For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer…lorlatinib.

Non-Small Cell Lung Cancer: ALK Rearrangement Positive…First-line therapy…Lorlatinib… ALK REARRANGEMENT POSITIVE….SUBSEQUENT THERAPY...Alectinib or brigatinib or ceritinib or lorlatinib

In ALK-rearranged patients progressing on crizotinib, treatment with next-generation ALK TKIs, such as alectinib [I, A], ceritinib [I, A] brigatinib [III, A] or lorlatinib [III, A], is recommended.

...- Histologically or cytologically diagnosis of metastatic NSCLC that carries an ALK rearrangement or a ROS1 rearrangement...

...- Histologically or cytologically confirmed diagnosis of metastatic non-small cell lung cancer (Stage IV, AJCC v7.0) that carries an ALK or ROS1 rearrangement (ROS1-positive patients will only be allowed in dose escalation) as determined using a local diagnostic test or a commercial test or by the Food and Drug Administration (FDA)-approved FISH test, using Vysis® ALK Break apart FISH Probe, or the Ventana® immunohistochemistry (IHC) test....

...Evidence of histologically or cytologically confirmed diagnosis of unresectable advanced and/or recurrent NSCLC that carries an ALK rearrangement, as detected by an appropriate test....

...- Participants must have evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, American Joint Committee on Cancer [AJCC] v7.0) that carries an ALK rearrangement....

...UICC 2015) that carries an ALK rearrangement, as determined by the molecular biology platform of the investigator by FISH assay or by Immunohistochemistry (IHC), or Next Generation Sequencing (NGS) or RNA sequencing approach ....

...PFS`Resistance mechanism of first-line lorlatinib treatment by tumor tissue, and peripheral blood ctDNA (circulating tumor Deoxyribonucleic acid) biomarkers including, but not limited to, ALK gene rearrangement and/or ALK kinase domain mutations as measured by next-generation sequencing (NGS);`Resistance mechanism of lorlatinib...

...- Confirmed ALK gene rearrangement by any validated test....

...- Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT)....

...- Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by fluorescence in situ hybridization (FISH) assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc) approved by food and drug administration (FDA)...

We reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS)....Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4-11.8); the median OS was 20.7 months (95% CI: 16.3-30.5).

We aimed to report result of lorlatinib in real-world practice....A total 52 ALK -positive patients were enrolled....The objective response rate was 22% and disease control rate was 88%....This real-world efficacy and adverse event on lorlatinib for Taiwanese ALK-rearranged NSCLC are compatible to those reported in global clinical trial.

We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK‐rearranged NSCLC...five studies compared a next‐generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib....Next‐generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high‐certainty evidence), particularly in participants with baseline brain metastases….Next‐generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate‐certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate‐certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib.

Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC….Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS....According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively.

This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements...Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively...

NSCLCBM patients between 2010 and 2019 were evaluated....16 ALK positive patients received first-generation ALK inhibitor (crizotinib)...17 patients received second-generation (alectinib, ceritinib, brigatinib) and third-generation ALK inhibitors (lorlatinib)...The 5-year OS rate was 49% (95% confidence interval (CI) = 24%, 71%) for first-generation ALK inhibitors and 76% (95% CI = 40%, 92%) for second and third-generation ALK inhibitors (p-value (p) = 0.019).

Lorlatinib showed clinically meaningful responses and IC-responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.

Lorlatinib is a potent ALK and ROS-1 inhibitor that also has activity against many acquired ALK resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in ALK rearranged advanced NSCLC.

In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail.