Ongoing clinical trials of EGFR‐TKIs for patients with CNS metastases from NSCLC
| Drug/study no. . | Patient population . | Phase . | Treatment . | Primary endpoint . | Secondary efficacy endpoints . |
|---|---|---|---|---|---|
| Erlotinib | |||||
| NCT02556593 | 4‐10 BM from EGFR WT NSCLC | II | Erlotinib + IMR vs. WBRT | CNS PFS | |
| NCT00871923 | BM from NSCLC | II | Erlotinib + WBRT | Median survival | |
| NCT02655536 | Asymptomatic BM from EGFR+ NSCLC | II | Erlotinib vs. bevacizumab + erlotinib | PFS | OS; ORR; time to CNS progression; time to extra‐CNS progression; time to neurological symptom progression; PFS‐2 in patients with CNS progression |
| NCT01518621 | BM from NSCLC | II | WBRT + erlotinib vs. WBRT | OS | Local control rate; time to neurologic progression; QoL |
| NCT01454102 | BM from EGFR+ NSCLC | I | Nivolumab ± chemotherapy, bevacizumab, erlotinib, or ipilimumab | Safety and tolerability | ORR; PFS |
| NCT02714010 | BM from EGFR+ NSCLC | III | Erlotinib or gefitinib or icotinib ± WBRT | Intracranial PFS | OS; ORR; cognitive impairment; QoL |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Gefitinib | |||||
| NCT01951469 | BM from EGFR+ NSCLC | II | Gefitinib ± pemetrexed/cisplatin | Intracranial PFS | RR; PFS; OS |
| NCT02338011 | BM from EGFR+ NSCLC | II/III | Gefitinib ± WBRT | Time to progression; intracranial, extracranial, and overall PFS | OS; intracranial or extracranial disease progression; QoL/ECOG performance status; mental status |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Osimertinib | |||||
| NCT02736513 | Asymptomatic BM from NSCLC | II | Osimertinib | Intracranial ORR | Intracranial DCR; median time to intracranial response, median intracranial PFS (all by modified RECIST) |
| NCT02971501 | BM from EGFR+ NSCLC | II | Osimertinib ± bevacizumab | PFS | Brain metastases response rate; intracranial response rate; intracranial response according to RANO; ORR by RECIST; time to CNS progression; time to intracranial progression; OS |
| NCT02972333 | BM from T790M+ NSCLC | III | Osimertinib ± radiation therapy | PFS | Extracranial and intracranial PFS, ORR, DCR, and DoR; OS; QoL; cognitive function |
| NCT02856893 | T790M+ NSCLC | II | Osimertinib vs. gefitinib then osimertinib | PFS | ORR; OS; time to brain progression; time to symptomatic brain metastases in patients with brain metastases at study entry |
| NCT02228369 | BM or LM from EGFR+ NSCLC | I | Osimertinib/AZD3759 | Safety and tolerability | Plasma and CSF concentrations; PK; CSF RR for patients with LM or BM; change in neurological exam and CNS symptoms (LM); ORR, DCR, PFS |
| Icotinib | |||||
| NCT01926171 | BM from NSCLC | IV | Icotinib + WBRT | Intracranial ORR | Extracranial ORR; intracranial PFS |
| NCT02726568 | BM from EGFR+ NSCLC | II | High‐dose icotinib | Intracranial PFS | PFS; QoL; neurocognitive effects |
| Other EGFR‐TKIs | |||||
| NCT02616393 | BM or LM from EGFR+ NSCLC previously treated with EGFR‐TKI | II | Tesevatinib | Activity against BM using RECIST 1.1; activity against LM using symptom resolution | QoL; PFS; rate of CNS nonprogression; CNS and non‐CNS TTP; OS; activity against LM using cytology |
| NCT03046992 | T790M+ NSCLC (including asymptomatic BM) | I/II | YH25448 | Safety and tolerability; ORR | DoR; DCR; PFS; OS; tumor shrinkage; intracranial ORR, DoR, PFS |
| Drug/study no. . | Patient population . | Phase . | Treatment . | Primary endpoint . | Secondary efficacy endpoints . |
|---|---|---|---|---|---|
| Erlotinib | |||||
| NCT02556593 | 4‐10 BM from EGFR WT NSCLC | II | Erlotinib + IMR vs. WBRT | CNS PFS | |
