Table 3 Combination strategies targeting RAS-mutant tumors

From: Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS

Combination Targets	Drug	Biomarker	Disease Setting^a	Clinical Trials.gov
KRAS^G12C inhibitor Combinations
PD-1/PD-L1 antibody	Sotorasib and PD-1 /PD-L1 antibodies	KRAS^G12C Mutation	Advanced NSCLC	NCT03600883
	Adagrasib and Pembrolizumab	KRAS^G12C Mutation	Advanced or Metastatic NSCLC	NCT04613596
	GDC-6036 and Atezolizumab	KRAS^G12C Mutation	Advanced Solid Tumors	NCT04449874
SOS1 inhibitor	Adagrasib and BI 1701963	KRAS^G12C Mutation	NSCLC, CRC	NCT04975256
SOS1 inhibitor	BI 1823911 and BI 1701963	KRAS Mutation	Solid Tumors	NCT04973163
Chemotherapy	Sotorasib and Cisplatin/Carboplatin and Pemetrexed	KRAS^G12C Mutation	Lung Cancer	NCT05118854
	Sotorasib and Docetaxel	KRAS^G12C Mutation	NSCLC	NCT04303780
	Sotorasib and Liposomal Irinotecan and 5 Fluorouracil + Leucovorin	KRAS^G12C Mutation	PDAC	NCT05251038
	Sotorasib and Gemcitabine + Nab-paclitaxel	KRAS^G12C Mutation	PDAC	NCT05251038
SHP2 inhibitor	Sotorasib and RMC-4630	KRAS^G12C Mutation	NSCLC	NCT05054725
	JAB-21822 and JAB-3312	KRAS^G12C Mutation	Advanced Solid Tumors	NCT05288205
	Adagrasib and TNO155	KRAS^G12C Mutation	Advanced or Metastatic solid Tumors	NCT04330664
	JDQ443 and TNO155	KRAS^G12C Mutation	Advanced solid Tumors	NCT04699188
	GDC-6036 and GDC-1971	KRAS^G12C Mutation	Advanced Solid Tumors	NCT04449874
EGFR inhibitor	GDC-6036 and Cetuximab	KRAS^G12C Mutation	Advanced Solid Tumors	NCT04449874
	GDC-6036 and Erlotinib	KRAS^G12C Mutation	Advanced Solid Tumors	NCT04449874
	JAB-21822 and Cetuximab	KRAS^G12C Mutation	Advanced CRC	NCT05194995
	Sotorasib and Panitumumab	KRAS^G12C Mutation	CRC	NCT05198934
RAF/MEK Inhibitor	Sotorasib and VS-6766	KRAS^G12C Mutation	NSCLC	NCT05074810
HER inhibitor	Sotorasib and Tarloxotinib	KRAS^G12C Mutation	NSCLC	NCT05313009
CDK 4/6 inhibitor	Adagrasib and Palbociclib	KRAS^G12C Mutation	Advanced Solid Tumor	NCT05178888
ERK inhibitor Combinations
CDK 4/6 inhibitor	LY3214996 and Abemaciclib	BRAF or RAS Mutations	Advanced or Metastatic solid Tumors	NCT02857270
Chemotherapy	LY3214996 and Nab-Paclitaxel and Gemcitabine	BRAF or RAS Mutations	Advanced or Metastatic solid Tumors	NCT02857270
RAF and EGFR inhibitors	LY3214996 and Encorafenib + Cetuximab	BRAF or RAS Mutations	Advanced or Metastatic solid Tumors	NCT02857270
Autophagy	Ulixertinib and Hydroxychloroquine	RAS, non- BRAF^V600, ERK, or MEK Mutations	Advanced Gastrointestinal Malignancies	NCT05221320
RAF inhibitor	JSI-1187 and Dabrafenib	MAPK pathway Mutations	Advanced Solid Tumors	NCT04418167
MEK inhibitor Combinations
EGFR inhibitor	Binimetinib and Erlotinib	KRAS or EGFR Mutations	NSCLC	NCT01859026
FGFR inhibitor	Binimetinib and Futibatinib	KRAS Mutation	Advanced or Metastatic Solid Tumors	NCT04965818
ALK inhibitor	Trametinib and TPX-0005	KRAS Mutation	Advanced or Metastatic Tumors	NCT05071183
Multi-targeting tyrosine kinase inhibitor	Trametinib and Anlotinib	KRAS Mutation	NSCLC	NCT04967079
SOS1 inhibitor	Trametinib and BI 1701963	KRAS Mutation	Solid Tumors	NCT04111458
Chemotherapy	Selumetinib and Docetaxel	KRAS Mutation	Advanced or Metastatic NSCLC	NCT01933932
CDK4/6 inhibitor	PD-0325901 and Palbociclib	KRAS Mutation	Solid Tumors	NCT02022982
CDK4/6 inhibitor	Binimetinib and Palbociclib	KRAS or NRAS Mutation	Metastatic CRC	NCT03981614
