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

The NCCN Panel preference stratified first-line therapy with brigatinib, ceritinib, or crizotinib for patients with ALK-rearrangement-positive metastatic NSCLC. Non-Small Cell Lung Cancer….ALK REARRANGEMENT POSITIVE….SUBSEQUENT THERAPY...Continue alectinib or brigatinib or ceritinib or lorlatinib

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.

...Have documentation of anaplastic lymphoma kinase (ALK) rearrangement by a positive result from any laboratory test® approved by the food and drug administration (FDA) or Have documented ALK rearrangement by a different test (non-FDA-approved local lab tests) and have provided tumor sample to the central laboratory....

...Must have documented ALK rearrangement....

...Expansion cohort 1: Non-small cell lung cancer (NSCLC) participants whose tumors exhibit anaplastic lymphoma kinase (ALK) rearrangements and who have...

...Participants with ALK gene rearrangement confirmed by local hospital medical records....

...Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline....

...ALK rearrangement by one of the following methods:...

...- Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine's FoundationOne CDx....

...Have documentation of ALK rearrangement that meets following criteria....

...Documented ALK rearrangement (VENTANA ALK (D5F3) CDx Assay or appropriate diagnostic method) 6....

...Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or 2....

...Have histologically or cytologically confirmed locally advanced or metastatic NSCLC that is determined to have an ALK-rearrangement detected according to local standard procedure....

...Histologically confirmed, locally advanced (stage III) and not suitable for curative treatment, i.e. R0 operation or definitive chemo-/radiation, or metastatic (stage IV) ALK+ NSCLCNOTE: Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline. ...

...If ALK rearrangement diagnostic is performed using IHC and the result is + or 2+, a confirmation with a second method performed locally (DNA-based or RNA-based next generation sequencing (NGS) assay, nCounter Nanostring assay or ALK FISH performed) is required.4. ...

...Patients who have documented locally ALK rearrangement5. ...

...Locally advanced or metastatic NSCLC that has been cytologically or histologically confirmed ALK rearrangement based on FDA approved test (e.g....

...If ALK rearrangement diagnostic is performed using IHC and the result is + or 2+, a confirmation with a second method performed locally (DNA-based or RNA-based next generation sequencing (NGS) assay, nCounter Nanostring assay or ALK FISH performed) is required....

The ORR was 91.9% with alectinib and 92.2% for brigatinib (p-value: 0.54, 95% CI: 0.35–7.30); the intracranial ORR rates were 94.6% and 100%, respectively….Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.

Brigatinib with LCT is safe in patients with ALK-rearranged advanced NSCLC and yielded promising outcomes when compared to historical outcomes from brigatinib alone. Lower post-induction volume and complete LCT, but not number of metastases at baseline (oligo vs poly) were associated with increased benefit for LCT.

At the data cutoff point, the median follow-up duration was 16.5 months (95% CI; 14.7-18.3) in the brigatinib group and 27.5 months (95% CI; 24.6-30.4) in the alectinib group. The ORR was 92.5% with alectinib and 93.8% for brigatinib. The intracranial ORR rates were 92.7% (38/41) and 100% (10/10), respectively....Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.

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.

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).

Disease control rate was 79% (95% CI, 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI, 3.7-9.3)....Brigatinib showed clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without prior crizotinib).

Brigatinib with LCT is safe and feasible in patients with ALK-rearranged advanced NSCLC irrespective of number of metastatic sites.

Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated...four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response.