P08.02 Lorlatinib in First Line Treatment of Patients With ALK-Positive NSCLC: A Network Meta-Analysis


      Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), showed a 72% reduction in risk of progression/death (HR 0.28: 95% CI, 0.19 to 0.41; p<0.0001) versus crizotinib in the Phase 3 CROWN study (NCT03052608). The study included previously untreated patients with anaplastic lymphoma kinase-positive (ALK+), advanced non-small-cell lung cancer. To understand the relative effects of lorlatinib compared to other treatments of interest not investigated in CROWN, we conducted a network meta-analysis (NMAs).


      We used comparator evidence, identified from a systematic literature review, to form a connected network of studies including the ALK TKIs lorlatinib (CROWN), alectinib (ALEX, ALESIA, J-ALEX), brigatinib (ALTA-1L), ceritinib (ASCEND-4, ASCEND-8), crizotinib (CROWN, ALEX, ALESIA, J-ALEX, ALTA-1L, PROFILE 1014, PROFILE 1029, eXalt3), ensartinib (eXalt3) and chemotherapy (ASCEND-4, PROFILE 1014, PROFILE 1029). The primary outcome for the analysis was progression-free survival (PFS) by independent radiologic review (IRR). Secondary outcomes (to be presented) included intracranial time to progression, objective response rate, adverse events, and overall survival. We used Bayesian, fixed and random-effects proportional hazards NMAs to derive estimates of the relative treatment effect (hazard ratios [HR]) of lorlatinib compared to the other treatments.


      Fixed-effects models are presented due to the small evidence base and as these provided the best fitting models, based on DIC value. The results for PFS by IRR including all studies ranged from HR (95% credible interval) = 0.12 (0.08 to 0.19) for lorlatinib compared to chemotherapy; to 0.82 (0.36 to 1.85) for lorlatinib compared to alectinib (300 mg) [Table]. A sensitivity analysis was performed which removed studies that were solely based in Asian countries (J-ALEX, ALESIA, PROFILE1029) as this was believed to be a source of heterogeneity. The results for the analysis including only global studies ranged from 0.13 (0.08 to 0.20) for lorlatinib compared to chemotherapy; to 0.57 (0.34 to 0.95) for lorlatinib compared to brigatinib. Further sensitivity analyses using the investigator definition of PFS did not alter the conclusions of the NMA.
      Tabled 1
      Treatment comparison Lorlatinib vs:StudiesPFS HR (95% CrI)
      Alectinib (600 mg)ALEX, ALESIA*0.61 (0.38 to 0.99)
      Alectinib (300 mg)J-ALEX*0.82 (0.36 to 1.85)
      BrigatinibALTA-1L0.57 (0.34 to 0.95)
      Ceritinib (750 mg)ASCEND-4, ASCEND-80.22 (0.13 to 0.37)
      Ceritinib (450 mg)ASCEND-80.31 (0.15 to 0.66)
      Ceritinib (600 mg)ASCEND-80.25 (0.12 to 0.54)
      CrizotinibCROWN, ALEX, ALESIA*, J-ALEX*, ALTA-1L, ASCEND-4, ASCEND-8, PROFILE 1014, PROFILE 1029*, eXalt30.28 (0.19 to 0.41)
      EnsartinibeXalt30.55 (0.32 to 0.93)
      ChemotherapyASCEND-4, PROFILE 1014, PROFILE 1029*0.12 (0.08 to 0.19)
      Key: CrI, credible interval; HR hazard ratio; PFS, progression-free survival Notes: *Study in Asian population only


      For PFS, lorlatinib reduced the hazard of progression or death compared to all other treatments based on analyses conducted using all studies when comparing to all studies. This NMA suggest that lorlatinib is an effective first line treatment for ALK+ NSCLC patients when compared to other next-generation ALK TKIs.


      Lorlatinib, Network meta-analysis, ALK-positive NSCLC