Autophagy	Trametinib and Hydroxychloroquine	KRAS Mutation	Biliary Cancer	NCT04566133
Autophagy	Binimetinib and Hydroxychloroquine	KRAS Mutation	NSCLC	NCT04735068
Autophagy and PD-L1 antibody	Cobimetinib and Hydroxychloroquine + Atezolizumab	KRAS Mutation	Gastrointestinal Cancer	NCT04214418
RAF/MEK inhibitor Combinations
FAK inhibitor	VS-6766 and Defactinib	KRAS Mutation	NSCLC	NCT04620330
RTK inhibitor	VS-6766 and Cetuximab	KRAS Mutation	Advanced CRC	NCT05200442
RAF inhibitor Combinations
MEK inhibitor	Lifirafenib and PD-0325901	KRAS Mutation	Solid Tumor	NCT03905148
	Belvarafenib and Cobimetinib	RAS or RAF Mutations	Advanced or Metastatic Tumors	NCT03284502
	lifirafenib and PD-0325901	KRAS-mutant NSCLC or endometrial cancer	Advanced or Metastatic Tumors	NCT03905148
	LXH-254 and Trametinib	KRAS-mutant or BRAF-mutant NSCLC or NRAS-mutant melanoma	Advanced or Metastatic Tumors	NCT02974725
	LXH-254 and Trametinib	BRAF^V600 or NRAS Mutation	Melanoma	NCT04417621
	Dabrafenib and Trametinib	RAS or BRAF^V600 Mutation	Metastatic DTC	NCT03244956
PD-1 antibody	LXH-254 and PD-1 antibody	NRAS-mutant Melanoma and KRAS-Mutation	Advanced or Metastatic Tumors	NCT02607813
ERK1/2 inhibitor	LXH-254 and LTT462	KRAS-mutant or BRAF-mutant NSCLC or NRAS-mutant Melanoma	Advanced or Metastatic Tumors	NCT02974725
ERK1/2 inhibitor	LXH-254 and LTT462	BRAF^V600 or NRAS Mutation	Melanoma	NCT04417621
CDK4/6 inhibitor	LXH-254 and Ribociclib	BRAF^V600 or NRAS Mutation	Melanoma	NCT04417621
CDK4/6 inhibitor	LXH-254 and Ribociclib	KRAS-mutant or BRAF-mutant NSCLC or NRAS-mutant Melanoma	Advanced or Metastatic Tumors	NCT02974725
SHP2 inhibitor Combinations
ERK inhibitor	RMC-4630 and LY3214996	KRAS Mutation	PDAC, CRC, NSCLC	NCT04916236
PD-1 inhibitor	TNO155 and Spartalizumab	EGFR or WT ALK NSCLC	Advanced solid Tumors	NCT04000529
CDK4/6 inhibitor	TNO155 and Ribociclib	WT EGFR or WT ALK NSCLC, KRAS-mutant CRC or NSCLC	Advanced solid Tumors	NCT04000529
HER2/EGFR inhibitor Combinations
mTOR inhibitor	Neratinib and Everolimus	EGFR Mutation, HER2 Mutation, or HER3/4 Mutation or KRAS Mutation	Advanced Malignant Solid Neoplasm	NCT03065387
CDK4/6 inhibitor	Neratinib and Palbociclib	EGFR Mutation, HER2 Mutation, or HER3/4 Mutation or KRAS Mutation	Advanced Malignant Solid Neoplasm	NCT03065387
MEK inhibitor	Neratinib and Trametinib	EGFR Mutation, HER2 Mutation, or HER3/4 Mutation or KRAS Mutation	Advanced Malignant Solid Neoplasm	NCT03065387
PLK inhibitor Combinations
PD-1 antibody	Rigosertib and Nivolumab	KRAS Mutation	NSCLC	NCT04263090
Apoptosis inducer Combinations
Chemotherapy	Cisplatin and Pemetrexed	KRAS Mutation	NSCLC	NCT02743923
anti-PD-1 therapy Combinations
Chemotherapy	Cyclophosphamide and Fludarabine + Anti-PD-1 monoclonal Antibody	KRAS^G12V Mutation	PDAC	NCT04146298
Cancer vaccine	Pembrolizumab and mRNA-5671	HLA- A11:01 and/or HLA- C08:02; KRAS^G12C, KRAS^G12D, KRAS^G12V or KRAS^G13D Mutation	NSCLC, non- MSI-H CRC,	NCT03948763

^aCRC colorectal cancer, DTC differentiated thyroid cancer, HLA human leukocyte antigen, MSI-H microsatellite instability-high, NSCLC non-small-cell lung cancer, PDAC pancreatic ductal adenocarcinoma

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Table 3 Combination strategies targeting RAS-mutant tumors

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