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Lorlatinib in patients with previously treated ALK+ advanced non-small cell lung cancer: efficacy and safety


Despite advancement of 2nd generation ALK tyrosine kinase inhibitors ( TKIs ), patients with ALK+ non-small cell lung cancer ( NSCLC ) continue to develop resistance and CNS metastases become more difficult to manage.
Lorlatinib, a potent brain-penetrant 3rd generation ALK/ROS1 tyrosine kinase inhibitor, has shown robust clinical activity in ALK+ or ROS1+ NSCLC patients, most of whom had CNS metastases and failed greater than or equal to 1 ALK tyrosine kinase inhibitor.

This ongoing phase 2 study enrolled 275 patients with ALK+ or ROS1+ advanced NSCLC ± CNS metastases in cohorts ( ALK: EXP 1–5; ROS1: EXP 6 ) based on prior treatment; starting dose was Lorlatinib 100 mg QD.
Antitumor activity ( by independent central review per RECIST 1.1 ), safety and biomarkers were evaluated.

In 198 ALK+ patients assessed for antitumor activity ( ITT population ) in pooled subgroups ( EXP 2–3A [ only prior Crizotinib ± chemotherapy ( CT ) ], EXP 3B [ only 1 prior 2nd gen ALK TKI ± CT ], and EXP 4–5 [ 2 or 3 prior ALK TKIs ± CT ] ), Lorlatinib led to rapid ( median time to response 1.4 months ) deep and durable systemic and intracranial ( IC ) responses.

Of a total 139 patients in EXP 3B + EXP 4–5, 62, 47 and 8 received Alectinib, Ceritinib and Brigatinib, respectively, as last ALK TKI prior to Lorlatinib.

The most common treatment-related adverse effects ( TRAEs ) and grade 3/4 TRAEs across all cohorts ( n=275 ) were hypercholesterolemia ( 84%/16% ) and hypertriglyceridemia ( 66%/16% ); 32% and 24% of patients had TRAEs that led to dose delays and reductions, respectively.

No treatment-related deaths occurred; TRAEs led to permanent discontinuation in 8 pts.

Antitumor activity was seen across a range of ALK resistance mutations, eg G1202R and G1202del.

In conclusion, Lorlatinib has shown clinically meaningful benefit in ALK+ NSCLC patients with greater than or equal to 1 prior ALK TKI and was generally tolerable with adverse effects managed by dose modification or supportive therapy. ( Xagena )

Source: American Society of Clinical Oncology - ASCO Meeting, 2018

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