Crizotinib inhibits ALK rearrangements, ROS1 rearrangements, and MET (ie, high-level MET amplification, METex14 mutation).

...• Histologically confirmed diagnosis of NSCLC • Availability of tumor tissue for ROS1, and MET analyses • Patient positive for ROS1 translocation or MET amplification • Radiological measurable disease according to RECIST criteria • At least 1 previous standard chemotherapy regimen • Performance status 0-2 (ECOG) • Patient compliance to trial procedures • Age ≥ 18 years • Written informed consent • Diagnosi di NSCLC confermata istologicamente • Disponibilità di tessuto tumorale per le analisi di ROS1 e MET • Paziente positivo per la traslocazione ROS1 o per l'amplificazione MET • Malattia misurabile radiologicamente in accordo ai criteri RECIST • Almeno 1 regime precedente di chemioterapia standard • Performance status 0-2 (ECOG) • Compliance del paziente alle procedure cliniche • Età ≥ 18 anni • Consenso informato scritto...

...- Patient positive for ROS1 translocation or MET amplification...

...- Histologically or cytologically confirmed diagnosis of stage IV or incurable non-squamous non-small cell lung cancer with a documented ROS1 rearrangement (cohort 1) or MET-activating mutation (exon 14) (cohort 2) or MET-amplification (cohort 3) tested in either plasma or tissue, as applicable...

Eight of 28 patients who received crizotinib treatment had c-MET amplification….Progression-free survival and overall survival in these eight patients were 9.4 and 10.9 months, respectively, and objective response rate was 50%.

...median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively....MET-amplified NSCLC responded to crizotinib with the highest ORR.

A total of 88 patients...received crizotinib....MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations.

Among evaluable patients harboring MET-ex14 alterations, longer progression-free survival (PFS) was observed with crizotinib than with chemotherapy (8.5 months versus 4.0 months, p = 0.041), but there was no difference in overall survival (OS, 11.3 months versus 12.0 months, p = 0.66)... Concurrent MET amplification results in a shorter PFS (4.2 months versus 8.5 months, p = 0.029) but a comparable OS (7.8 months versus 14.0 months, p = 0.12)...A novel MET Y1003C mutation was detected and demonstrated a clinical response to crizotinib.

Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1).

Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally...At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5).

We present a metastatic c-MET-amplified non-small cell lung cancer (NSCLC) patient who was treated with crizotinib….After c-MET amplification was shown, crizotinib 250 mg BID was started. A partial response was achieved with the initiation of crizotinib, and his performance score improved after treatment.

A 64-year-old female never-smoker (patient 15) was diagnosed with stage IV NSCLC...A mutation was identified in MET exon 14 in 94% of 867 reads (Fig 5A), in association with high-level MET amplification...the patient started crizotinib 250 mg orally twice per day, and repeat imaging 8 weeks later showed dramatic improvement in multiple lesions throughout her body.

Mutational analysis was performed using a targeted multiplex next-generation sequencing assay (Foundation Medicine, Cambridge, MA), which revealed both MET and hepatocyte growth factor gene (HGF) amplification by the company’s algorithm, with no detectable MET exon 14 alterations, ROS1, or ALK rearrangement....Crizotinib, 250 mg orally twice a day, was initiated and the patient experienced significant symptomatic improvement and a near-complete response after 2 months of treatment (Fig. 1C).