| NCT00871923 | BM from NSCLC | II | Erlotinib + WBRT | Median survival | |
| NCT02655536 | Asymptomatic BM from EGFR+ NSCLC | II | Erlotinib vs. bevacizumab + erlotinib | PFS | OS; ORR; time to CNS progression; time to extra‐CNS progression; time to neurological symptom progression; PFS‐2 in patients with CNS progression |
| NCT01518621 | BM from NSCLC | II | WBRT + erlotinib vs. WBRT | OS | Local control rate; time to neurologic progression; QoL |
| NCT01454102 | BM from EGFR+ NSCLC | I | Nivolumab ± chemotherapy, bevacizumab, erlotinib, or ipilimumab | Safety and tolerability | ORR; PFS |
| NCT02714010 | BM from EGFR+ NSCLC | III | Erlotinib or gefitinib or icotinib ± WBRT | Intracranial PFS | OS; ORR; cognitive impairment; QoL |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Gefitinib | |||||
| NCT01951469 | BM from EGFR+ NSCLC | II | Gefitinib ± pemetrexed/cisplatin | Intracranial PFS | RR; PFS; OS |
| NCT02338011 | BM from EGFR+ NSCLC | II/III | Gefitinib ± WBRT | Time to progression; intracranial, extracranial, and overall PFS | OS; intracranial or extracranial disease progression; QoL/ECOG performance status; mental status |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Osimertinib | |||||
| NCT02736513 | Asymptomatic BM from NSCLC | II | Osimertinib | Intracranial ORR | Intracranial DCR; median time to intracranial response, median intracranial PFS (all by modified RECIST) |
| NCT02971501 | BM from EGFR+ NSCLC | II | Osimertinib ± bevacizumab | PFS | Brain metastases response rate; intracranial response rate; intracranial response according to RANO; ORR by RECIST; time to CNS progression; time to intracranial progression; OS |
| NCT02972333 | BM from T790M+ NSCLC | III | Osimertinib ± radiation therapy | PFS | Extracranial and intracranial PFS, ORR, DCR, and DoR; OS; QoL; cognitive function |
| NCT02856893 | T790M+ NSCLC | II | Osimertinib vs. gefitinib then osimertinib | PFS | ORR; OS; time to brain progression; time to symptomatic brain metastases in patients with brain metastases at study entry |
| NCT02228369 | BM or LM from EGFR+ NSCLC | I | Osimertinib/AZD3759 | Safety and tolerability | Plasma and CSF concentrations; PK; CSF RR for patients with LM or BM; change in neurological exam and CNS symptoms (LM); ORR, DCR, PFS |
| Icotinib | |||||
| NCT01926171 | BM from NSCLC | IV | Icotinib + WBRT | Intracranial ORR | Extracranial ORR; intracranial PFS |
| NCT02726568 | BM from EGFR+ NSCLC | II | High‐dose icotinib | Intracranial PFS | PFS; QoL; neurocognitive effects |
| Other EGFR‐TKIs | |||||
| NCT02616393 | BM or LM from EGFR+ NSCLC previously treated with EGFR‐TKI | II | Tesevatinib | Activity against BM using RECIST 1.1; activity against LM using symptom resolution | QoL; PFS; rate of CNS nonprogression; CNS and non‐CNS TTP; OS; activity against LM using cytology |
| NCT03046992 | T790M+ NSCLC (including asymptomatic BM) | I/II | YH25448 | Safety and tolerability; ORR | DoR; DCR; PFS; OS; tumor shrinkage; intracranial ORR, DoR, PFS |
Abbreviations: BM, brain metastases; CNS, central nervous system; DCR, disease control rate; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EGFR+, EGFR mutation positive; IMR, intensity‐modulated radiotherapy; LM, leptomeningeal metastases; no., number; NSCLC, non‐small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival; PK, pharmacokinetic; QoL, quality of life; RANO, Response Assessment in Neuro‐Oncology; RR, response rate; SRS, stereotactic radiosurgery; T790M+, T790M mutation positive; TKI, tyrosine kinase inhibitor; TTP, time to progression; WBRT, whole‐brain radiotherapy; WT, wild type.
