Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Figures & data

Figure 1 Schematic representation of the known pharmacological mechanisms of lenvatinib.

Table 1 Relevant Studies on the Combination of Immune Checkpoint Inhibitors and Lenvatinib for HCC

Group	Study Type	Regimen	Patients (n)	PFS (RECIST/mRECIST) (months)	OS (months)	ORR (RECIST/mRECIST)
Finn RS et al^Citation32	Open-label multicenter study phase Ib	Lenvatinib+ Pembrolizumab	104(L+P)	m*8.6/ m*9.3	m*22	36%/ 46%
Wu WC et al^Citation34	Retrospective study	Lenvatinib+ Nivolumab vs Lenvatinib	40 (L+N) 47 (L)	7.5 4.8	22.9 10.3	45.0% 23.4%
Li Q et al^Citation35	Retrospective study	Lenvatinib+ Camrelizumab vs. Lenvatinib	48 (L+C) 44 (L)	m*10.3 m*7.5	not reached m*13.9	37.5%/ 41.7% 13.6%/ 20.5%
Huang X et al^Citation37	Retrospective study	Lenvatinib+ Nivolumab vs. Lenvatinib+ Pembrolizumab	16 (L+N) 13 (L+P)	-	-	-

Note: *. median time.

Abbreviations: PFS, Progression-free survival; OS, Overall survival; ORR, Objective response rate; RECIST, Response evaluation criteria in solid tumors; mRECIST, Mrecist Modified response evaluation criteria in solid tumors.

Table 2 Relevant Studies on Multiple Treatments for HCC

Authors	Study Type/Date	Patients (n)	Regimen	PFS (months)	OS (months)	ORR (RECIST/mRECIST)
He MK et al^Citation51	Retrospective (2019.06–2019.08)	71	Lenvatinib+Toripalimab+ HAIC vs.	11.1	not reached	59.2%/ 67.6%
		86	Lenvatinib	5.1	11	9.3%/ 16.3%
				p< 0.001	p< 0.001	p< 0.001
Qu S et al^Citation52	Prospective (2017.11–2020.11)	56	Lenvatinib+ PD-1 inhibitor+ TACE vs.	m*11.9	m*23.9	67.9%
		54	TACE	m*6.9	m*15.3	29.6%
				P= 0.003	P < 0.001	P < 0.001
Cai M et al^Citation53	Prospective (2019.01–2020.12)	41	Lenvatinib+ PD-1 inhibitor+ TACE vs.	7.3	16.9	56.1%
		40	TACE	4.0	12.1	32.5%
				P = 0.009	P = 0.002	P =0.033
Liu Y et al^Citation54	Retrospective (2018.11–2021.06)	53	Lenvatinib+ HAIC+ Ablation vs.	12.8	>30
		97	Lenvatinib+ HAIC	5.6	13.6
				P = 0.010	P <0.001
Chen S et al^Citation55	Retrospective (2016–2020)	70	Lenvatinib+ Pembrolizumab+ TACE vs.	m*9.2	m*18.1
		72	Lenvatinib+ TACE	m*5.5	m*14.1
				P =0.006	P =0.004
Chen S et al^Citation56	Retrospective (2018–2021)	84	Lenvatinib+ Pembrolizumab HAIC vs.	m*10.9	m*17.7
		86	Lenvatinib+ Pembrolizumab	m*6.8	m*12.6
				P = 0.001	P = 0.001
Lai Z et al^Citation57	Phase II single-arm	36	Lenvatinib+ Toripalimab+ HAIC	m*10.4	17.9	63.9%/ 66.7%
Mei J et al^Citation58	Retrospective (2018.07–2021.12)	45	Lenvatinib+ PD-1 inhibitor+ HAIC vs.	m*8.8	m*15.9	40%
		25	Lenvatinib+ PD-1 inhibitor	m*5.4	m*8.6	16%
				P = 0.0320	P =0.0015	P =0.038
Qu WF et al^Citation59	Retrospective (2018.11–2021.01)	30	Lenvatinib+ Toripalimab+ TACE vs.	Not reached	Not reached	76.7%
		21	Lenvatinib+ TACE	Not reached	Not reached	47.6%
						P =0.042
Guo P et al^Citation60	Retrospective (2018.01–2022.01)	75	Lenvatinib+ PD-1 inhibitor+ TACE vs.		m*30.4	68.8%
		91	Lenvatinib+ TACE		m*21.4	41.7%
					P = 0.030	P =0.01
Xiang YJ et al^Citation61	Retrospective	56	Lenvatinib+ PD-1 inhibitor+ TACE vs.	m*22.5	m*26.0	64.3%
		47	Lenvatinib+ TACE	m*14.0	not reached	38.3%
				P = 0.001	P = 0.005	P =0.010
Li X et al^Citation62	Retrospective (2019.06–2021.05)	114	Lenvatinib+ PD-1 inhibitor+ TACE	m*10.4	m*18	69.3%

