Table 3. Selected key studies or trials targeting RET alterations.

Trial	Trial type	Drug	Target	Molecular selection	Patient population	N= respective RET fusion partner	RR	PFS	Common adverse events
Yoh et al., 2017 (57) (UMIN000010095)	Phase II	Vandetanib	RET inhibitor	RET rearrangements detected by RT-PCR then confirmed using FISH	Advanced NSCLC without EGFR mutation who have failed at least one line of chemotherapy	19 pt (17 analyzed); 6 pts with CCDC6-RET, 10 with KIFB-RET, 3 pts with unknown RET type	49% (9 out of the 17 pts); In CCDC6-RET cohort, five (83%) of 6 responded; KIFB-RET cohort, two (20%) of 10 responded	4.7 months	Most frequently observed AE: hypertension (16, 84%), diarrhea (15, 79%), rash acneiform (12, 63%), dry skin (8, 42%), prolonged QT corrected interval (8, 42%), anorexia (6, 2%), and increased creatinine (6,32%); grade 3–4 TRAE included hypertension (58%), rash (16%), diarrhea (11%), and QTc prolongation (11%)
Lee et al., 2017 (58) NCT01823068	Phase II	Vandetanib	RET inhibitor	RET rearrangements detected by FISH then confirmed with IHC or targeted deep sequencing or RT-PCR	Advanced NSCLC patients that have failed platinum-based chemotherapy with no other oncogenic drivers	18; only 10 screened 5 pts had KIF5B-RET, 2 pts with CCDC6-RET, 1 pt with MYO5C-RET	18% (3 out of 17 pts)	4.5 months	More than 70% of patients reported to have hypertension and skin rash of grade 1–2; Two grade 3 hypertension, two QT prolongation AEs, one AST/ALT elevation were reported
Drilon et al., 2016 (59) NCT01639508	Prospective Phase II	Cabozantinib	RET multikinase inhibitor	RET rearrangements detected by FISH and or NGS	Metastatic or unresectable lung cancer	26; 16 pts with KIF5B-RET, 1 pt with CCDC6-RET, 1 pt with MYO5C, 1 pt with TRIM33-RET, 1 pt with CLIP1-RET, 1 pt with ERC1-RET, 6 pt with unknown fusion type	28% (95, 12–49); Response only found in pts with KIF5B-RET fusion	5.5 months	Grade 3 treatment-related AE: lipase elevation (15%), increased alanine aminotransferase (8%), increased aspartate aminotransferase (8%), thrombocytopenia (8%), and hypophosphatemia (8%)
Gautschi et al., 2017 (60)	Retrospective study	Cabozantinib, vandetanib, sunitinib, sorafenib, alectinib, lenvatinib, nintedanib, ponatinib and regorafenib	RET multi-kinase inhibitor	RET rearrangement detected by molecular profiling (RT- PCR/FISH/NGS)	Any staged NSCLC	53 cabozantinib [21], vandetanib [11], sunitinib [10], sorafenib [2], alectinib [2], lenvatinib [2], nintedanib [2], ponatinib [2], and regorafenib [1]	37%, 18%, 22% (cabozantinib, vandetanib, sunitinib)	2.3 months (95, 1.6 to 5.0 months)	TRAE not reported

NSCLC, non-small cell lung cancer; ORR, objective response rate; PFS, progression-free survival; pt, patient; TRAE, treatment-related adverse event; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing IHC, immunohistochemistry.