Ongoing clinical trials of EGFR‐TKIs for patients with CNS metastases from NSCLC
| Drug/study no. . | Patient population . | Phase . | Treatment . | Primary endpoint . | Secondary efficacy endpoints . |
|---|---|---|---|---|---|
| Erlotinib | |||||
| NCT02556593 | 4‐10 BM from EGFR WT NSCLC | II | Erlotinib + IMR vs. WBRT | CNS PFS | |
| NCT00871923 | BM from NSCLC | II | Erlotinib + WBRT | Median survival | |
| NCT02655536 | Asymptomatic BM from EGFR+ NSCLC | II | Erlotinib vs. bevacizumab + erlotinib | PFS | OS; ORR; time to CNS progression; time to extra‐CNS progression; time to neurological symptom progression; PFS‐2 in patients with CNS progression |
| NCT01518621 | BM from NSCLC | II | WBRT + erlotinib vs. WBRT | OS | Local control rate; time to neurologic progression; QoL |
| NCT01454102 | BM from EGFR+ NSCLC | I | Nivolumab ± chemotherapy, bevacizumab, erlotinib, or ipilimumab | Safety and tolerability | ORR; PFS |
| NCT02714010 | BM from EGFR+ NSCLC | III | Erlotinib or gefitinib or icotinib ± WBRT | Intracranial PFS | OS; ORR; cognitive impairment; QoL |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Gefitinib | |||||
| NCT01951469 | BM from EGFR+ NSCLC | II | Gefitinib ± pemetrexed/cisplatin | Intracranial PFS | RR; PFS; OS |
| NCT02338011 | BM from EGFR+ NSCLC | II/III | Gefitinib ± WBRT | Time to progression; intracranial, extracranial, and overall PFS | OS; intracranial or extracranial disease progression; QoL/ECOG performance status; mental status |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Osimertinib | |||||
| NCT02736513 | Asymptomatic BM from NSCLC | II | Osimertinib | Intracranial ORR | Intracranial DCR; median time to intracranial response, median intracranial PFS (all by modified RECIST) |
| NCT02971501 | BM from EGFR+ NSCLC | II | Osimertinib ± bevacizumab | PFS | Brain metastases response rate; intracranial response rate; intracranial response according to RANO; ORR by RECIST; time to CNS progression; time to intracranial progression; OS |
| NCT02972333 | BM from T790M+ NSCLC | III | Osimertinib ± radiation therapy | PFS | Extracranial and intracranial PFS, ORR, DCR, and DoR; OS; QoL; cognitive function |
| NCT02856893 | T790M+ NSCLC | II | Osimertinib vs. gefitinib then osimertinib | PFS | ORR; OS; time to brain progression; time to symptomatic brain metastases in patients with brain metastases at study entry |
| NCT02228369 | BM or LM from EGFR+ NSCLC | I | Osimertinib/AZD3759 | Safety and tolerability | Plasma and CSF concentrations; PK; CSF RR for patients with LM or BM; change in neurological exam and CNS symptoms (LM); ORR, DCR, PFS |
| Icotinib | |||||
| NCT01926171 | BM from NSCLC | IV | Icotinib + WBRT | Intracranial ORR | Extracranial ORR; intracranial PFS |
| NCT02726568 | BM from EGFR+ NSCLC | II | High‐dose icotinib | Intracranial PFS | PFS; QoL; neurocognitive effects |
| Other EGFR‐TKIs | |||||
| NCT02616393 | BM or LM from EGFR+ NSCLC previously treated with EGFR‐TKI | II | Tesevatinib | Activity against BM using RECIST 1.1; activity against LM using symptom resolution | QoL; PFS; rate of CNS nonprogression; CNS and non‐CNS TTP; OS; activity against LM using cytology |
| NCT03046992 | T790M+ NSCLC (including asymptomatic BM) | I/II | YH25448 | Safety and tolerability; ORR | DoR; DCR; PFS; OS; tumor shrinkage; intracranial ORR, DoR, PFS |
| Drug/study no. . | Patient population . | Phase . | Treatment . | Primary endpoint . | Secondary efficacy endpoints . |
|---|---|---|---|---|---|
| Erlotinib | |||||
| NCT02556593 | 4‐10 BM from EGFR WT NSCLC | II | Erlotinib + IMR vs. WBRT | CNS PFS | |
| NCT00871923 | BM from NSCLC | II | Erlotinib + WBRT | Median survival | |
