Ensartinib is a novel second-generation ALK tyrosine kinase inhibitor ( TKI ). In phase 1/2 studies, Ensartinib showed promising activity in patients with ALK+ non-small cell lung cancer ( NSCLC ) who were ALK TKI-naive or received prior Crizotinib and/or second-generation ALK TKIs, including efficacy against brain metastases.
Ensartinib was well tolerated, with grade 1/2 rash, pruritus, edema, and transaminitis as the most frequent related adverse effects.
Phase 3, open-label, eXalt3 study is evaluating the efficacy and safety of Ensartinib compared with Crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who had received no prior ALK TKI and up to one prior chemotherapy regimen.
The results of the interim analysis were presented.
Patients with locally tested ALK+ NSCLC ( ITT population ) were randomized 1:1 to Ensartinib ( 225 mg QD orally ) or Crizotinib ( 250 mg BID orally ).
No crossover was allowed.
Patients were stratified by prior chemotherapy, ECOG PS, brain metastases, and geographic region.
The modified ITT ( mITT ) population was prespecified to include all centrally ALK+ patients by Abbott FISH test.
The primary endpoint was blinded independent review committee ( BIRC )–assessed progression-free survival ( PFS; RECIST v.1.1 ). Secondary endpoints included overall survival ( OS ), overall response rate ( ORR ), and time to treatment failure ( TTF ) in the brain.
One interim analysis was planned after 75% of PFS events ( 143/190 ) in the ITT population.
In total, 290 patients were randomized ( Ensartinib [ n=143 ]; Crizotinib [ n=147 ] ). Baseline characteristics were well balanced between the 2 groups: median age was 54.1 years, 26% of patients had prior chemotherapy, and 36% of patients had baseline CNS metastases ( 5% had prior brain radiotherapy ).
The mITT population included 247 patients ( Ensartinib [ n=121 ]; Crizotinib [ n=126 ] ).
At the July 1, 2020, data cutoff, treatment was ongoing in 64 Ensartinib patients ( 45% ) and 25 Crizotinib patients ( 17% ); 139 BIRC-assessed PFS events ( 73% ) occurred in the ITT population and 119 BIRC-assessed PFS events ( 63% ) in the mITT population.
Median PFS was 25.8 months with Ensartinib versus 12.7 months with Crizotinib ( HR, 0.52; 95% CI, 0.36-0.75; P=.0003 by log-rank test ) with a median follow-up of 23.8 and 20.2 months in the ITT population.
Median progression-free survival was not reached with Ensartinib versus 12.7 months with Crizotinib in the mITT population ( HR, 0.48; 95% CI, 0.32-0.71; P=0.0002 by log-rank test ).
In the mITT population, ORR by BIRC was 75% ( 91/121 ) with Ensartinib vs 67% ( 85/126 ) with Crizotinib; among patients with measurable brain metastases, the BIRC-assessed intracranial ORR was 54% ( 7/13 ) with Ensartinib vs 19% ( 4/21 ) with Crizotinib; TTF rate in the brain in patients with no baseline brain metastases was lower with Ensartinib versus Crizotinib ( 4% vs 24% at 12 months; cause-specific HR, 0.33; P=0.0016 ).
Median overall survival was not reached in both arms ( HR=0.91 ) in the mITT population; 24-month OS rate was 78% in both arms.
No new safety signals were noted.
In conclusion, in patients with ALK+ NSCLC, Ensartinib has significantly prolonged progression-free survival over Crizotinib with a favorable safety profile, representing a new option in the first-line setting. ( Xagena )
Source: IASLC Virtual Presidential Symposium, 2020