the NCCN NSCLC Panel recommends crizotinib as a first-line therapy or subsequent therapy option (category 2A; useful in certain circumstances) for patients with metastatic NSCLC who are positive for METex14 skipping mutations...

Pfizer Inc. (NYSE:PFE) announced today that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for XALKORI (crizotinib) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with MET exon 14 alterations with disease progression on or after platinum-based chemotherapy. The FDA also granted Breakthrough Therapy designation for XALKORI for the treatment of patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is anaplastic lymphoma kinase (ALK)-positive.

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Previously treated and treatment naïve pts with METmut aNSCLC were included and treated with crizotinib 250 mg BID until disease progression or intolerable toxicity….1 (4%) complete response (CR), 14 (58%) partial responses and 2 (8%) SDs ≥ 16 weeks were observed, with resulting OR-rate of 62% (95% CI, 41 – 81) and CB-rate of 71% (95% CI, 49 – 87). After 20.2 months median follow-up, median progression-free and overall survival were 8.3 (95% CI, 6.0 – NA) and 13.0 months (95% CI, 8.0 – NA), respectively....The pt who achieved CR had a TK domain mutation (p.H1094Y), all others exon 14 skipping METmuts.

...the phase I PROFILE 1001 study (n = 69) and reported the efficacy of crizotinib (median PFS [mPFS] 7.3 months; objective response rate [ORR] 32%) in patients with advanced stage NSCLC harboring MET exon 14 skipping alteration and showed that MET inhibition with crizotinib remains a treatment option for NSCLCs with MET exon 14 alterations.

A total of 55 patients were included in the study, of which 36 with ALK fusion, and 13 with ROS1 fusion....the ORR of crizotinib was 53% with a median PFS of 12 months (range: 1–102 months)...confirmed the therapeutic benefit of crizotinib in ALK/ROS-1fusion-positive advanced NSCLC, and also in NSCLC with MET ex14 mutation. Our data showed crizotinib is tolerable and effective, which is comparable with literature report.

CONTRADICTING EVIDENCE: We identified 46 patients with MET alterations, of whom 32 had MET ex14...MET TKIs were received by 21 patients (17 crizotinib, 3 capmatinib, 1 cabozantinib), with an ORR of 29%. The median PFS with TKIs was 2.6 months (1.2-8.4)….Patients who received initial TKI (n=13) compared to those who received initial ICI (n=14) had significantly shorter OS (13.6 vs 48.3 months)...Patients with MET ex14 NSCLC benefit from ICI irrespective of PD-L1 expression and smoking history. ORR and PFS with earlier generation TKIs (crizotinib) were poor.

CONTRADICTING EVIDENCE: MET TKIs were received by 18 patients (16 crizotinib, 1 capmatinib, 1 cabozantinib), with an ORR of 28% (30% amongst those who received crizotinib first line). The median PFS with TKIs was 2.6 months (1.2-8.9)....ORR and PFS with earlier generation TKIs (crizotinib) were poor.

Median overall survival for metastatic patients treated with any systemic therapy was 15.4 months….Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy.

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)...Patients with undetectable baseline plasma MET-ex14 had a trend of longer PFS (p = 0.097) but comparable OS (p = 0.18). A novel MET Y1003C mutation was detected and demonstrated a clinical response to crizotinib.

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).

The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients.

Crizotinib has antitumor activity in pts with MET exon 14-altered NSCLC.

Among the patients with a c-met exon 14 skip mutation, the overall survival was 22.8 months and the median PFS on crizotinib treatment was 12.4 months. Of the patients with c-met amplification, the median overall survival was 5.4 months and the median PFS with crizotinib treatment was 2.6 months....Crizotinib was found to be an optimal treatment for NSCLC harboring c-MET exon 14 skipping mutations.

On the other hand, cabozantinib ledto rapid intracranial responses in a case report ofMETex14-mutated NSCLC resistant to crizotinib.

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.