| NCT02655536 | Asymptomatic BM from EGFR+ NSCLC | II | Erlotinib vs. bevacizumab + erlotinib | PFS | OS; ORR; time to CNS progression; time to extra‐CNS progression; time to neurological symptom progression; PFS‐2 in patients with CNS progression |
| NCT01518621 | BM from NSCLC | II | WBRT + erlotinib vs. WBRT | OS | Local control rate; time to neurologic progression; QoL |
| NCT01454102 | BM from EGFR+ NSCLC | I | Nivolumab ± chemotherapy, bevacizumab, erlotinib, or ipilimumab | Safety and tolerability | ORR; PFS |
| NCT02714010 | BM from EGFR+ NSCLC | III | Erlotinib or gefitinib or icotinib ± WBRT | Intracranial PFS | OS; ORR; cognitive impairment; QoL |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Gefitinib | |||||
| NCT01951469 | BM from EGFR+ NSCLC | II | Gefitinib ± pemetrexed/cisplatin | Intracranial PFS | RR; PFS; OS |
| NCT02338011 | BM from EGFR+ NSCLC | II/III | Gefitinib ± WBRT | Time to progression; intracranial, extracranial, and overall PFS | OS; intracranial or extracranial disease progression; QoL/ECOG performance status; mental status |
| NCT02882984 | BM from EGFR+ NSCLC | III | Hypofractionated SRS + EGFR‐TKI vs. WBRT + EGFR‐TKI (erlotinib, gefitinib, icotinib) | Intracranial PFS | OS; cognitive function; QoL |
| Osimertinib | |||||
| NCT02736513 | Asymptomatic BM from NSCLC | II | Osimertinib | Intracranial ORR | Intracranial DCR; median time to intracranial response, median intracranial PFS (all by modified RECIST) |
| NCT02971501 | BM from EGFR+ NSCLC | II | Osimertinib ± bevacizumab | PFS | Brain metastases response rate; intracranial response rate; intracranial response according to RANO; ORR by RECIST; time to CNS progression; time to intracranial progression; OS |
| NCT02972333 | BM from T790M+ NSCLC | III | Osimertinib ± radiation therapy | PFS | Extracranial and intracranial PFS, ORR, DCR, and DoR; OS; QoL; cognitive function |
| NCT02856893 | T790M+ NSCLC | II | Osimertinib vs. gefitinib then osimertinib | PFS | ORR; OS; time to brain progression; time to symptomatic brain metastases in patients with brain metastases at study entry |
| NCT02228369 | BM or LM from EGFR+ NSCLC | I | Osimertinib/AZD3759 | Safety and tolerability | Plasma and CSF concentrations; PK; CSF RR for patients with LM or BM; change in neurological exam and CNS symptoms (LM); ORR, DCR, PFS |
| Icotinib | |||||
| NCT01926171 | BM from NSCLC | IV | Icotinib + WBRT | Intracranial ORR | Extracranial ORR; intracranial PFS |
| NCT02726568 | BM from EGFR+ NSCLC | II | High‐dose icotinib | Intracranial PFS | PFS; QoL; neurocognitive effects |
| Other EGFR‐TKIs | |||||
| NCT02616393 | BM or LM from EGFR+ NSCLC previously treated with EGFR‐TKI | II | Tesevatinib | Activity against BM using RECIST 1.1; activity against LM using symptom resolution | QoL; PFS; rate of CNS nonprogression; CNS and non‐CNS TTP; OS; activity against LM using cytology |
| NCT03046992 | T790M+ NSCLC (including asymptomatic BM) | I/II | YH25448 | Safety and tolerability; ORR | DoR; DCR; PFS; OS; tumor shrinkage; intracranial ORR, DoR, PFS |
Abbreviations: BM, brain metastases; CNS, central nervous system; DCR, disease control rate; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EGFR+, EGFR mutation positive; IMR, intensity‐modulated radiotherapy; LM, leptomeningeal metastases; no., number; NSCLC, non‐small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival; PK, pharmacokinetic; QoL, quality of life; RANO, Response Assessment in Neuro‐Oncology; RR, response rate; SRS, stereotactic radiosurgery; T790M+, T790M mutation positive; TKI, tyrosine kinase inhibitor; TTP, time to progression; WBRT, whole‐brain radiotherapy; WT, wild type.
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