Table 1.
Targeted therapy outcomes by MET copy number status
| Drug | Trial (n) | Amplification Criteria | Assay Used | All Patients | MET Amplification Status | |||
|---|---|---|---|---|---|---|---|---|
| Solid tumors | MET-Amplified | |||||||
| SAR125844193 | Phase I (n=72)* | MET GCN >4 and MET/CEP7 ≤2.0a | FISH | ORR | - | 17% (5/29) | ||
| capmatinib198 | Phase I (n=38)€ | MET/CEP7 ≥ 2.0 or MET GCN ≥5b | FISH |
MET
GCN <4 |
MET 4< GCN <6 |
MET
GCN ≥6 |
||
| ORR | 0% (0/36) | 0% (0/22) | 0% (0/6) | 0% (0/3) | ||||
| 95%CI | (0–9.3%) | - | - | - | ||||
| AMG 337199 | Phase I* (n=111) | MET/CEP7 ≥2.0 | FISH | MET/CEP7 <4 | MET/CEP7 ≥ 4 | |||
| mDOR | 6.6 mo | - | - | |||||
| ORR | 10% (11/111) | 0% (0/2) | 60% (6/10) | |||||
| 95%CI | (5–17%) | - | - | |||||
| Gastroesophageal cancers | MET-Amplified | |||||||
| AMG 337200 | Phase II (n=60)¥ | MET/CEP7 ≥2.0 | FISH | mDOR | - | 6.0 mo | ||
| 95%CI | - | (3.7–16.7) | ||||||
| ORR | - | 18% (8/45) | ||||||
| 95%CI | - | (8%–32%) | ||||||
| foretinib201 | Phase II (n=74) | MET/CEP7 ≥2.0 | FISH | mPFS | 1.7 mo | - | ||
| 95%CI | (1.6 –1.8) | - | ||||||
| ORR | 0% (0/71) | 0% (0/3) | ||||||
| Hepatocellular carcinoma | ||||||||
| capmatinib202 | Phase II (n=30) | MET/CEP7 ≥2.0 or GCN ≥5a | FISH | ORR | - | 10% (3/30) | ||
| 95%CI | - | (2.1–27%) | ||||||
| Non-small cell lung cancers | MET/CEP7 ≥1.8 and ≤2.2 | MET/CEP7 >2.2 – <4.0 | MET/CEP7 ≥4.0 | |||||
| crizotinib | Phase I66 (n=37) | MET/CEP7 ≥1.8 | FISH | mPFS | - | 1.8 mo | 1.9 mo | 6.7 mo |
| 95%CI | - | (0.8–14.0) | (1.3–5.5) | (3.4–7.4) | ||||
| ORR | - | 33% (1/3) | 14% (2/14) | 40% (8/20) | ||||
| 95%CI | - | (0.8–91%) | (2%–43%) | (19%–64%) | ||||
| Phase II203 (n=25)* | MET GCN ≥6 and IHC 2+/3+ | FISH | MET/CEP7 ≥1.8 and ≤2.2 | MET/CEP7 >2.2 –<5.0 | MET/CEP7 ≥5.0 | |||
| mPFS | 5.0 mo | - | 4.4 mo | NE | ||||
| 95%CI | (2.7–7.3) | - | (2.9–5.9) | - | ||||
| ORR | 31% (5/16) | - | 36% | 0% (0/2) | ||||
| 95%CI | (5.2–71.4%) | - | (6.0–77%) | - | ||||
| Phase II65 (n=25)* | MET GCN ≥6 and IHC 2+/3+ | FISH | mPFS | 3.2 mo | - | - | - | |
| 95%CI | (1.9–3.7) | - | - | - | ||||
| ORR | 32% (8/25) | - | - | - | ||||
| capmatinib79 | Phase I (n=44) | MET/CEP7 ≥2.0 or MET GCN ≥5c,d | FISH |
MET
GCN <4 |
MET 4< GCN <6 |
MET
GCN ≥6 |
||
| ORR | 20% (11/55) | 0% (0/17) | 17% (2/12) | 47% (7/15) | ||||
| 95%CI | - | - | (2–48%) | (21–73%) | ||||
| Non-small cell lung cancers (EGFR-mutant) | MET-amplified | |||||||
| osimertinib/ savolitinib 300 mg daily204 | Phase I (n=36) | Previously treated with 1st/2nd generation EGFR-TKI and T790M negative; MET/CEP7 ratio ≥2 or MET GCN ≥5 by FISH or MET GCN ≥5 by NGSd | FISH or NGS | mPFS | - | 9.1 mo | ||
| 95%CI | - | (5.4–12.9) | ||||||
| ORR | - | 64% | ||||||
| 95%CI | - | (46%–79%) | ||||||
| osimertinib/ savolitinib 300 or 600 mg daily204 | Phase I (n=51) | Previously treated with 1st/2nd generation EGFR-TKI and T790M negative; MET/CEP7 ratio ≥2 or MET GCN ≥5 by FISH or MET GCN ≥5 by NGSd | FISH or NGS | mPFS | - | 9.0 | ||
