; control arm: pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 | 115 | 17/66 | 35 |
| Solomon et al. | 2016 | Phase 3 | Advanced nonsquamous, ALK-rearrangement–positive NSCLC; no prior systemic treatment of advanced disease. BM was treated and neurologically stable for over 2 weeks before enrollment, with no ongoing corticosteroid requirement | None | Experimental arm: oral crizotinib, 250 mg twice per day; control arm: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin at area under the curve 5 to 6 | 172 | NR/39 | NA |
| Soria et al. | 2017 | Phase 3 | Histologically or cytologically confirmed locally advanced or metastatic non-squamous ALK-rearranged NSCLC, untreated with any systemic anticancer therapy; PS 0–2, and asymptomatic or neurologically stable brain metastases | None | Experimental arm: oral ceritinib, 750 mg once daily; control arm: cisplatin (75 mg/m2), or carboplatin (target area under the curve of 5–6) plus pemetrexed (500 mg/m2) | 189 | 22/54 | 72.7 |
| Tamura et al. | 2017 | Phase 2 | Aged 20 years or older; had histologically or cytologically confirmed advanced or metastatic ALK-rearranged stage IIIB, IV, or recurrent NSCLC; ECOG PS of 0 or 1; received two or more (phase 1 portion) or one or more (phase 2 portion) previous chemotherapy regimens; previous treatment with any ALK inhibitor was not allowed | None | Oral alectinib, 300 mg twice daily | 46 | 14/NR | NA |
| Xing et al. | 2016 | Retrospective | Pathological diagnosis of NSCLC with brain metastases developed either before or during the treatment of crizotinib | None | Oral crizotinib, 250 mg twice per day | 34 | NR/20 | 15 |
| Yoshida et al. | 2016 | Retrospective | ALK-positive NSCLC patients who had been treated with crizotinib as the initial ALK inhibitor | None | Oral crizotinib, 250 mg twice per day | 59 | 10/26 | 20 |
NSCLC, non-small cell lung cancer; ALK, anaplastic lymphoma kinase; ECOG, Eastern Cooperative Oncology Group; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; NR, not report.