Note: *Median time.

Abbreviations: PFS, Progression-free survival; OS, Overall survival; ORR, Objective response rate; RECIST, Response evaluation criteria in solid tumors; mRECIST, Mrecist Modified response evaluation criteria in solid tumors; TACE, Transarterial chemoembolization; HAIC, Hepatic artery infusion chemotherapy.

Table 3 Other Ongoing Combined Therapies for HCC

Trial NCT number	Intervention	Phase	State	Characteristic
NCT04642547	Lenvatinib+Gefitinib	I Single arm	Recruiting	Lenvatinib-resistant
NCT04911959	Lenvatinib+TACE vs. □ TACE	I	Not yet recruiting	MVI-positive HCC
NCT05042336	Camrelizumab+Lenvatinib + TACE	Ib/II Single arm	Not yet recruiting	Borderline resectable HCC
NCT05185739	Pembrolizumab vs. □ Lenvatinib vs. □ Pembrolizumab+ Lenvatinib	II triple arm	Not yet recruiting	Resectable HCC
NCT04425226	Pembrolizumab+ Lenvatinib	I	Recruiting	Before liver transplant
NCT05103904	Lenvatinib	II	Recruiting	Recurrence after liver transplantation

Abbreviations: MVI, Microvascular invasion; TACE, Transarterial chemoembolization.

Table 4 Drug Resistance Pathways and Combination Therapy

Year	First author	Key gene	Signaling pathways	Combined drug
2021	Lu Y et al^Citation69	NF1, DUSP9	PI3K/AKT and MAPK/ERK	Trametinib (pathway inhibitor for MEK)
2021	Zhao Z et al^Citation70	ETS-1	RAS/MEK/ERK	Sophocarpine
2021	Jin H et al^Citation11	EGFR	EGFR-PAK2-ERK2	Gefitinib (pathway inhibitor for EGFR)
2022	Sun D et al^Citation71	MDRP1, BCRP	MEK/ERK and I3K/AKT	Elacridar (dual MDR1 and BCRP inhibitor)
2022	Huang S et al^Citation72	DUSP4	p-ERK and p-MEK	Selumetinib (pathway inhibitor for MEK)
2022	Hu B et al^Citation66	ABCB1	EGFR-STAT3-ABCB1	Erlotinib (pathway inhibitor for EGFR)
2022	Hou W et al^Citation73	ITGβ8, HSP90	AKT	MK-2206 (AKT inhibitor) 17-AAG (HSP90 inhibitor)

Abbreviations: NF1, Neurofibromin 1; DUSP9, Dual specificity phosphatase 9; ETS-1, E-twenty-six-1; EGFR, Epidermal growth factor receptor; MDRP1, Multidrug resistance protein 1; BCRP, Breast cancer resistance protein; DUSP4, Dual specificity phosphatase 4; ABCB1, P-glycoprotein-1; ITGβ8, Integrin subunit beta 8; HSP90, Heat shock protein 90.

Figure 2 Combination therapy for drug resistance mechanisms.

Notes: Gefitinib, Erlotinib (EGFR inhibitor); Elacridar (dual MDR1 and BCRP inhibitor); Selumetinib, Trametinib (MEK inhibitor); MK-2206 (AKT inhibitor); 17-AAG (HSP90 inhibitor).

Abbreviations: BCRP, breast cancer resistance protein; MDR1, multidrug resistance protein 1; ITGB8, identified integrin subunit beta 8; HSP90, heat shock protein 90; METTL1, methyltransferase-like 1; METTL3, methyltransferase-like 3.

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