In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended .
There are insufficient data to recommend routine third-line cytotoxic therapy .
Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) .
Results This guideline up date reflects changes in evidence since the previous guideline .
Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.
BACKGROUND Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer ( NSCLC ) . Brigatinib ( AP26113 ) is an investigational ALK inhibitor with potent pre clinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors . We aim ed to assess brigatinib in patients with advanced malignancies , particularly ALK-rearranged NSCLC . METHODS In this ongoing , single-arm , open-label , phase 1/2 trial , we recruited patients from nine academic hospitals or cancer centres in the USA and Spain . Eligible patients were at least 18 years of age and had advanced malignancies , including ALK-rearranged NSCLC , and disease that was refractory to available therapies or for which no curative treatments existed . In the initial dose-escalation phase 1 stage of the trial , patients received oral brigatinib at total daily doses of 30 - 300 mg ( according to a st and ard 3 + 3 design ) . The phase 1 primary endpoint was establishment of the recommended phase 2 dose . In the phase 2 expansion stage , we assessed three oral once-daily regimens : 90 mg , 180 mg , and 180 mg with a 7 day lead-in at 90 mg ; one patient received 90 mg twice daily . We enrolled patients in phase 2 into five cohorts : ALK inhibitor-naive ALK-rearranged NSCLC ( cohort 1 ) , crizotinib-treated ALK-rearranged NSCLC ( cohort 2 ) , EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor ( cohort 3 ) , other cancers with abnormalities in brigatinib targets ( cohort 4 ) , and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active , measurable , intracranial CNS metastases ( cohort 5 ) . The phase 2 primary endpoint was the proportion of patients with an objective response . Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment . This trial is registered with Clinical Trials.gov , number NCT01449461 . FINDINGS Between Sept 20 , 2011 , and July 8 , 2014 , we enrolled 137 patients ( 79 [ 58 % ] with ALK-rearranged NSCLC ) , all of whom were treated .  Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase ( 240 mg daily ) and grade 4 dyspnoea ( 300 mg daily ) . We initially chose a dose of 180 mg once daily as the recommended phase 2 dose ; however , we also assessed two additional regimens ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) in the phase 2 stage . four ( 100 % [ 95 % CI 40 - 100 ] ) of four patients in cohort 1 had an objective response , 31 ( 74 % [ 58 - 86 ] ) of 42 did in cohort 2 , none ( of one ) did in cohort 3 , three ( 17 % [ 4 - 41 ] ) of 18 did in cohort 4 , and five ( 83 % [ 36 - 100 ] ) of six did in cohort 5 . 51 ( 72 % [ 60 - 82 ] ) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response ( 44 [ 62 % ( 50 - 73 ) ] had a confirmed objective response ) . All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response ( 100 % [ 63 - 100 ] ) . Three ( 50 % [ 95 % CI 12 - 88 ] ) of six patients in cohort 5 had an intracranial response . The most common grade 3 - 4 treatment-emergent adverse events across all doses were increased lipase concentration ( 12 [ 9 % ] of 137 ) , dyspnoea ( eight [ 6 % ] ) , and hypertension ( seven [ 5 % ] ) . Serious treatment-emergent adverse events ( excluding neoplasm progression ) reported in at least 5 % of all patients were dyspnoea ( ten [ 7 % ] ) , pneumonia ( nine [ 7 % ] ) , and hypoxia ( seven [ 5 % ] ) . 16 ( 12 % ) patients died during treatment or within 31 days of the last dose of brigatinib , including eight patients who died from neoplasm progression . INTERPRETATION Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC . These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC . A r and omised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospect ively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) . FUNDING ARIAD Pharmaceuticals
In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended .
There are insufficient data to recommend routine third-line cytotoxic therapy .
Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) .
Results This guideline up date reflects changes in evidence since the previous guideline .