20-40% of patients with NSCLC will develop brain metastases at some point during their course of disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this study is to compare the effects of Osimertinib alone versus SRS plus Osimertinib on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.
Name: Osimertinib
Name: Stereotactic Radiosurgery (SRS)
Description: To assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib by assessment of intracranial progression free survival at 12 months.
Measure: Intracranial progression free survival at 12 months Time: 12 months post randomisationDescription: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on use of salvage whole-brain radiotherapy (WBRT) +/- neurosurgery.
Measure: Use of salvage whole-brain radiotherapy (WBRT) Time: 18 months post randomisationDescription: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.
Measure: Local brain failure Time: 18 months post randomisationDescription: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.
Measure: Distant brain failure Time: 18 months post randomisationDescription: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.
Measure: Extra-cranial progression Time: 18 months post randomisationDescription: To further assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib in terms of overall survival.
Measure: Overall Survival Time: 18 months post randomisationAllocation: Randomized
Parallel Assignment
There are 4 SNPs
2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R ---
2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R --- --- L861G ---
2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R --- --- L861G --- --- S768I ---
6. Documented EGFR mutation; 1. Patients who developed brain metastases as a site of disease progression while on first line EGFR TKIs must have T790M mutation. --- T790M ---
2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R --- --- L861G --- --- S768I --- --- T790M ---
7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M ---
7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M ---
7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M ---
7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M --- --- T790M ---
7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---