For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib.

The NCCN Panel preference stratified first-line therapy with brigatinib, ceritinib, or crizotinib for patients with ALK-rearrangement-positive metastatic NSCLC.

First-line treatment of ALK-rearranged NSCLC…In patients with CNS involvement, front-line use of ALK TKIs is effective, and alectinib [III, A], brigatinib [III, B] or ceritinib [IV, B] are recommended.

Ceritinib was effective and safe in treatment-naïve Asian patients with advanced ALK-rearranged NSCLC...Median PFS (by BIRC) was 26.3 months (95% CI: 8.6–NE) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (HR = 0.66, 95% CI: 0.41–1.05) in the ceritinib arm versus chemotherapy arm.

...Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1–6·9] for ceritinib vs 1·6 months [1·4–2·8] for chemotherapy; hazard ratio 0·49 [0·36–0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group.These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population.

In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer... Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001).

...376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42–0·73]; p<0·00001)....First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.

...- Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carries an ALK rearrangement, as per the FDA-approved FISH assay (Abbott Molecular Inc.)....

...- Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carried an ALK rearrangement, as per the FDA-approved Vysis ALK break-apart FISH assay (Abbott Molecular Inc.)...

...Histologically or cytologically confirmed diagnosis of lung adenocarcinoma that demonstrates ALK rearrangement as detected by the approved FISH test (Abbott Molecular Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); or the Ventana IHC test....

...- Histologically or cytologically confirmed diagnosis of NSCLC that carries an ALK rearrangement defined as positive using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria) or positive as assessed by the CFDA approved immunohistochemistry (IHC) test (Ventana Medical Systems, Inc)...

...- Presence of known ALK gene rearrangement....

The intracranial ORR and DCR of ceritinib were 73.7% and 93.0%, respectively. The median intracranial PFS in patients reaching the endpoint was 8.75 months….Ceritinib administered at 450 mg QD to ALK-rearrangement NSCLC patients with BM in China exhibited superior ORR and DCR, as well as PFS and event free probability.

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...six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy....Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high‐certainty evidence)….ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high‐certainty evidence).

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).

A total of 57 ALK-rearrangement NSCLC patients with brain metastases (BM) were enrolled...The intracranial ORR and DCR were 73.7% and 93.0%, respectively. The whole body ORR and DCR were 87.7% and 98.2%, respectively. The median intracranial PFS and median whole body PFS in patients reached the endpoint were 8.75 months and 7.6 months, respectively...The estimated 12-month event-free probabilities (EFP) of intracranial lesions was 68.1% ; and these of whole body lesions was 74.7%. Subgroup analysis showed the estimated 12-month EFP of intracranial lesions was relatively higher in patients with prior brain radiotherapy (93.8% vs 47.1%, P=0.0006). Additionally, we reported a 74-year-old female ALK-rearrangement NSCLC patient with BM achieved continuous response (intracranial PFS: 12.9 months) to ceritinib reduced to 150mg QD due to intolerable AE and administered for 7.5 months. Ceritinib administered at a dose of 450mg QD to ALK-rearrangement NSCLC patients with BM in China demonstrates superior ORR and DCR, as well as PFS and EFP that are expected to be improved. Especially the estimated 12-month EFP of intracranial lesions was improved in patients with prior brain radiotherapy.

The PFS and OS of ceritinib were 7.26 months (95% CI, 5.10-9.43) and 18.73 months (95% CI; 14.59-22.87). These results suggested that ceritinib can effectively treat patients with ALK-rearranged NSCLC....Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months.

The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib.

Similarly, ceritinib was more potent than crizotinib against two ALK-rearranged lung cancer cell lines, H3122 and H2228…