First line settingr
The evidence to support the use of lorlatinib in the first line setting is provided by results from a double-blind, multicentre phase III trial (CROWN).
The CROWN trial enrolled 296 patients with locally advanced or metastatic non-small cell lung cancer, with ALK rearrangement. Between May 2017 and February 2019, 149 patients were randomised to lorlatinib 100 mg daily and 147 patients to crizotinib 250 mg twice daily. Treatment in both arms was continued until disease progression, unacceptable toxicity, death or withdrawal.
The primary end point was progression-free survival (PFS) [as determined by blinded independent central review]. Secondary end points included investigator assessed progression free survival, overall survival (OS), objective response rate (ORR), objective intracranial response (OIR), and safety.r
Second line settingr
There is a lack of strong evidence to support the use of lorlatinib in the second line setting the reference panel was most strongly influenced by Solomon et al. in supporting publication of this protocol. Solomon et al, was a phase II single arm study, which included 276 patients recruited from September 2015 to October 2016 with advanced non- small cell lung cancer who were either ALK-positive or ROS-1 positive, and were enrolled into different cohorts based on ALK and ROS1 status and prior treatment. In the ALK-positive cohort, 59 patients had received previous crizotinib (EXP2 and EXP3A), 28 patients had received non-crizotinib ALK TKI (EXP3B), 112 had received two or three previous ALK TKI’s (EXP4-5). Other cohorts included treatment naive ALK positive (EXP1) and ROS1 positive (EXP6).r
Efficacy
First line settingr
At data cut-off median duration of follow up was 19.3 months in the lorlatinib group and 14.8 months in the crizotinib group. With regards to primary outcome, the median progression free survival (PFS) was not reached (NR) in the lorlatinib arm and 9.3 months (95% CI 7.6-11.1) in the crizotinib arm [HR 0.28; 95% CI 0.19-0.41 p<0.001]. The 12 month PFS was 78% in the lorlatinib group and 39% in the crizotinib group.r
Secondary outcomes showed a higher overall response rate (ORR) for lorlatinib in comparison to crizotinib [76 v 58%]. Lorlatinib also exhibited higher CNS penetration with higher CNS response rates in comparison to crizotinib [66 v 20%]. Patients alive, and without CNS progression at 12 months was higher in the lorlatinib arm [96 v 60%; HR 0.07; 95% CI 0.03 to 0.17]. Lorlatinib also had a lower cumulative incidence of CNS progression as first event [3 v 33%; HR 0.06; 95% CI 0.02-0.18]. Overall survival data is still immature.r
Kaplan-Meier estimates for Progression-free Survival (A), Survival without CNS progression (B), CNS progression as first event (C) and Overall survival (D)r
© N Engl J Med 2020
Second line settingr
Response rates to lorlatinib in the second line setting in different expansion cohorts are highlighted in the table belowr
Outcome |
EXP2 and 3A (n=59)* |
EXP 3B (n=28)** |
EXP 4-5 (n=111)*** |
Median PFS (months) |
Not reached
|
5.5
|
6.9
|
ORR |
41 (69.5%)
CR - 1 (2%
PR - 8 (29%)
|
9 (32%)
CR - 1 (4%)
PR - 8 (29%)
|
43 (39%)
CR - 2 (2%)
PR - 41 (37%)
|
Intracranial ORR |
20 (87%)
CR - 5 (22%)
PR - 15 (65%)
|
5 (55.6%)
CR - 1 (11%)
PR 4 (44%)
|
26 (53/1%)
CR - 10 (20%)
PR - 16 (33%)
|
CR: Complete Response, PR: Partial Response
* EXP 2 and 3A: previous crizotinib with or without chemotherapy
** EXP3B: Expansion Cohort 3B - previous non-crizotinib ALK TKI with or without chemotherapy
*** EXP4-5: Expansion Cohorts 4-5 - ≥2 previous ALK TKIs with or without chemotherapy
Toxicity
A summary of the toxicities associated with this protocol are included in the table below. The most clinically significant toxicities for this treatment are hypercholesterolaemia and hypertriglyceridaemia. Cognitive and mood effects related to lorlatinib were typically grade 1 and reversible with dose interruption. r
Adverse eventsr
© The Oncologist 2020