New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2

Table 1 Phase II trials with BRAF inhibitors

Drug	n	ORR (%)	PFS (mo)	OS (mo)
Vemurafenib BRAF V600E[8]	62	37.1	6.51	15.38
Vemurafenib V600E[9]	101	0	5.2	10
Vemurafenib non-V600E[9]	17	44.9	NR	NR
Dabrafenib in 2nd line or beyond[10]	78	33.3	5.5	12.7
Dabrafenib + trametinib in 2nd line or beyond[11]	57	63.2	10.2	18.2
Dabrafenib + trametinib en 1st line[12]	36	64	10.9	24.6

ORR: Overall response rate; PFS: Progression free survival; OS: Overall survival; NR: Not reported.

Table 2 Phase II trials with multikinase RET inhibitors

Drug	n	ORR	PFS	OS
Cabozantinib[22]	25	28%	5.5 mo	9.9 mo
Vandetanib[23]	18	18%	4.5 mo	11.6 mo
Lenvatinib[24]	25	16%	7.3 mo	NR
Sorafenib[25]	3	0	NR	NR
Selpercatinib[26]	105	64% in platinum chemotherapy pretreated	90% in response at 6 mo	NR
		85% in platinum chemotherapy naïve
Pralsetinib[27]	106	61% in platinum chemotherapy pretreated	NR	NR
		73% in platinum chemotherapy naïve

ORR: Overall response rate; PFS: Progression free survival; OS: Overall survival; NR: Not reported.

Table 3 Mesenchymal-epithelial transition factor inhibitors

Drug	MET-specific	Type	Other targets	IC50 (nmol/L)
Crizotinib	No	Ia	ALK, ROS1	22.5
Capmatinib	Yes	Ib	--	0.6
Tepotinib	Yes	Ib	--	3
Salovitinib	Yes	Ib	--	2.1
Bozitinib	Yes	I	--	0.51
Cabozantinib	No	II	RET, ROS1, VEGFR2, KIT	7.8
Merestinib	No	II	TIE-1, AXL, ROS1, DDR1/2, FLT3, MERTK, RON	8.1
Glesatinib	No	II	MET, VEGFR, RON, TIE-2	21.1

IC50: Half maximal inhibitory concentration; MET: Mesenchymal-epithelial transition factor.

Table 4 Clinical trials of mesenchymal-epithelial transition factor inhibitors

Drug	Clinical trial	Phase	Treatment	Objective	Status
Glesatinib	NCT02954991	2	Glesatinib + Nivolumab	ORR	Active, not recruiting
Multi-TKI
Glesatinib	NCT02544633	2	Glesatinib	ORR	Completed
Multi-TKI
Merestinib	NCT02920996	2	Merestinib	ORR	Active, not recruiting
Multi-TKI
Savolitinib	NCT02897479	2	Savolitinib	ORR	Active, not recruiting
Selective-TKI
Telisotuzumab (ABBV 399)	NCT03574753	2	ABBV-399	ORR	Completed
MET-mab
JNJ-61186372	NCT02609776	1	JNJ-61186372	ORR, security	Recruiting
EGFR and MET mab

TKI: Tyrosine kinase inhibitor; mab: Monoclonal antibody; ORR: Overall response rate; MET: Mesenchymal-epithelial transition factor; EGFR: Epidermal growth factor receptor.

Table 5 Phase II trials with HER2 inhibitors

Drug	Molecular alteration	n	ORR%	PFS (mo)	OS (mo)
Dacomitinib[44]	HER2 mutant	26	12	NR	NR
	HER2-amplified	4	0	NR	NR
Neratinib + Trastuzumab[46]	HER2 mutant	52	17	4	10.2
Neratinib + Temsirolimus[46]	HER2 mutant	43	19	4	15.1
Pyrotinib[47]	HER2 mutant	60	30	6.9	14.4
Poziotinib[48]	HER2 mutant	90	28	5.5	NR
Trastuzumab emtansine[49]	IHC 2+	29	0	2.6	12.2
	IHC 3+	20	20	2.7	15.3
Trastuzumab deruxtecan[49]	HER-2 mutant	42	61.9	NR	NR
Trastuzumab deruxtecan[49]	IHC 2+	39	25.6	5.4	11.3
	IHC 3+	10	20

ORR: Overall response rate; PFS: Progression free survival; OS: Overall survival; NR: Not reported.