Table 1.

Preliminary activity of MET TKIs in the treatment of MET exon 14 mutant NSCLC, de novo and acquired MET amplification in lung cancer, and MET-dysregulated pRCC in clinical trials

StudyPhaseDrugNLineMET alterationORRPFSDORRef.
MET exon 14 mutations and de novo MET amplification (NSCLC)
PROFILE 1001ICrizotinib 250 mg b.i.d.691st: 26MET exon 14 skipping32%7.3 months (95% CI, 5.4–9.1)9.1 months (95% CI, 6.4–12.7)(90)
NCT00585195>2nd: 43
GEOMETRY mono-1IICapmatinib 400 mg b.i.d.281st lineMET exon 14 skippingBIRC: 67.9%9.69 months (95% CI, 5.52–13.86)11.14 months (95% CI, 5.55–NR)(91)
NCT02414139692nd/3rd lineInv: 60.7%5.42 months (95% CI, 4.17–6.97)9.72 months (95% CI, 5.55–12.98)
BIRC: 40.6%
Inv: 42%
VISIONIITepotinib 500 mg/day871st: 33MET exon 14 skippingBIRC:BIRC:BIRC:(92)
NCT028649922nd: 31liquid biopsy: 50%liquid biopsy: 9.5 months (95% CI, 6.7–NR)liquid biopsy: 12.4 months (95% CI, 5.8-NR)
>2nd: 23tissue biopsy: 45.1%tissue biopsy: 10.8 months (95% CI, 6.9–NR)tissue biopsy: 15.7 months (95% CI, 9.0-NR)
Inv:Inv:Inv:
liquid biopsy: 55.3%liquid biopsy: 9.5 months (95% CI, 5.3–21.1)liquid biopsy: 17.1 months (95% CI, 7.1-NR)
tissue biopsy: 54.9%tissue biopsy: 12.2 months (95% CI, 6.3–NR)tissue biopsy: 14.3 months (95% CI, 5.7-NR)
NCT02897479IISavolitinib 600 mg/day341st: 17MET exon 14 skipping12/31 (38.7%)Not reported34 weeks (range, 16–96)(93)
2nd: 13
>2nd: 4
METROSIICrizotinib 250 mg b.i.d.262nd: 21MET exon 14 skipping7 (27%)4.4 months (95% CI, 3.0–5.8)3.7 months (95% CI, 1.1–6.3)(94)
NCT02499614>2nd: 5MET/CEP7 ratio > 2.2
NCT00585195ICrizotinib 250 mg b.i.d.3Low: ≥1.8–≤2.2 copies1 (33.3%)1.8 months (95% CI, 0.8–14.0)12.1 months (95% CI, 12.1–12.1)(53)
14Medium: >2.2–<4 copies2 (14.3%)1.9 months (95% CI, 1.3–5.5)3.7 months (95% CI, 3.7–3.7)
20High: ≥4 copies8 (40%)6.7 months (95% CI, 3.4–7.4)5.5 months (95% CI, 3.3–25.8)
MET amplification in EGFR TKI resistance (NSCLC)
NCT01610336IIGefitinib 250 mg daily + capmatinib 400 mg b.i.d.41Post 1st-/2nd-generation EGFR TKICopy number < 45 (12%)5.6 months (95% CI, 3.8–7.2)(64)
18Copy number ≥ 4 < 64 (22%)Copy number ≥ 6
36Copy number ≥ 617 (47%)5.49 months (95% CI, 4.21–7.29)
42nd: 86IHC: 01 (25%)
2IHC: +10 (0%)IHC: +3
16>2nd: 75IHC: +23 (19%)5.45 months
78IHC: +325 (32%)(95% CI, 3.71–7.10)
TATTONIbSavolitinib 300 mg or 600 mg daily + osimertinib 80 mg/daily51Post 1st-/2nd-generation EGFR TKI T790MEGFR mutant and MET amplification (FISH copies ≥ 5 or MET/CEP7 ratio ≥ 2,NGS ≥ 20% tumor cells and ≥ 5 copies),or MET overexpression (3+)33 (65%)9.0 months (95% CI, 5⋅5–11⋅9)9.0 months (95% CI, 6⋅1–22⋅7)(65)
NCT02143466
18Post 1st-/2nd- generation EGFR TKI T790M+12 (67%)11⋅0 months (95% CI, 4⋅0–NR)12.4 months (95% CI, 2⋅8–NR)
69Post 3rd-generation EGFR TKI21 (30%)5.4 months (95% CI, 4.1–8.0)7.9 months (95% CI, 4.0–10.5)
Savolitinib 300 mg +Osimertinib 80 mg/daily36Post 1st-/2nd-generation EGFR TKI T790M23 (64%)9.1 months (95% CI, 5⋅4–12⋅9)8.0 months (95% CI, 4⋅5–NR)
MET kinase domain–mutant/amplified (pRCC)
NCT02127710IISavolitinib 600 mg/daily441st: 26MET mutation, polysomy, amplification4 (18%)6.2 months (95% CI, 4.1–7.0)Range, 2.4–16.4 months(40)
>1st: 18
461st: 23MET-independent0 (0%)1.4 months (95% CI, 1.4–2.7)
>1st: 23
191st: 11Unknown MET status0 (0%)
>1st: 8
NCT00726323IIForetinib741st: 60MET mutation10 (13.5%)9.3 months (95% CI, 6.9–12.9)18.5 months(39)
≥2nd: 14MET amplification
Chromosome 7 polysomy
  • Abbreviations: b.i.d., twice daily; BIRC, blinded independent review committee; CI, confidence interval; DOR, duration of response; Inv, investigator; NR, not reached; ORR, objective response rate; Ref., reference.