Table 3.

Summary of toxicity profiles of main novel c-MET inhibitors

Compound Class	Molecule	Setting	Dose	Most commonly reported AEs
Monoclonal antibodies
	Rilotumumab (AMG 102, Amgen)	First-line HER2-negative c-MET-positive advanced GC or GEJ cancer (+ECX or CX) [92, 93]	15 mg/kg IV every 3 weeks	Most common grade ≥3: neutropenia, anemia, and fatigue; increased deaths due to AEs related to disease progression in the rilotumumab arm
		Recurrent malignant glioma (+bevacizumab) [95]	20 mg/kg IV every 2 weeks	Most frequent grade ≤ 2: weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥ 3: venous thromboembolism, one death from pulmonary embolism
		Previously treated metastatic NSCLC (+erlotinib) [96]	15 mg/kg IV every 3 weeks	Grade 1–2 rash, fatigue, diarrhea, hypertension edema, lymphopenia, increased bilirubin, and alkaline phosphatase
	Ficlatuzumab (AV-229, AVEO Pharmaceuticals)	Asians patients with advanced NSCLC (+gefitinib) [97, 98]	20 mg/kg IV every 2 weeks	Diarrhea, acneiform dermatitis, and paronychia
	Onartuzumab (MetMAb®, Genentech)	Previously treated advanced NSCLC (+erlotinib) [99]	15 mg/kg IV every 3 weeks	Fatigue, peripheral edema, decreased appetite, constipation, nausea, hypoalbuminemia, acneiform dermatitis, and rash
		First-line HER2-negative c-MET-positive advanced GC or GEJ cancer (+FOLFOX) [101]	10 mg/kg IV every 2 weeks	Most common grade ≥ 3: neutropenia, hypoalbuminemia, peripheral edema, thrombocytopenia, pulmonary embolism, and gastric perforation
	Emibetuzumab (LY2875358, Eli Lilly and Company)	Advanced solid tumors [102]	750 mg IV every 2 weeks	Nausea, vomiting, and diarrhea
	Telisotuzumab vedotin (Teliso-V, formerly ABBV-399, ABBvie)	c-MET-positive advanced NSCLC (single-agent or + erlotinib) [107]	2.7 mg/kg IV every 3 weeks	Fatigue, neuropathy, decreased appetite, nausea, and vomiting
Small molecule c-MET kinase inhibitors
	Capmatinib (INC280, Novartis)	EGFR wild-type c-MET-positive advanced NSCLC [108] EGFR-mutant NSCLC after progression to gefitinib (+gefitinib) [109]	400 mg orally, twice daily	Most frequent grade ≤ 2: nausea, vomiting, peripheral edema, decreased appetite, fatigue; grade ≥ 3: anemia, hypokalemia, and pneumonia
	Tepotinib (EMD 1214063, Merck)	Previously treated EGFR-negative ALK-negative advanced NSCLC with c-MET exon 14 skipping mutations [110]	500 mg/die orally	Peripheral edema, decreased appetite constipation, fatigue, nausea, vomiting, and diarrhea; one serious AE: interstitial pneumonia
		Advanced HCC Child–Pugh class A [111]	3 dose levels: 300 mg/die, 500 mg/die, 1000 mg/die, orally	Most frequent grade ≤ 2: diarrhea, nausea, and increased AST/ALT; grade ≥ 3 increased AST/ALT, and increased lipase
	Foretinib (GSK1363089, GlaxoSmithKline)	Advanced solid tumors [115, 116]	3.6 mg/kg day 1–5 every 14 days, orally [115] 80 mg/die orally [116]	Increased AST, increased lipase, fatigue, hypertension, nausea, and diarrhea
		Previously treated advanced NSCLC (+erlotinib) [117]	30 mg/die starting cycle 1 day 15, orally	AEs ≥ 20%: diarrhea, fatigue, anorexia, dry skin, rash, and hypertension; grade ≥ 3: pain, mucositis, fatigue, and rash
	TAS-115 (Taiho Pharmaceutical CO, LTD)	Treatment refractory CRPC with bone metastases [122]	2 dose levels: 450 mg/body/day, 650 mg/body/, orally (5-days-on/2-days-off schedule for up to 21 days per cycle)	AEs ≥ 30%: anorexia, fatigue, thrombocytopenia, anemia, increased AST, rash, nausea, vomiting, and edema; rate of grade ≥ 3 AEs = 18.8%
	S49076 (Servier)	Advanced solid tumors [123] EGFR-mutated NSCLC progressing on EGFR TKI (+gefitinib) [124]	600 mg/die orally	93% grade 1–2 AEs; most frequent: hypoalbuminemia, and peripheral edema
	Tivantinib (ARQ197, Daiichi-Sankyo)	MET-high advanced HCC after progression to or intolerant to sorafenib [128]	120 mg orally, twice daily	Most common grade ≥ 3: ascites, anemia, abdominal pain, and neutropenia; three fatal AEs (1%): one sepsis, one anemia and acute renal failure, and one acute coronary syndrome
		Previously treated advanced NSCLC (+erlotinib) [129]	360 mg orally, twice daily	Rash, diarrhea, asthenia or fatigue, and neutropenia

AE adverse event, ALK anaplastic lymphoma kinase, ALT alanine aminotransferase, AST aspartate aminotransferase, c-MET hepatocyte growth factor receptor, CRPC castration-resistant prostate cancer, CX cisplatin and capecitabine, ECX epirubicin, cisplatin and capecitabine, EGFR epidermal growth factor receptor, FOLFOX 5-fluorouraciI, folinic acid and oxaliplatin, GC gastric cancer, GEJ gastroesophageal junction cancer, HCC hepatocellular carcinoma, IV intravenously, NSCLC non-small cell lung cancer, TKI tyrosine kinase inhibitor