Table 2.

Trials of interest across different tumor types and novel treatment combinations with approved c-MET inhibitors

Compound	Study name	Phase	Treatment	Setting	NCT identifier	References	Safety notes
Crizotinib	MErCuRIC trial	Phase I/II	Crizotinib + binimetinib (MEK1/2 inhibitor)	Third-line treatment of RAS mutant or RAS wild-type with aberrant c-MET expression metastatic CRC	NCT02510001	–	–
	EORTC 90101 CREATE study	Phase II	Crizotinib	Locally advanced and/or metastatic:  Anaplastic large cell lymphoma  Inflammatory myofibroblastic tumor  Papillary renal cell carcinoma type 1  Alveolar soft part sarcoma  Clear cell sarcoma  Alveolar rhabdomyosarcoma, characterized by MET and/or ALK alterations	NCT01524926	[35–37]	–
	–	Phase I	Crizotinib + erlotinib (EGFR inhibitor)	Advanced NSCLC, after failure of one or two prior chemotherapy regimens	NCT00965731	[38]	Combination treatment development halted due to minimal activity and unfavorable toxicity profile
	–	Phase I	Crizotinib + dacomitinib (pan-HER and ALK/ROS1/MET inhibitor)	Advanced NSCLC, progressive after at least one line of chemotherapy or targeted therapy	NCT01121575	[39]	Combination treatment development halted due to minimal activity and unfavorable toxicity profile
	–	Phase I	Crizotinib + dasatinib (multi-target TKI)	Adults with advanced tumors and pediatric patients with recurrent/progressive high-grade and diffuse intrinsic pontine glioma	NCT01744652 and NCT01644773	[40, 41]	Minimal activity and limited tolerability
	–	Phase I	Crizotinib + ipilimumab or nivolumab	ALK-mutated stage IV NSCLC	NCT01998126	–	–
	Javelin Lung 101	Phase Ib/II	Crizotinib + avelumab	Advanced NSCLC	NCT02584634	–	–
	CheckMate 370	Phase Ib/II	Crizotinib + nivolumab single-arm cohort	First-line treatment of advanced ALK translocation-positive NSCLC	NCT2574078	[42]	Discontinued due to severe hepatic toxicities
Cabozantinib	–	Phase I	Cabozantinib + nivolumab with or without ipilimumab	Metastatic urothelial carcinoma and other genitourinary malignancies	NCT02496208	[59, 60]	–
	CheckMate 9ER	Phase III	Cabozantinib + nivolumab vs sunitinib	First-line treatment of advanced or metastatic RCC	NCT03141177	[61]	–
	–	Phase II, RDT	Cabozantinib	Pretreated metastatic breast cancer	NCT00940225	[62]	–
	–	Phase II	Cabozantinib + nivolumab	Metastatic triple-negative breast cancer	NCT03316586	–	–
		Phase II	Cabozantinib	RET fusion-positive advanced NSCLC or those with other genotypes: ROS1 or NTRK fusions or increased MET or AXL activity	NCT01639508	[49]	–
	CaboMAb	Phase I	a. Cabozantinib + panitumumab b. Cabozantinib monotherapy	a. Previously-treated, KRAS wild-type metastatic CRC b. MET-amplified treatment-refractory CRC	NCT02008383	–	–

ALK anaplastic lymphoma kinase, AXL tyrosine-protein kinase receptor UFO, c-MET hepatocyte growth factor receptor, CRC colorectal cancer, EGFR epidermal growth factor receptor, EORTC European Organization for Research and Treatment of Cancer, KRAS Kirsten rat sarcoma, NSCLC non-small cell lung cancer, NTRK neurotrophic tropomyosin receptor kinase, RCC renal cell carcinoma, RAS Rat Sarcoma, RET REarranged during Transfection, RDT randomized discontinuation trial, ROS1 ROS proto-oncogene 1, TKI tyrosine kinase inhibitor