First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.
METHODS
We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.
RESULTS
The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.
CONCLUSIONS
In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels.
Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
Visit your Preferences and Settings section to Manage All Topic Alerts
Additional Info
First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer
N. Engl. J. Med 2020 Nov 19;383(21)2018-2029, AT Shaw, TM Bauer, F de Marinis, E Felip, Y Goto, G Liu, J Mazieres, DW Kim, T Mok, A Polli, H Thurm, AM Calella, G Peltz, BJ SolomonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
ALK TKIs in NSCLC: Progress With New Generation Drugs
In a study published online in The New England Journal of Medicine on November 19, 2020, Alice T. Shaw and coauthors presented the results of CROWN, a phase III trial evaluating the third-generation tyrosine kinase inhibitor (TKI) lorlatinib in patients with advanced non–small cell lung cancer (NSCLC) harboring an ALK translocation. A summary of the trial results was posted on the Practice Update website/Daily Digest Oncology on November 22, 2020.
ALK translocation and mutations occur in 2% to 7% of NSCLC, mostly adenocarcinoma. Several first-generation (crizotinib) and second-generation ALK TKIs (ceritinib, alectinib, brigatinib, ensartinib) have been developed and approved since 2011. ALK TKIs have been practice-changing and are now the standard first-line treatment of ALK-positive NSCLC as recommended in guidelines.
Multiple ALK TKIs are available for upfront treatment, and second-generation ALK TKIs have shown improved results when compared with crizotinib in randomized trials; chronologically, these include alectinib, brigatinib, ensartinib, and, this month, lorlatinib as a third-generation ALK TKI.
With the exceptions of crizotinib and ceritinib compared with platinum-based chemotherapy, the most recent second- and third-generation ALK TKIs were challenging crizotinib as the standard treatment.
Population characteristics in all these trials were very similar: mostly ALK-positive adenocarcinoma, previously untreated for advanced disease in most of the trials except for brigatinib (ALTA-L1; 27% pretreated) and lorlatinib (CROWN; 7% pretreated), brain metastasis were allowed, with an incidence ranging from 26% to 40% depending on the trials. Progression-free survival (PFS) was always the primary endpoint.
In cross-trial comparison (with all the limitation of such analysis), ceritinib (ASCEND-4 trial) was very similar to crizotinib (PROFILE 1014) compared with platinum-based chemotherapy in terms of response rate and PFS (primary endpoint), with a median of 16.6 months with ceritinib versus 10.9 months in the crizotinib trial but a PFS hazard ratio in favor of crizotinib (0.55 with ceritinib vs 0.45 with crizotinib).
For all the other trials, the new-generation ALK TKIs were compared with crizotinib. Results of crizotinib as a control arm varied slightly among trials for median PFS and ORR. The primary endpoint PFS was improved step-by-step with additional second- and third-generation drugs as shown in the table below:
ALK TKI
Trial
PFS HR vs crizotinib
Median PFS
% ORR
Alectinib
ALEX
0.50
25.7 months
82.9
Brigatinib
ALTA-1L
0.49
24 months
74
Ensartinib
eXalt3
0.45
NR (25.8+)
75
Lorlatinib
CROWN
0.28
NR (78% vs 39% at 12 months)
76
Overall survival (OS) data are not available in this publication. Crossover was not allowed in ALEX (alectinib), eXalt3 (ensartinib), and CROWN (lorlatinib) but was allowed in ALTA-1L. Nevertheless, OS data might be difficult to analyze if ever available, considering that alectinib, brigatinib, and ensartinib are now approved and available. As their mechanisms of action differ according to possible acquired mutations, they could be considered as an option in the second line post crizotinib when the trials are closed, some of them having demonstrated efficacy in that setting in earlier trials and possibly impacting OS.
Another point to be mentioned for the second- and third-generation TKIs is their efficacy on brain metastases. Response rate and duration as well as CNS PFS was evaluated in most of the trials and clearly showed a benefit over crizotinib. This is an important point to consider since brain metastases have a high incidence in the natural history of lung cancer.
Overall, toxicities of second- and third-generation TKIs are acceptable, and their tolerance profile looks globally better than crizotinib's in terms of grade 3 and higher serious adverse events.
Continuous drug development for treatment of ALK-positive NSCLC has clearly improved disease control and is a perfect illustration of the impact of precision medicine, using the right drug, at the right time, for the right patient selected on genomic alteration.
Lorlatinib is a third-generation inhibitor of anaplastic lymphoma kinase (ALK) that has demonstrated activity in previously treated patients with ALK-positive non–small cell lung cancer (NSCLC). ALK-positive NSCLC constitutes 4% to 7% of all NSCLC. This was a phase III randomized trial comparing lorlatinib with crizotinib, a first-generation inhibitor of ALK, in approximately 300 patients with advanced ALK-positive NSCLC who were treatment-naïve for metastatic disease. The primary endpoint was progression-free survival as assessed by blinded independent central review. The percentage of patients alive without disease progression at 12 months was 78% in the lorlatinib arm versus 39% in the crizotinib arm, with an impressive hazard ratio for disease progression or death of 0.28. In patients with measurable brain metastases, 82% with lorlatinib had a response, of whom 71% had an intracranial complete response. Only 23% of the patients treated with crizotinib had a response. These impressive results build on the high response rates we have seen with third-generation inhibitors like osimertinib for EGFR-mutant lung cancer brain metastases and other newer-generation ALK inhibitors like alectinib, ceritinib, and brigatinib. These blood–brain penetrant small molecule tyrosine kinase inhibitors have changed the landscape of management of oncogenic-driven brain metastases. Similarly, HER2-positive breast cancer and BRAF-mutant melanoma can be successfully targeted with specific inhibitors that have shown responses in the brain metastases, ushering in a new era in the management of these patients.