Targeting SHP2: Dual breakthroughs in colorectal cancer therapy–from signaling pathway modulation to immune microenvironment remodeling

Table 1 Clinical trials targeting SHP2

Trial name (NCT number)	Phase	Combination/therapeutic strategy	Target indication	Key populations/findings	Status/updates
NCT03634982	Phase 1	RMC-4630	Advanced solid tumors (including CRC)	Monotherapy	Active
NCT04121286	Phase 1	JAB-3312	Advanced solid tumors (including CRC)	Monotherapy	Recruiting
NCT03518554*	Phase 1	JAB-3068	Advanced solid tumors (including CRC)	Monotherapy	Complete
NCT03565003	Phase 1/2	JAB-3068	Advanced solid tumors (including CRC)	Monotherapy	Complete
NCT05354843	Phase 1	ET0038	Advanced solid tumors (including CRC)	Monotherapy	Recruiting
NCT04528836	Phase 1	BBP-398	Advanced solid tumors (including CRC)	Monotherapy	Terminated in 2024
NCT03114319	Phase 1	TNO155 + nazartinib	Advanced EGFR/KRAS-mutant solid tumors	Monotherapy or combination use with EGFR TKIs	Active
NCT04330664	Phase 1	TNO155 + MRTX849	Advanced solid tumors with KRASG12C mutation	Combination therapy	Complete
NCT04294160	Phase 1	Dabrafenib + LTT462 + TNO155 Dabrafenib + trametinib + TNO155	Advanced or metastatic BRAFV600E-mutated CRC	Combination therapy	Terminated in 2024
NCT04000529	Phase 1	TNO155 + spartalizumab/ribociclib	Selected malignancies	Monotherapy or combination of TNO155 with spartalizumab or with ribociclib	Terminated in 2024
NCT04699188	Phase 1/2	JDQ443 + TNO155 + tislelizumab	KRASG12C-mutant NSCLC, CRC	Monotherapy or with KRASG12C inhibitor, Dose Escalation Study	Active
NCT04916236	Phase 1	RMC-4630 + LY3214996	Metastatic KRAS-mutant CRC, PDAC, and NSCLC	Combination therapy of RMC-4630 (SHP2 inhibitor) and LY3214996 (ERK inhibitor)	Terminated in 2024
NCT04185883	Phase 1	Sotorasib + RMC-4630	KRASG12C mutant advanced solid tumors	Combination therapy	Recruiting
NCT04670679	Phase 1	ERAS-601 + cetuximab/pembrolizumab	Advanced solid tumors (including CRC)	Monotherapy or combination treatment with cetuximab/pembrolizumab	Active
NCT04252339	Phase 1	RLY-1971	Advanced or metastatic solid tumors	Monotherapy, dose escalation, and expansion study	Complete

NCT: National clinical trial; CRC: Colorectal cancer.

Table 2 Food and Drug Administration-approved drugs for colorectal cancer

Drug name	Target	Approval year	Current clinical use	Developer/company
Cetuximab	HER1 (EGFR/ErbB1)	2004	First-line therapy for KRAS wild-type CRC combined with chemotherapy	Bristol-Myers Squibb
Panitumumab	HER1 (EGFR/ErbB1)	2006	Preferred in EU/US	Takeda/Amgen
Regorafenib	KIT/PDGFRβ/RAF/RET	2012	Third-line therapy for refractory CRC, OS extended by 2.5 months	Bayer
Aflibercept	VEGFA/B	2012	Combined with FOLFIRI for second-line therapy in EU/US	Sanofi
Ramucirumab	VEGFR2	2014	Primarily used in gastric cancer; limited CRC application	Eli Lilly
Bevacizumab	VEGFR	2004	Cornerstone agent combined with chemotherapy across lines	Genentech
Encorafenib	BRAFV600E	2020	Core drug in triple therapy for BRAF-mutant CRC	Bristol-Myers Squibb
Pembrolizumab	PD-1	2017	First-line immunotherapy for MSI-H/dMMR CRC	Merck & Co.
Ipilimumab	CTLA-4	2011	Combined with PD-1 inhibitors for MSI-H CRC	Bristol-Myers Squibb
Fruquintinib (FRUZAQLA)	VEGFR1/2/3	2023	Previously treated metastatic CRC, regardless of biomarker status	Takeda/HUTCHMED
Trifluridine/tipiracil+bevacizumab	Thymidine analog + TP inhibitor + VEGF	2023	Metastatic CRC progressing after prior chemotherapy and anti-VEGF/EGFR therapies	Taiho Oncology
Encorafenib+cetuximab+mFOLFOX6	BRAFV600E + EGFR	2024	Metastatic CRC with BRAFV600E mutation (accelerated approval)	Pfizer/Array BioPharma
Sotorasib + panitumumab	KRASG12C + EGFR	2025	KRASG12C-mutated metastatic CRC	Amgen
Nivolumab	PD-1	2024	MSI-H/dMMR metastatic CRC progressing after fluoropyrimidine, oxaliplatin, and irinotecan	Bristol Myers Squibb
Nivolumab+ipilimumab	PD-1 + CTLA-4	2025	First-line treatment for unresectable or metastatic MSI-H/dMMR CRC	Bristol Myers Squibb

CRC: Colorectal cancer; OS: Overall survival; MSI-H: Microsatellite instability high; dMMR: DNA mismatch repair deficiency.