| 95%CI | - | (5.5–11.9) | ||||||
| ORR | - | 65% (33/51) | ||||||
| 95%CI | - | (50%–78%) | ||||||
| osimertinib/ savolitinib 300 or 600 mg daily204 | Phase I (n=18) | Previously treated with 1st/2nd generation EGFR-TKI and T790M positive MET/CEP7 ratio ≥2 or MET GCN ≥5 by FISH or MET GCN ≥5 by NGSd | FISH or NGS | mPFS | - | 11.0 mo | ||
| 95%CI | - | (4.0-NE) | ||||||
| ORR | - | 67% (12/18) | ||||||
| 95%CI | - | (41–87%) | ||||||
| osimertinib/ savolitinib 300 or 600 mg daily204 | Phase I (n=69) | Previously treated with 3rd generation EGFR-TKI; MET/CEP7 ratio ≥2 or MET GCN ≥5 by FISH or MET GCN ≥5 by NGSd | FISH or NGS | mPFS | - | 5.4 mo | ||
| 95%CI | - | (4.1–8.0) | ||||||
| ORR | - | 30% (21/69) | ||||||
| 95%CI | - | (20–43%) | ||||||
|
gefitinib/ tepotinib205 |
Phase II (n=12) | MET/CEP7 ratio ≥2 or MET GCN ≥5; after prior EGFR-TKI and T790M negative | FISH | mPFS | - | 16.6 mo | ||
| 90%CI | - | (8.3-NE) | ||||||
| ORR | - | 67% (8/12) | ||||||
| 90%CI | - | (39%–88%) | ||||||
|
gefitinib/ savolitinib206 |
Phase I (n=44) | MET/CEP7 ratio ≥2 or MET GCN ≥5; after prior EGFR-TKI | FISH | ORR | - | 25% (11/44) | ||
| gefitinib/capmatinib82 | Phase II (n=100) | GCN ≥5 or IHC 2+/3+ in >50%; then, GCN ≥5 plus IHC 2+/3+; then, GCN ≥4 or IHC 3+; MET/CEP7 ≥1.8 | FISH |
MET
GCN <4 |
MET
4 ≤ GCN <6 |
MET
GCN ≥6 |
||
| mPFS | 5.5 mo | 3.9 mo | 5.4 mo | 5.5 mo | ||||
| 95%CI | (3.8–5.6) | (3.7–5.6) | (3.7–7.5) | (4.2–7.3) | ||||
| ORR | 29% (29/100) | 12% (12/41) | 22% (4/18) | 47% (17/36) | ||||
| Papillary renal cell carcinoma | MET GCN <6 and not MET-driven§ | MET GCN ≥6 | ||||||
| savolitinib80 | Phase II (n=79)* | Focal MET GCN ≥6 | NGS | ORR | 10% (8/79) | 0% (0/32) | 43% (3/7) | |
MET positivity also defined as
immunohistochemistry (IHC) ≥50% with 2+/3+
H-score ≥150 or IHC ≥50% with 2+/3+ or H-score ≥50 for hepatocellular carcinoma and glioblastoma
H-score ≥150 or IHC ≥50% with 2+/3+
IHC ≥50 with % 3+.
Available patient level data with MET gene copy numbers or MET/CEP7 ratio and response results were used to produce these results.
Response and outcome data derived from dosing regimen #3 cohort of the study, but response rates by MET amplification status in this cohort was not available.
Only data from patients receiving a stable dose in the dose expansion cohort were used.
One patient with partial response had both a MET exon 14 alteration and MET copy number 2.3.
Only patients from cohort 1 was used.
Not MET-driven defined as no MET focal amplification, no MET kinase domain mutation, no HGF amplification, and no chromosome 7 gain. CI, confidence interval; ORR, objective response rate; mPFS, median progression-free survival; mDOR, median duration of response; GCN, gene copy number; NE, not estimable; NGS, next-generation sequencing; FISH, fluorescence in-situ hybridization; IHC, immunohistochemistry; mo, month(s); HCC, hepatocellular carcinoma; GBM, glioblastoma; PRCC, papillary renal cell carcinoma